Rheumatoid Arthritis

Key clinical point: Significant proportion of patients with high-risk early rheumatoid arthritis (RA) achieved the treatment target with a combination of methotrexate and step-down prednisolone, whereas nonresponders benefited from treatment intensification albeit with more adverse events.

Major finding: Overall, 73% of patients at high risk achieved the treatment target at 13 weeks. A significant proportion of nonresponders who were at high risk achieved the treatment target with treatment intensification vs continuation (80% vs 44%; difference 36%; P = .04), but experienced more adverse events (P < .01).

Study details: This study included 190 patients with early RA from the COBRA treat-to-target trial, of which high-risk patients received prednisolone (30 mg/day tapered to 7.5 mg/day) and methotrexate (increased from 10 to 25 mg/week). At 13 weeks, nonresponders were randomly assigned to treatment continuation or intensification (methotrexate 25 mg/week; prednisolone 60 mg/day tapered to 7.5 mg/day; sulfasalazine 2 g/day; and hydroxychloroquine 400 mg/day).

Disclosures: This study was supported by an unrestricted grant from Pfizer. M Boers and WF Lems reported ties with various sources.

Source: Hartman L et al. Favorable effect of a ‘second hit’ after 13 weeks in early RA non-responders: The Amsterdam COBRA treat-to-target randomized trial. Rheumatology (Oxford). 2022 (Oct 7). Doi: 10.1093/rheumatology/keac582

Key clinical point: Significant proportion of patients with high-risk early rheumatoid arthritis (RA) achieved the treatment target with a combination of methotrexate and step-down prednisolone, whereas nonresponders benefited from treatment intensification albeit with more adverse events.

Major finding: Overall, 73% of patients at high risk achieved the treatment target at 13 weeks. A significant proportion of nonresponders who were at high risk achieved the treatment target with treatment intensification vs continuation (80% vs 44%; difference 36%; P = .04), but experienced more adverse events (P < .01).

Study details: This study included 190 patients with early RA from the COBRA treat-to-target trial, of which high-risk patients received prednisolone (30 mg/day tapered to 7.5 mg/day) and methotrexate (increased from 10 to 25 mg/week). At 13 weeks, nonresponders were randomly assigned to treatment continuation or intensification (methotrexate 25 mg/week; prednisolone 60 mg/day tapered to 7.5 mg/day; sulfasalazine 2 g/day; and hydroxychloroquine 400 mg/day).

Disclosures: This study was supported by an unrestricted grant from Pfizer. M Boers and WF Lems reported ties with various sources.

Source: Hartman L et al. Favorable effect of a ‘second hit’ after 13 weeks in early RA non-responders: The Amsterdam COBRA treat-to-target randomized trial. Rheumatology (Oxford). 2022 (Oct 7). Doi: 10.1093/rheumatology/keac582

Key clinical point: Significant proportion of patients with high-risk early rheumatoid arthritis (RA) achieved the treatment target with a combination of methotrexate and step-down prednisolone, whereas nonresponders benefited from treatment intensification albeit with more adverse events.

Major finding: Overall, 73% of patients at high risk achieved the treatment target at 13 weeks. A significant proportion of nonresponders who were at high risk achieved the treatment target with treatment intensification vs continuation (80% vs 44%; difference 36%; P = .04), but experienced more adverse events (P < .01).

Study details: This study included 190 patients with early RA from the COBRA treat-to-target trial, of which high-risk patients received prednisolone (30 mg/day tapered to 7.5 mg/day) and methotrexate (increased from 10 to 25 mg/week). At 13 weeks, nonresponders were randomly assigned to treatment continuation or intensification (methotrexate 25 mg/week; prednisolone 60 mg/day tapered to 7.5 mg/day; sulfasalazine 2 g/day; and hydroxychloroquine 400 mg/day).

Disclosures: This study was supported by an unrestricted grant from Pfizer. M Boers and WF Lems reported ties with various sources.

Source: Hartman L et al. Favorable effect of a ‘second hit’ after 13 weeks in early RA non-responders: The Amsterdam COBRA treat-to-target randomized trial. Rheumatology (Oxford). 2022 (Oct 7). Doi: 10.1093/rheumatology/keac582

PHILADELPHIA – The new American College of Rheumatology Guideline for Vaccinations in Patients with Rheumatic and Musculoskeletal Diseases (RMDs) emphasizes that both adult and pediatric patients should receive recommended vaccinations whenever possible.

But the guideline, currently in press, also offers recommendations about whether and when to withhold vaccines from patients with RMDs, such as avoiding the use of live attenuated virus vaccines in patients who are on immunosuppressive drug regimens, such as conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, or targeted synthetic DMARDs.

The new consensus guideline was formulated with the understanding that patients with RMDs are at increased risk for vaccine-preventable infections and more serious complications from infections, compared with the general population.

However, the guideline also acknowledges that the immunogenicity and safety of vaccines may differ among patients with RMDs, and that, depending on the patient age and disease state, individuals may benefit from modified vaccine indications, schedules, or modified medication schedules, said guideline panel member Anne Bass, MD, a rheumatologist at Hospital for Special Surgery and a professor of clinical medicine at Weill Cornell Medicine in New York, who presented the guideline with other panel members in a session outlining the recommendations at the annual meeting of the ACR.

“In addition, vaccination recommendations – since much of it relates to medications – really applies across diseases, and so the ACR felt that, rather than having vaccine recommendations tacked onto the end of treatment guidelines for each individual disease, that the topic should be discussed or tackled as a whole,” she said.

The guideline does not cover vaccinations in patients taking nonsteroidal anti-inflammatory drugs because this class of agents has minimal or no impact on antibody responses to vaccines. The guideline also does not address vaccinations against COVID-19 infections since the rapidly changing formulations would make the recommendations obsolete before they were even published, and because the U.S. Centers for Disease Control and Prevention provides up-to-date guidance on COVID-19 vaccinations in patients with compromised immunity, she said.
 

Guiding principles

The overarching principles of the guideline are to give indicated vaccines to patients with RMD whenever possible and that any decision to hold medications before or after vaccination consider the dosage used, RMD disease activity, and the patient’s risk for vaccine-preventable infection.

The guideline also states that “shared decision-making with patients is a key component of any vaccination strategy.”

Panel member Clifton O. Bingham III, MD, professor of medicine at Johns Hopkins University in Baltimore, outlined expanded indications for vaccinations against influenza, pneumococcal infections, varicella zoster virus (VZV) and human papillomavirus (HPV).
 

Influenza

The guideline conditionally recommends that patients with RMD aged 65 years and older and adults older than age 18 years who are on immunosuppressive medications should receive either high-dose or adjuvanted influenza vaccination rather than regular-dose vaccines.

“It’s recognized that the high-dose or adjuvanted vaccinations may be unavailable for patients when they’re seen in your practice,” Dr. Bingham said,” and we came out with two additional statements within the guidelines that said that any flu vaccine is recommended over no flu vaccinations, because we do know that responses are elicited, and a flu vaccination today is preferred over a flu vaccination delay.”
 

Pneumococcal vaccination

The panelists strongly recommended that patients with RMD younger than age 65 years who are on immunosuppressive medication receive pneumococcal vaccinations.

The ACR guideline is in sync with those issued by the CDC’s Advisory Committee on Immunization Practices, Dr. Bingham said. He urged audience members to visit a CDC-ACIP web page for more information on who should receive pneumococcal vaccination and when.
 

Recombinant varicella zoster

The recommendations strongly support that patients aged 18 years and over who are on immunosuppressive therapies should receive the recombinant VZV vaccine (Shingrix).

HPV

A less robust, conditional recommendation is for patients with RMDs who are between the ages of 26 and 45 years and on immunosuppressive medications to receive the HPV vaccine (if they have not already received the vaccine).

Non-live attenuated vaccines

Kevin Winthrop, MD, MPH, professor of infectious diseases and public health at Oregon Health & Science University, Portland, summarized the recommendations for managing immunosuppressive therapies in patients scheduled to receive vaccinations using killed or nonactive antigens.

“In influenza season, don’t pass up the opportunity to vaccinate,” he said, adding, “if you can wait on rituximab dosing, do it, and if you can’t, go ahead and vaccinate.”

The guidelines also recommend a 2-week methotrexate hold at the time of influenza vaccination; other DMARD dosing changes are likely not necessary at the time of vaccination, “but this is an area of fervent study, and I think in a year or two we’ll have more experimental hold data with regard to other DMARDs,” Dr. Winthrop said.

For other nonlive attenuated vaccinations, recommendations are similar to those for influenza, except with more flexible timing because these vaccinations are not seasonal. When and how to hold methotrexate is still up in the air, he said.

Additionally, it’s recommended that vaccinations be delayed in patients on high-dose prednisone until the drug is tapered to below 20 mg per day, and ideally to less than 10 mg per day, he said.
 

Live-attenuated vaccines

The guideline conditionally recommends deferring live-attenuated vaccines in patients on immunosuppressive drugs. It also recommends holding these medications “for an appropriate period before” vaccination and for 4 weeks afterward.

“Although the evidence around conventional synthetic DMARDs and TNF inhibitors is reassuring in terms of their safety at the time of live attenuated vaccines, as you can see the number of studies is quite small, and so the voting panel conditionally recommend against administering live-attenuated virus vaccines to patients who are on conventional synthetics, biologic, or targeted DMARDs,” Dr. Bass said.
 

In utero exposures

Most women with RMD who have recently given birth will consult their general pediatricians rather than rheumatologists for infant vaccinations, but pediatricians may not be aware of the affect that in utero exposures to biologic DMARDs can have on vaccine safety and immunogenicity in infants, Dr, Bass said.

“It’s important that you, as a provider, give your recommendations regarding infant rotavirus vaccination after in utero exposure to the pregnant rheumatic disease patient prior to delivery, and let that patient know that this is something that they should share with their pediatrician to be,” she advised audience members.
 

Getting the message out

In an interview, session moderator and guidelines panelist Lisa F. Imundo, MD, director of the center for adolescent rheumatology at Columbia University in New York, noted that rheumatologists don’t usually have the full schedule of pediatric vaccinations in stock and often leave the decisions about what to give – and when – to general practitioners.

“Pediatric rheumatologists sometimes will give patients flu vaccinations because they’re a high-risk population of patients, and we want to make sure that they’re getting it in a timely manner,” she said.

In addition, because pneumococcal polysaccharide vaccines are not indicated in the general pediatric population, children on biologic DMARDs who have completed their standard series of pneumococcal conjugate vaccines (PCV13 or PVC15) are recommended to get a 23-valent pneumococcal polysaccharide vaccine, Dr. Imundo said.

She also noted that communication between pediatric rheumatologists and general practitioners about vaccine recommendations can be challenging.

“It’s a huge issue, figuring out how we’re going to communicate all of this information to our pediatric colleagues,” she said. “With individual patients, we may sometimes remind doctors, especially with our younger patients who haven’t gotten their live vaccines, that they really shouldn’t get live vaccines until they’re off medication or until we arrange holding medication for some period of time.”

She said that ACR vaccine committee members are working with infectious disease specialists and guideline developers for the American Academy of Pediatrics to ensure guidelines include the most important vaccination recommendations for pediatric patients with RMDs.

The development process for the guidelines was supported by the ACR. Dr. Bass reported no relevant disclosures, Dr. Bingham disclosed consulting activities, grant/research support, and royalties from various corporate entities. Dr. Winthrop disclosed consulting activities for and research funding from various companies. Dr. Imundo reported no relevant financial relationships.

PHILADELPHIA – The new American College of Rheumatology Guideline for Vaccinations in Patients with Rheumatic and Musculoskeletal Diseases (RMDs) emphasizes that both adult and pediatric patients should receive recommended vaccinations whenever possible.

But the guideline, currently in press, also offers recommendations about whether and when to withhold vaccines from patients with RMDs, such as avoiding the use of live attenuated virus vaccines in patients who are on immunosuppressive drug regimens, such as conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, or targeted synthetic DMARDs.

The new consensus guideline was formulated with the understanding that patients with RMDs are at increased risk for vaccine-preventable infections and more serious complications from infections, compared with the general population.

However, the guideline also acknowledges that the immunogenicity and safety of vaccines may differ among patients with RMDs, and that, depending on the patient age and disease state, individuals may benefit from modified vaccine indications, schedules, or modified medication schedules, said guideline panel member Anne Bass, MD, a rheumatologist at Hospital for Special Surgery and a professor of clinical medicine at Weill Cornell Medicine in New York, who presented the guideline with other panel members in a session outlining the recommendations at the annual meeting of the ACR.

“In addition, vaccination recommendations – since much of it relates to medications – really applies across diseases, and so the ACR felt that, rather than having vaccine recommendations tacked onto the end of treatment guidelines for each individual disease, that the topic should be discussed or tackled as a whole,” she said.

The guideline does not cover vaccinations in patients taking nonsteroidal anti-inflammatory drugs because this class of agents has minimal or no impact on antibody responses to vaccines. The guideline also does not address vaccinations against COVID-19 infections since the rapidly changing formulations would make the recommendations obsolete before they were even published, and because the U.S. Centers for Disease Control and Prevention provides up-to-date guidance on COVID-19 vaccinations in patients with compromised immunity, she said.
 

Guiding principles

The overarching principles of the guideline are to give indicated vaccines to patients with RMD whenever possible and that any decision to hold medications before or after vaccination consider the dosage used, RMD disease activity, and the patient’s risk for vaccine-preventable infection.

The guideline also states that “shared decision-making with patients is a key component of any vaccination strategy.”

Panel member Clifton O. Bingham III, MD, professor of medicine at Johns Hopkins University in Baltimore, outlined expanded indications for vaccinations against influenza, pneumococcal infections, varicella zoster virus (VZV) and human papillomavirus (HPV).
 

Influenza

The guideline conditionally recommends that patients with RMD aged 65 years and older and adults older than age 18 years who are on immunosuppressive medications should receive either high-dose or adjuvanted influenza vaccination rather than regular-dose vaccines.

“It’s recognized that the high-dose or adjuvanted vaccinations may be unavailable for patients when they’re seen in your practice,” Dr. Bingham said,” and we came out with two additional statements within the guidelines that said that any flu vaccine is recommended over no flu vaccinations, because we do know that responses are elicited, and a flu vaccination today is preferred over a flu vaccination delay.”
 

Pneumococcal vaccination

The panelists strongly recommended that patients with RMD younger than age 65 years who are on immunosuppressive medication receive pneumococcal vaccinations.

The ACR guideline is in sync with those issued by the CDC’s Advisory Committee on Immunization Practices, Dr. Bingham said. He urged audience members to visit a CDC-ACIP web page for more information on who should receive pneumococcal vaccination and when.
 

Recombinant varicella zoster

The recommendations strongly support that patients aged 18 years and over who are on immunosuppressive therapies should receive the recombinant VZV vaccine (Shingrix).

HPV

A less robust, conditional recommendation is for patients with RMDs who are between the ages of 26 and 45 years and on immunosuppressive medications to receive the HPV vaccine (if they have not already received the vaccine).

Non-live attenuated vaccines

Kevin Winthrop, MD, MPH, professor of infectious diseases and public health at Oregon Health & Science University, Portland, summarized the recommendations for managing immunosuppressive therapies in patients scheduled to receive vaccinations using killed or nonactive antigens.

“In influenza season, don’t pass up the opportunity to vaccinate,” he said, adding, “if you can wait on rituximab dosing, do it, and if you can’t, go ahead and vaccinate.”

The guidelines also recommend a 2-week methotrexate hold at the time of influenza vaccination; other DMARD dosing changes are likely not necessary at the time of vaccination, “but this is an area of fervent study, and I think in a year or two we’ll have more experimental hold data with regard to other DMARDs,” Dr. Winthrop said.

For other nonlive attenuated vaccinations, recommendations are similar to those for influenza, except with more flexible timing because these vaccinations are not seasonal. When and how to hold methotrexate is still up in the air, he said.

Additionally, it’s recommended that vaccinations be delayed in patients on high-dose prednisone until the drug is tapered to below 20 mg per day, and ideally to less than 10 mg per day, he said.
 

Live-attenuated vaccines

The guideline conditionally recommends deferring live-attenuated vaccines in patients on immunosuppressive drugs. It also recommends holding these medications “for an appropriate period before” vaccination and for 4 weeks afterward.

“Although the evidence around conventional synthetic DMARDs and TNF inhibitors is reassuring in terms of their safety at the time of live attenuated vaccines, as you can see the number of studies is quite small, and so the voting panel conditionally recommend against administering live-attenuated virus vaccines to patients who are on conventional synthetics, biologic, or targeted DMARDs,” Dr. Bass said.
 

In utero exposures

Most women with RMD who have recently given birth will consult their general pediatricians rather than rheumatologists for infant vaccinations, but pediatricians may not be aware of the affect that in utero exposures to biologic DMARDs can have on vaccine safety and immunogenicity in infants, Dr, Bass said.

“It’s important that you, as a provider, give your recommendations regarding infant rotavirus vaccination after in utero exposure to the pregnant rheumatic disease patient prior to delivery, and let that patient know that this is something that they should share with their pediatrician to be,” she advised audience members.
 

Getting the message out

In an interview, session moderator and guidelines panelist Lisa F. Imundo, MD, director of the center for adolescent rheumatology at Columbia University in New York, noted that rheumatologists don’t usually have the full schedule of pediatric vaccinations in stock and often leave the decisions about what to give – and when – to general practitioners.

“Pediatric rheumatologists sometimes will give patients flu vaccinations because they’re a high-risk population of patients, and we want to make sure that they’re getting it in a timely manner,” she said.

In addition, because pneumococcal polysaccharide vaccines are not indicated in the general pediatric population, children on biologic DMARDs who have completed their standard series of pneumococcal conjugate vaccines (PCV13 or PVC15) are recommended to get a 23-valent pneumococcal polysaccharide vaccine, Dr. Imundo said.

She also noted that communication between pediatric rheumatologists and general practitioners about vaccine recommendations can be challenging.

“It’s a huge issue, figuring out how we’re going to communicate all of this information to our pediatric colleagues,” she said. “With individual patients, we may sometimes remind doctors, especially with our younger patients who haven’t gotten their live vaccines, that they really shouldn’t get live vaccines until they’re off medication or until we arrange holding medication for some period of time.”

She said that ACR vaccine committee members are working with infectious disease specialists and guideline developers for the American Academy of Pediatrics to ensure guidelines include the most important vaccination recommendations for pediatric patients with RMDs.

The development process for the guidelines was supported by the ACR. Dr. Bass reported no relevant disclosures, Dr. Bingham disclosed consulting activities, grant/research support, and royalties from various corporate entities. Dr. Winthrop disclosed consulting activities for and research funding from various companies. Dr. Imundo reported no relevant financial relationships.

PHILADELPHIA – The new American College of Rheumatology Guideline for Vaccinations in Patients with Rheumatic and Musculoskeletal Diseases (RMDs) emphasizes that both adult and pediatric patients should receive recommended vaccinations whenever possible.

But the guideline, currently in press, also offers recommendations about whether and when to withhold vaccines from patients with RMDs, such as avoiding the use of live attenuated virus vaccines in patients who are on immunosuppressive drug regimens, such as conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, or targeted synthetic DMARDs.

The new consensus guideline was formulated with the understanding that patients with RMDs are at increased risk for vaccine-preventable infections and more serious complications from infections, compared with the general population.

However, the guideline also acknowledges that the immunogenicity and safety of vaccines may differ among patients with RMDs, and that, depending on the patient age and disease state, individuals may benefit from modified vaccine indications, schedules, or modified medication schedules, said guideline panel member Anne Bass, MD, a rheumatologist at Hospital for Special Surgery and a professor of clinical medicine at Weill Cornell Medicine in New York, who presented the guideline with other panel members in a session outlining the recommendations at the annual meeting of the ACR.

“In addition, vaccination recommendations – since much of it relates to medications – really applies across diseases, and so the ACR felt that, rather than having vaccine recommendations tacked onto the end of treatment guidelines for each individual disease, that the topic should be discussed or tackled as a whole,” she said.

The guideline does not cover vaccinations in patients taking nonsteroidal anti-inflammatory drugs because this class of agents has minimal or no impact on antibody responses to vaccines. The guideline also does not address vaccinations against COVID-19 infections since the rapidly changing formulations would make the recommendations obsolete before they were even published, and because the U.S. Centers for Disease Control and Prevention provides up-to-date guidance on COVID-19 vaccinations in patients with compromised immunity, she said.
 

Guiding principles

The overarching principles of the guideline are to give indicated vaccines to patients with RMD whenever possible and that any decision to hold medications before or after vaccination consider the dosage used, RMD disease activity, and the patient’s risk for vaccine-preventable infection.

The guideline also states that “shared decision-making with patients is a key component of any vaccination strategy.”

Panel member Clifton O. Bingham III, MD, professor of medicine at Johns Hopkins University in Baltimore, outlined expanded indications for vaccinations against influenza, pneumococcal infections, varicella zoster virus (VZV) and human papillomavirus (HPV).
 

Influenza

The guideline conditionally recommends that patients with RMD aged 65 years and older and adults older than age 18 years who are on immunosuppressive medications should receive either high-dose or adjuvanted influenza vaccination rather than regular-dose vaccines.

“It’s recognized that the high-dose or adjuvanted vaccinations may be unavailable for patients when they’re seen in your practice,” Dr. Bingham said,” and we came out with two additional statements within the guidelines that said that any flu vaccine is recommended over no flu vaccinations, because we do know that responses are elicited, and a flu vaccination today is preferred over a flu vaccination delay.”
 

Pneumococcal vaccination

The panelists strongly recommended that patients with RMD younger than age 65 years who are on immunosuppressive medication receive pneumococcal vaccinations.

The ACR guideline is in sync with those issued by the CDC’s Advisory Committee on Immunization Practices, Dr. Bingham said. He urged audience members to visit a CDC-ACIP web page for more information on who should receive pneumococcal vaccination and when.
 

Recombinant varicella zoster

The recommendations strongly support that patients aged 18 years and over who are on immunosuppressive therapies should receive the recombinant VZV vaccine (Shingrix).

HPV

A less robust, conditional recommendation is for patients with RMDs who are between the ages of 26 and 45 years and on immunosuppressive medications to receive the HPV vaccine (if they have not already received the vaccine).

Non-live attenuated vaccines

Kevin Winthrop, MD, MPH, professor of infectious diseases and public health at Oregon Health & Science University, Portland, summarized the recommendations for managing immunosuppressive therapies in patients scheduled to receive vaccinations using killed or nonactive antigens.

“In influenza season, don’t pass up the opportunity to vaccinate,” he said, adding, “if you can wait on rituximab dosing, do it, and if you can’t, go ahead and vaccinate.”

The guidelines also recommend a 2-week methotrexate hold at the time of influenza vaccination; other DMARD dosing changes are likely not necessary at the time of vaccination, “but this is an area of fervent study, and I think in a year or two we’ll have more experimental hold data with regard to other DMARDs,” Dr. Winthrop said.

For other nonlive attenuated vaccinations, recommendations are similar to those for influenza, except with more flexible timing because these vaccinations are not seasonal. When and how to hold methotrexate is still up in the air, he said.

Additionally, it’s recommended that vaccinations be delayed in patients on high-dose prednisone until the drug is tapered to below 20 mg per day, and ideally to less than 10 mg per day, he said.
 

Live-attenuated vaccines

The guideline conditionally recommends deferring live-attenuated vaccines in patients on immunosuppressive drugs. It also recommends holding these medications “for an appropriate period before” vaccination and for 4 weeks afterward.

“Although the evidence around conventional synthetic DMARDs and TNF inhibitors is reassuring in terms of their safety at the time of live attenuated vaccines, as you can see the number of studies is quite small, and so the voting panel conditionally recommend against administering live-attenuated virus vaccines to patients who are on conventional synthetics, biologic, or targeted DMARDs,” Dr. Bass said.
 

In utero exposures

Most women with RMD who have recently given birth will consult their general pediatricians rather than rheumatologists for infant vaccinations, but pediatricians may not be aware of the affect that in utero exposures to biologic DMARDs can have on vaccine safety and immunogenicity in infants, Dr, Bass said.

“It’s important that you, as a provider, give your recommendations regarding infant rotavirus vaccination after in utero exposure to the pregnant rheumatic disease patient prior to delivery, and let that patient know that this is something that they should share with their pediatrician to be,” she advised audience members.
 

Getting the message out

In an interview, session moderator and guidelines panelist Lisa F. Imundo, MD, director of the center for adolescent rheumatology at Columbia University in New York, noted that rheumatologists don’t usually have the full schedule of pediatric vaccinations in stock and often leave the decisions about what to give – and when – to general practitioners.

“Pediatric rheumatologists sometimes will give patients flu vaccinations because they’re a high-risk population of patients, and we want to make sure that they’re getting it in a timely manner,” she said.

In addition, because pneumococcal polysaccharide vaccines are not indicated in the general pediatric population, children on biologic DMARDs who have completed their standard series of pneumococcal conjugate vaccines (PCV13 or PVC15) are recommended to get a 23-valent pneumococcal polysaccharide vaccine, Dr. Imundo said.

She also noted that communication between pediatric rheumatologists and general practitioners about vaccine recommendations can be challenging.

“It’s a huge issue, figuring out how we’re going to communicate all of this information to our pediatric colleagues,” she said. “With individual patients, we may sometimes remind doctors, especially with our younger patients who haven’t gotten their live vaccines, that they really shouldn’t get live vaccines until they’re off medication or until we arrange holding medication for some period of time.”

She said that ACR vaccine committee members are working with infectious disease specialists and guideline developers for the American Academy of Pediatrics to ensure guidelines include the most important vaccination recommendations for pediatric patients with RMDs.

The development process for the guidelines was supported by the ACR. Dr. Bass reported no relevant disclosures, Dr. Bingham disclosed consulting activities, grant/research support, and royalties from various corporate entities. Dr. Winthrop disclosed consulting activities for and research funding from various companies. Dr. Imundo reported no relevant financial relationships.

Celiac disease is linked to juvenile idiopathic arthritis (JIA) in children and rheumatoid arthritis (RA) in adults, according to an analysis of nationwide data in Sweden.

Children with celiac disease are nearly three times as likely to develop JIA relative to the general population. Adults with celiac disease are nearly two times as likely to be diagnosed with RA.

“I hope that our study can ultimately change clinical practice by lowering the threshold to evaluate celiac disease patients for inflammatory joint diseases,” John B. Doyle, MD, a gastroenterology fellow at Columbia University Irving Medical Center in New York, told this news organization.

“Inflammatory joint diseases, such as JIA and RA, are notoriously difficult to diagnose given their variable presentations,” he said. “But if JIA or RA can be identified sooner by physicians, patients will ultimately benefit by starting disease-modifying therapy earlier in their disease course.”

The study was published online in The American Journal of Gastroenterology.
 

Analyzing associations

Celiac disease has been linked to numerous autoimmune diseases, including type 1 diabetes, autoimmune thyroid disease, lupus, and inflammatory bowel disease (IBD), Dr. Doyle noted. However, a definitive epidemiologic association between celiac disease and inflammatory joint diseases such as JIA or RA hasn›t been established.

Dr. Doyle and colleagues conducted a nationwide population-based, retrospective matched cohort study using the Epidemiology Strengthened by Histopathology Reports in Sweden. They identified 24,014 patients diagnosed with biopsy-proven celiac disease between 2004 and 2017.

With these data, each patient was matched to five reference individuals in the general population by age, sex, calendar year, and geographic region, for a total of 117,397 people without a previous diagnosis of celiac disease. The researchers calculated the incidence and estimated the relative risk for JIA in patients younger than 18 years and RA in patients aged 18 years or older.

For those younger than 18 years, the incidence rate of JIA was 5.9 per 10,000 person-years among the 9,415 patients with celiac disease versus 2.2 per 10,000 person-years in the general population, over a follow-up of 7 years. Those with celiac disease were 2.7 times as likely to develop JIA.

The association between celiac disease and JIA remained similar after adjustment for education, Nordic country of birth, type 1 diabetes, autoimmune thyroid disease, lupus, and IBD. The incidence rate of JIA among patients with celiac disease was higher in both females and males, and across all age groups studied.

When 6,703 children with celiac disease were compared with their 9,089 siblings without celiac disease, the higher risk for JIA in patients with celiac disease fell slightly short of statistical significance.

For those aged 18 years or older, the incidence rate of RA was 8.4 per 10,000 person-years among the 14,599 patients with celiac disease versus 5.1 per 10,000 person-years in the general population, over a follow-up of 8.8 years. Those with celiac disease were 1.7 times as likely to develop RA.

As with the younger cohort, the association between celiac disease and RA in the adult group remained similar after adjustment for education, Nordic country of birth, type 1 diabetes, autoimmune thyroid disease, lupus, and IBD. Although both men and women with celiac disease had higher rates of RA, the risk was higher among those in whom disease was diagnosed at age 18-59 years compared with those who received a diagnosis at age 60 years or older.

When 9,578 adults with celiac disease were compared with their 17,067 siblings without celiac disease, the risk for RA remained higher in patients with celiac disease.

This suggests “that the association between celiac disease and RA is unlikely to be explained by environmental factors alone,” Dr. Doyle said.
 

Additional findings

Notably, the primary analysis excluded patients diagnosed with JIA or RA before their celiac disease diagnosis. In additional analyses, however, significant associations emerged.

Among children with celiac disease, 0.5% had a previous diagnosis of JIA, compared with 0.1% of matched comparators. Those with celiac disease were 3.5 times more likely to have a JIA diagnosis.

Among adults with celiac disease, 0.9% had a previous diagnosis of RA, compared with 0.6% of matched comparators. Those with celiac disease were 1.4 times more likely to have a RA diagnosis.

“We found that diagnoses of these types of arthritis were more common before a diagnosis of celiac disease compared to the general population,” Benjamin Lebwohl, MD, director of clinical research at the Celiac Disease Center at Columbia University, New York, told this news organization.

“This suggests that undiagnosed and untreated celiac disease might be contributing to these others autoimmune conditions,” he said.

Dr. Doyle and Dr. Lebwohl emphasized the practical implications for clinicians caring for patients with celiac disease. Among patients with celiac disease and inflammatory joint symptoms, clinicians should have a low threshold to evaluate for JIA or RA, they said.

“Particularly in pediatrics, we are trained to screen patients with JIA for celiac disease, but this study points to the possible bidirectional association and the importance of maintaining a clinical suspicion for JIA and RA among established celiac disease patients,” Marisa Stahl, MD, assistant professor of pediatrics and associate program director of the pediatric gastroenterology, hepatology, and nutrition fellowship training program at the University of Colorado at Denver, Aurora, said in an interview.

Dr. Stahl, who wasn’t involved with this study, conducts research at the Colorado Center for Celiac Disease. She and colleagues are focused on understanding the genetic and environmental factors that lead to the development of celiac disease and other autoimmune diseases.

Given the clear association between celiac disease and other autoimmune diseases, Dr. Stahl agreed that clinicians should have a low threshold for screening, with “additional workup for other autoimmune diseases once an autoimmune diagnosis is established.”

The study was supported by Karolinska Institutet and the Swedish Research Council. Dr. Lebwohl coordinates a study on behalf of the Swedish IBD quality register, which has received funding from Janssen. The other authors declared no conflicts of interest. Dr. Stahl reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Celiac disease is linked to juvenile idiopathic arthritis (JIA) in children and rheumatoid arthritis (RA) in adults, according to an analysis of nationwide data in Sweden.

Children with celiac disease are nearly three times as likely to develop JIA relative to the general population. Adults with celiac disease are nearly two times as likely to be diagnosed with RA.

“I hope that our study can ultimately change clinical practice by lowering the threshold to evaluate celiac disease patients for inflammatory joint diseases,” John B. Doyle, MD, a gastroenterology fellow at Columbia University Irving Medical Center in New York, told this news organization.

“Inflammatory joint diseases, such as JIA and RA, are notoriously difficult to diagnose given their variable presentations,” he said. “But if JIA or RA can be identified sooner by physicians, patients will ultimately benefit by starting disease-modifying therapy earlier in their disease course.”

The study was published online in The American Journal of Gastroenterology.
 

Analyzing associations

Celiac disease has been linked to numerous autoimmune diseases, including type 1 diabetes, autoimmune thyroid disease, lupus, and inflammatory bowel disease (IBD), Dr. Doyle noted. However, a definitive epidemiologic association between celiac disease and inflammatory joint diseases such as JIA or RA hasn›t been established.

Dr. Doyle and colleagues conducted a nationwide population-based, retrospective matched cohort study using the Epidemiology Strengthened by Histopathology Reports in Sweden. They identified 24,014 patients diagnosed with biopsy-proven celiac disease between 2004 and 2017.

With these data, each patient was matched to five reference individuals in the general population by age, sex, calendar year, and geographic region, for a total of 117,397 people without a previous diagnosis of celiac disease. The researchers calculated the incidence and estimated the relative risk for JIA in patients younger than 18 years and RA in patients aged 18 years or older.

For those younger than 18 years, the incidence rate of JIA was 5.9 per 10,000 person-years among the 9,415 patients with celiac disease versus 2.2 per 10,000 person-years in the general population, over a follow-up of 7 years. Those with celiac disease were 2.7 times as likely to develop JIA.

The association between celiac disease and JIA remained similar after adjustment for education, Nordic country of birth, type 1 diabetes, autoimmune thyroid disease, lupus, and IBD. The incidence rate of JIA among patients with celiac disease was higher in both females and males, and across all age groups studied.

When 6,703 children with celiac disease were compared with their 9,089 siblings without celiac disease, the higher risk for JIA in patients with celiac disease fell slightly short of statistical significance.

For those aged 18 years or older, the incidence rate of RA was 8.4 per 10,000 person-years among the 14,599 patients with celiac disease versus 5.1 per 10,000 person-years in the general population, over a follow-up of 8.8 years. Those with celiac disease were 1.7 times as likely to develop RA.

As with the younger cohort, the association between celiac disease and RA in the adult group remained similar after adjustment for education, Nordic country of birth, type 1 diabetes, autoimmune thyroid disease, lupus, and IBD. Although both men and women with celiac disease had higher rates of RA, the risk was higher among those in whom disease was diagnosed at age 18-59 years compared with those who received a diagnosis at age 60 years or older.

When 9,578 adults with celiac disease were compared with their 17,067 siblings without celiac disease, the risk for RA remained higher in patients with celiac disease.

This suggests “that the association between celiac disease and RA is unlikely to be explained by environmental factors alone,” Dr. Doyle said.
 

Additional findings

Notably, the primary analysis excluded patients diagnosed with JIA or RA before their celiac disease diagnosis. In additional analyses, however, significant associations emerged.

Among children with celiac disease, 0.5% had a previous diagnosis of JIA, compared with 0.1% of matched comparators. Those with celiac disease were 3.5 times more likely to have a JIA diagnosis.

Among adults with celiac disease, 0.9% had a previous diagnosis of RA, compared with 0.6% of matched comparators. Those with celiac disease were 1.4 times more likely to have a RA diagnosis.

“We found that diagnoses of these types of arthritis were more common before a diagnosis of celiac disease compared to the general population,” Benjamin Lebwohl, MD, director of clinical research at the Celiac Disease Center at Columbia University, New York, told this news organization.

“This suggests that undiagnosed and untreated celiac disease might be contributing to these others autoimmune conditions,” he said.

Dr. Doyle and Dr. Lebwohl emphasized the practical implications for clinicians caring for patients with celiac disease. Among patients with celiac disease and inflammatory joint symptoms, clinicians should have a low threshold to evaluate for JIA or RA, they said.

“Particularly in pediatrics, we are trained to screen patients with JIA for celiac disease, but this study points to the possible bidirectional association and the importance of maintaining a clinical suspicion for JIA and RA among established celiac disease patients,” Marisa Stahl, MD, assistant professor of pediatrics and associate program director of the pediatric gastroenterology, hepatology, and nutrition fellowship training program at the University of Colorado at Denver, Aurora, said in an interview.

Dr. Stahl, who wasn’t involved with this study, conducts research at the Colorado Center for Celiac Disease. She and colleagues are focused on understanding the genetic and environmental factors that lead to the development of celiac disease and other autoimmune diseases.

Given the clear association between celiac disease and other autoimmune diseases, Dr. Stahl agreed that clinicians should have a low threshold for screening, with “additional workup for other autoimmune diseases once an autoimmune diagnosis is established.”

The study was supported by Karolinska Institutet and the Swedish Research Council. Dr. Lebwohl coordinates a study on behalf of the Swedish IBD quality register, which has received funding from Janssen. The other authors declared no conflicts of interest. Dr. Stahl reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Celiac disease is linked to juvenile idiopathic arthritis (JIA) in children and rheumatoid arthritis (RA) in adults, according to an analysis of nationwide data in Sweden.

Children with celiac disease are nearly three times as likely to develop JIA relative to the general population. Adults with celiac disease are nearly two times as likely to be diagnosed with RA.

“I hope that our study can ultimately change clinical practice by lowering the threshold to evaluate celiac disease patients for inflammatory joint diseases,” John B. Doyle, MD, a gastroenterology fellow at Columbia University Irving Medical Center in New York, told this news organization.

“Inflammatory joint diseases, such as JIA and RA, are notoriously difficult to diagnose given their variable presentations,” he said. “But if JIA or RA can be identified sooner by physicians, patients will ultimately benefit by starting disease-modifying therapy earlier in their disease course.”

The study was published online in The American Journal of Gastroenterology.
 

Analyzing associations

Celiac disease has been linked to numerous autoimmune diseases, including type 1 diabetes, autoimmune thyroid disease, lupus, and inflammatory bowel disease (IBD), Dr. Doyle noted. However, a definitive epidemiologic association between celiac disease and inflammatory joint diseases such as JIA or RA hasn›t been established.

Dr. Doyle and colleagues conducted a nationwide population-based, retrospective matched cohort study using the Epidemiology Strengthened by Histopathology Reports in Sweden. They identified 24,014 patients diagnosed with biopsy-proven celiac disease between 2004 and 2017.

With these data, each patient was matched to five reference individuals in the general population by age, sex, calendar year, and geographic region, for a total of 117,397 people without a previous diagnosis of celiac disease. The researchers calculated the incidence and estimated the relative risk for JIA in patients younger than 18 years and RA in patients aged 18 years or older.

For those younger than 18 years, the incidence rate of JIA was 5.9 per 10,000 person-years among the 9,415 patients with celiac disease versus 2.2 per 10,000 person-years in the general population, over a follow-up of 7 years. Those with celiac disease were 2.7 times as likely to develop JIA.

The association between celiac disease and JIA remained similar after adjustment for education, Nordic country of birth, type 1 diabetes, autoimmune thyroid disease, lupus, and IBD. The incidence rate of JIA among patients with celiac disease was higher in both females and males, and across all age groups studied.

When 6,703 children with celiac disease were compared with their 9,089 siblings without celiac disease, the higher risk for JIA in patients with celiac disease fell slightly short of statistical significance.

For those aged 18 years or older, the incidence rate of RA was 8.4 per 10,000 person-years among the 14,599 patients with celiac disease versus 5.1 per 10,000 person-years in the general population, over a follow-up of 8.8 years. Those with celiac disease were 1.7 times as likely to develop RA.

As with the younger cohort, the association between celiac disease and RA in the adult group remained similar after adjustment for education, Nordic country of birth, type 1 diabetes, autoimmune thyroid disease, lupus, and IBD. Although both men and women with celiac disease had higher rates of RA, the risk was higher among those in whom disease was diagnosed at age 18-59 years compared with those who received a diagnosis at age 60 years or older.

When 9,578 adults with celiac disease were compared with their 17,067 siblings without celiac disease, the risk for RA remained higher in patients with celiac disease.

This suggests “that the association between celiac disease and RA is unlikely to be explained by environmental factors alone,” Dr. Doyle said.
 

Additional findings

Notably, the primary analysis excluded patients diagnosed with JIA or RA before their celiac disease diagnosis. In additional analyses, however, significant associations emerged.

Among children with celiac disease, 0.5% had a previous diagnosis of JIA, compared with 0.1% of matched comparators. Those with celiac disease were 3.5 times more likely to have a JIA diagnosis.

Among adults with celiac disease, 0.9% had a previous diagnosis of RA, compared with 0.6% of matched comparators. Those with celiac disease were 1.4 times more likely to have a RA diagnosis.

“We found that diagnoses of these types of arthritis were more common before a diagnosis of celiac disease compared to the general population,” Benjamin Lebwohl, MD, director of clinical research at the Celiac Disease Center at Columbia University, New York, told this news organization.

“This suggests that undiagnosed and untreated celiac disease might be contributing to these others autoimmune conditions,” he said.

Dr. Doyle and Dr. Lebwohl emphasized the practical implications for clinicians caring for patients with celiac disease. Among patients with celiac disease and inflammatory joint symptoms, clinicians should have a low threshold to evaluate for JIA or RA, they said.

“Particularly in pediatrics, we are trained to screen patients with JIA for celiac disease, but this study points to the possible bidirectional association and the importance of maintaining a clinical suspicion for JIA and RA among established celiac disease patients,” Marisa Stahl, MD, assistant professor of pediatrics and associate program director of the pediatric gastroenterology, hepatology, and nutrition fellowship training program at the University of Colorado at Denver, Aurora, said in an interview.

Dr. Stahl, who wasn’t involved with this study, conducts research at the Colorado Center for Celiac Disease. She and colleagues are focused on understanding the genetic and environmental factors that lead to the development of celiac disease and other autoimmune diseases.

Given the clear association between celiac disease and other autoimmune diseases, Dr. Stahl agreed that clinicians should have a low threshold for screening, with “additional workup for other autoimmune diseases once an autoimmune diagnosis is established.”

The study was supported by Karolinska Institutet and the Swedish Research Council. Dr. Lebwohl coordinates a study on behalf of the Swedish IBD quality register, which has received funding from Janssen. The other authors declared no conflicts of interest. Dr. Stahl reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

PHILADELPHIA – Hydroxychloroquine (HCQ) isn’t any more effective at preventing or delaying the onset of rheumatoid arthritis than placebo, based on interim results of a randomized clinical trial reported at the annual meeting of the American College of Rheumatology. Despite that futility, the percentage of patients who actually went on to develop clinical RA was lower than investigators expected, and the trial supports the use of a key biomarker for identifying RA.

While the StopRA trial was halted early because of futility of the treatment, investigators are continuing to mine the gathered data to deepen their understanding of disease progression and the potential of HCQ to improve symptoms in RA patients, said lead study author Kevin D. Deane, MD, PhD, of the University of Colorado at Denver, Aurora.

Richard Mark Kirkner/MDedge News

Overall, around 35% of the study participants on average developed RA, Dr. Deane said. “We were expecting somewhat more,” he said. “Teasing out who’s really going to progress to RA during a study and who’s not is going to be incredibly important.”

StopRA enrolled 144 adults who had elevated anti–cyclic citrullinated peptide antibodies (CCP3) levels of at least 40 units (about twice the normal level) but no history if inflammatory arthritis, randomizing them on a 1:1 basis to either HCQ (200-400 mg a day based on weight) or placebo for a 1-year treatment regimen.

The study identified participants through rheumatology clinics, testing of first-degree relatives with established RA, health fairs, blood donors, and biobanks. The interim findings are based on 2 years of follow-up after the last dose.

The study focused on HCQ because it has a relatively low risk profile with good safety and tolerability, is easy to administer, and is relatively low cost, Dr. Deane said.

StopRA study failed to meet its primary endpoint: to determine if 1 year of treatment with HCQ reduced the risk of developing inflammatory arthritis and classifiable RA at the end of 3 years in the study population. At the time of the interim analysis, 34% of patients in the HCQ arm and 36% in the placebo arm had developed RA (P = .844), Dr. Deane said. Baseline characteristics were balanced in both treatment arms.

The findings also support the use of CCP3 as a biomarker for RA, Dr. Deane said.

Now that the trial has been terminated, Dr. Deane said investigators are going to review the final data and perform secondary analyses for further clarity on the impact HCQ may have on RA.

“The future analysis should hopefully say if this treatment actually changes symptoms,” he said in an interview. “Because, if somebody felt better on the drug or had a milder form of rheumatoid arthritis once they developed it, that could potentially be a benefit.”

Dr. Deane noted the TREAT EARLIER trial similarly found that a 1-year course of methotrexate didn’t prevent the onset of clinical arthritis, but it did alter the disease course as measured in MRI-detected inflammation, related symptoms, and impairment.

“We’re hoping to look at those things and hopefully look at biologic changes over time,” Dr. Deane said of the extended analysis. “We’re not sure if the drug was associated with changes in biomarkers yet still didn’t halt progression to RA. That might be interesting, because those biomarkers might not be fundamentally related to the disease, but other mechanisms may be. That could give us some insights.”

Richard Mark Kirkner/MDedge News

Session moderator Ted Mikuls, MD, a professor of rheumatology at the University of Nebraska Medical Center, Omaha, said further mining of the study data is warranted.

“It’s common in a study like that, which took a lot of time and investment, to really take a deep dive into the data to make sure there aren’t signals that we’re missing,” he said in an interview.

One of the challenges with the study may have been patient enrollment, Dr. Mikuls noted. “I wonder about the study population in terms of where they recruit patients from. Who’s more likely to get RA? Is it patients who already have symptoms? Is it asymptomatic patients from biobanks? If it’s arthralgia joint pain patients, maybe by the time you have joint and autoantibody positivity it’s too late to have an intervention.”

The National Institute of Allergy and Infectious Diseases sponsored the study. Dr. Deane disclosed a relationship with Werfen. Dr. Mikuls has no relevant disclosures.
 

PHILADELPHIA – Hydroxychloroquine (HCQ) isn’t any more effective at preventing or delaying the onset of rheumatoid arthritis than placebo, based on interim results of a randomized clinical trial reported at the annual meeting of the American College of Rheumatology. Despite that futility, the percentage of patients who actually went on to develop clinical RA was lower than investigators expected, and the trial supports the use of a key biomarker for identifying RA.

While the StopRA trial was halted early because of futility of the treatment, investigators are continuing to mine the gathered data to deepen their understanding of disease progression and the potential of HCQ to improve symptoms in RA patients, said lead study author Kevin D. Deane, MD, PhD, of the University of Colorado at Denver, Aurora.

Richard Mark Kirkner/MDedge News

Overall, around 35% of the study participants on average developed RA, Dr. Deane said. “We were expecting somewhat more,” he said. “Teasing out who’s really going to progress to RA during a study and who’s not is going to be incredibly important.”

StopRA enrolled 144 adults who had elevated anti–cyclic citrullinated peptide antibodies (CCP3) levels of at least 40 units (about twice the normal level) but no history if inflammatory arthritis, randomizing them on a 1:1 basis to either HCQ (200-400 mg a day based on weight) or placebo for a 1-year treatment regimen.

The study identified participants through rheumatology clinics, testing of first-degree relatives with established RA, health fairs, blood donors, and biobanks. The interim findings are based on 2 years of follow-up after the last dose.

The study focused on HCQ because it has a relatively low risk profile with good safety and tolerability, is easy to administer, and is relatively low cost, Dr. Deane said.

StopRA study failed to meet its primary endpoint: to determine if 1 year of treatment with HCQ reduced the risk of developing inflammatory arthritis and classifiable RA at the end of 3 years in the study population. At the time of the interim analysis, 34% of patients in the HCQ arm and 36% in the placebo arm had developed RA (P = .844), Dr. Deane said. Baseline characteristics were balanced in both treatment arms.

The findings also support the use of CCP3 as a biomarker for RA, Dr. Deane said.

Now that the trial has been terminated, Dr. Deane said investigators are going to review the final data and perform secondary analyses for further clarity on the impact HCQ may have on RA.

“The future analysis should hopefully say if this treatment actually changes symptoms,” he said in an interview. “Because, if somebody felt better on the drug or had a milder form of rheumatoid arthritis once they developed it, that could potentially be a benefit.”

Dr. Deane noted the TREAT EARLIER trial similarly found that a 1-year course of methotrexate didn’t prevent the onset of clinical arthritis, but it did alter the disease course as measured in MRI-detected inflammation, related symptoms, and impairment.

“We’re hoping to look at those things and hopefully look at biologic changes over time,” Dr. Deane said of the extended analysis. “We’re not sure if the drug was associated with changes in biomarkers yet still didn’t halt progression to RA. That might be interesting, because those biomarkers might not be fundamentally related to the disease, but other mechanisms may be. That could give us some insights.”

Richard Mark Kirkner/MDedge News

Session moderator Ted Mikuls, MD, a professor of rheumatology at the University of Nebraska Medical Center, Omaha, said further mining of the study data is warranted.

“It’s common in a study like that, which took a lot of time and investment, to really take a deep dive into the data to make sure there aren’t signals that we’re missing,” he said in an interview.

One of the challenges with the study may have been patient enrollment, Dr. Mikuls noted. “I wonder about the study population in terms of where they recruit patients from. Who’s more likely to get RA? Is it patients who already have symptoms? Is it asymptomatic patients from biobanks? If it’s arthralgia joint pain patients, maybe by the time you have joint and autoantibody positivity it’s too late to have an intervention.”

The National Institute of Allergy and Infectious Diseases sponsored the study. Dr. Deane disclosed a relationship with Werfen. Dr. Mikuls has no relevant disclosures.
 

PHILADELPHIA – Hydroxychloroquine (HCQ) isn’t any more effective at preventing or delaying the onset of rheumatoid arthritis than placebo, based on interim results of a randomized clinical trial reported at the annual meeting of the American College of Rheumatology. Despite that futility, the percentage of patients who actually went on to develop clinical RA was lower than investigators expected, and the trial supports the use of a key biomarker for identifying RA.

While the StopRA trial was halted early because of futility of the treatment, investigators are continuing to mine the gathered data to deepen their understanding of disease progression and the potential of HCQ to improve symptoms in RA patients, said lead study author Kevin D. Deane, MD, PhD, of the University of Colorado at Denver, Aurora.

Richard Mark Kirkner/MDedge News

Overall, around 35% of the study participants on average developed RA, Dr. Deane said. “We were expecting somewhat more,” he said. “Teasing out who’s really going to progress to RA during a study and who’s not is going to be incredibly important.”

StopRA enrolled 144 adults who had elevated anti–cyclic citrullinated peptide antibodies (CCP3) levels of at least 40 units (about twice the normal level) but no history if inflammatory arthritis, randomizing them on a 1:1 basis to either HCQ (200-400 mg a day based on weight) or placebo for a 1-year treatment regimen.

The study identified participants through rheumatology clinics, testing of first-degree relatives with established RA, health fairs, blood donors, and biobanks. The interim findings are based on 2 years of follow-up after the last dose.

The study focused on HCQ because it has a relatively low risk profile with good safety and tolerability, is easy to administer, and is relatively low cost, Dr. Deane said.

StopRA study failed to meet its primary endpoint: to determine if 1 year of treatment with HCQ reduced the risk of developing inflammatory arthritis and classifiable RA at the end of 3 years in the study population. At the time of the interim analysis, 34% of patients in the HCQ arm and 36% in the placebo arm had developed RA (P = .844), Dr. Deane said. Baseline characteristics were balanced in both treatment arms.

The findings also support the use of CCP3 as a biomarker for RA, Dr. Deane said.

Now that the trial has been terminated, Dr. Deane said investigators are going to review the final data and perform secondary analyses for further clarity on the impact HCQ may have on RA.

“The future analysis should hopefully say if this treatment actually changes symptoms,” he said in an interview. “Because, if somebody felt better on the drug or had a milder form of rheumatoid arthritis once they developed it, that could potentially be a benefit.”

Dr. Deane noted the TREAT EARLIER trial similarly found that a 1-year course of methotrexate didn’t prevent the onset of clinical arthritis, but it did alter the disease course as measured in MRI-detected inflammation, related symptoms, and impairment.

“We’re hoping to look at those things and hopefully look at biologic changes over time,” Dr. Deane said of the extended analysis. “We’re not sure if the drug was associated with changes in biomarkers yet still didn’t halt progression to RA. That might be interesting, because those biomarkers might not be fundamentally related to the disease, but other mechanisms may be. That could give us some insights.”

Richard Mark Kirkner/MDedge News

Session moderator Ted Mikuls, MD, a professor of rheumatology at the University of Nebraska Medical Center, Omaha, said further mining of the study data is warranted.

“It’s common in a study like that, which took a lot of time and investment, to really take a deep dive into the data to make sure there aren’t signals that we’re missing,” he said in an interview.

One of the challenges with the study may have been patient enrollment, Dr. Mikuls noted. “I wonder about the study population in terms of where they recruit patients from. Who’s more likely to get RA? Is it patients who already have symptoms? Is it asymptomatic patients from biobanks? If it’s arthralgia joint pain patients, maybe by the time you have joint and autoantibody positivity it’s too late to have an intervention.”

The National Institute of Allergy and Infectious Diseases sponsored the study. Dr. Deane disclosed a relationship with Werfen. Dr. Mikuls has no relevant disclosures.
 

PHILADELPHIA – For patients with rheumatoid arthritis who are already at increased risk for major adverse cardiovascular events (MACE), NSAIDs may be safer than opioids, results of a new-user active comparator study suggest.

Among 6,866 patients with RA who started on opioids and 13,698 patients who started on NSAIDs for pain, the use of both weak and strong opioids was associated with a 33% increase in risk for all-cause mortality and a trend toward higher rates of venous thromboembolism (VTE), compared with NSAID use, reported Gulsen Ozen, MD, of the University of Nebraska Medical Center, Omaha.

Neil Osterweil/MDedge News

“Pain in RA is a very complex process, and we know that it’s not solely dependent on the disease activity, but there is no evidence that opioids have any benefit in long-term pain management, and it can even cause hyperalgesia. And as we show, it’s not safer than NSAIDs,” she said in an oral abstract session at the annual meeting of the American College of Rheumatology.

She stressed that patients should be assessed for non-RA causes of pain and should use nonpharmacologic methods when possible.

“If a pharmacological treatment is needed and NSAIDs are contraindicated, the lowest possible dose of weak opioids can be used for a very limited time for acute pain only,” she said.
 

Pain despite disease control

Even when their disease is well controlled, approximately 60% of patients with RA still report pain. NSAIDs are commonly used to treat pain in patients with RA, but they are associated with modest increases in risk for cardiovascular disease (CVD), gastrointestinal bleeding, renal injury, and hypertension.

Some providers are leery of NSAIDs and will instead prescribe either regular or intermittent opioids for pain control in their patients.

Disease-modifying antirheumatic drugs have only minimal pain-relieving benefits, “and even worse, opioids can delay initiation of DMARDs in RA,” Dr. Ozen said.

Opioids have been shown to increase oxidative stress, platelet aggregation, and myocardial fibrosis, as well as hypogonadism, weight gain, and CVD risk factors.

There is little evidence, however, on whether opioids are associated with cardiovascular events in patients with RA. This dearth of data prompted Dr. Ozen and colleagues to study the relative risks for MACE in patients with RA starting on opioids or NSAIDs for pain.

Matched cohorts

They used data from FORWARD, a joint Canadian and U.S. databank for rheumatic diseases, to conduct a new-user active comparator cohort study. The cohort included adults with RA without cancer who participated in FORWARD for a minimum of 1 year between 1998 and 2021.

The patients were followed either from drug initiation until 3 months after the end of treatment, defined as either discontinuation or a switch to a different analgesic, end of study follow-up, or the development of a MACE outcome.

The investigators used propensity score matching to compare each opioid initiator with two NSAID initiators. The participants were matched by age, sex, body mass index, smoking, alcohol, RA duration, disease activity, Health Assessment Questionnaire, visual analog scale for pain, joint surgeries, prior CVD and VTE, hypertension, diabetes, rheumatic diseases comorbidity index, osteoporosis/fractures, thyroid, chronic liver, kidney, lung and mental health diseases, hospitalizations, 36-Item Short Form Health Survey scores, and sleep scores.

The two groups were well matched, except for a slightly higher incidence of VTE in opioid initiators, although incidence rates were low in both groups (0.9% vs. 0.6% of NSAID initiators).
 

Higher death rate in opioid users

The incidence rate of MACE among opioid initiators was 20.6% versus18.9% among NSAID initiators, a difference that was not statistically significant. There were also no significant differences in incidence rates of the individual components of the MACE composite outcome: myocardial infarction, stroke, heart failure, CVD death, or VTE.

There were, however, significantly more deaths from any cause among patients in the opioid group, with an incidence rate of 13.5% versus 10.8% in the NSAID group.

An analysis of the associaion of drug type with outcomes, adjusted for propensity score weight and prior VTE showed that patients on opioids had a statistically significant hazard ratio for death from any cause of 1.33 (95% confidence interval, 1.06-1.67).

The increased risk for all-cause mortality occurred both in patients starting on weak opioids (hydrocodone, tramadol, codeine, pentazocine, and propoxyphene) and on strong opioids (hydromorphone, dihydromorphinone, oxymorphone, butorphanol, methadone, morphine, oxycodone, meperidine, and fentanyl).

As noted before, there was a trend toward an increased risk for VTE among opioid initiators, but this was not statistically significant.

The increase in risk was higher among patients on strong versus weak opioids, suggesting a dose-dependent relationship, Dr. Ozen said.

A comparison of opioid-associated risk for all-cause mortality vs. NSAIDs according to type (nonselective or selective) showed that most of the increase in risk was relative to selective cycloxygenase-2 inhibitors.

‘Beautiful’ analysis

“This is a beautiful piece of analysis on a really difficult question to address because the confounding is really hard to unpick,” commented James Galloway, MBBS, deputy head of the center for rheumatic diseases at King’s College London and consulting rheumatologist at King’s College Hospital, also in London.

“The headline message is that there didn’t appear to be a clear signal that NSAIDs were worse, which is what I thought the preexisting view might have been. And so, people may have paradoxically prescribed opioids in favor of NSAIDs in a person with cardiovascular risk,” he said in an interview. Dr. Galloway attended the oral abstract session but was not involved in the study.

The study was supported by a grant to Dr. Ozen from the Rheumatology Research Foundation. Dr. Galloway reported having no relevant disclosures.

PHILADELPHIA – For patients with rheumatoid arthritis who are already at increased risk for major adverse cardiovascular events (MACE), NSAIDs may be safer than opioids, results of a new-user active comparator study suggest.

Among 6,866 patients with RA who started on opioids and 13,698 patients who started on NSAIDs for pain, the use of both weak and strong opioids was associated with a 33% increase in risk for all-cause mortality and a trend toward higher rates of venous thromboembolism (VTE), compared with NSAID use, reported Gulsen Ozen, MD, of the University of Nebraska Medical Center, Omaha.

Neil Osterweil/MDedge News

“Pain in RA is a very complex process, and we know that it’s not solely dependent on the disease activity, but there is no evidence that opioids have any benefit in long-term pain management, and it can even cause hyperalgesia. And as we show, it’s not safer than NSAIDs,” she said in an oral abstract session at the annual meeting of the American College of Rheumatology.

She stressed that patients should be assessed for non-RA causes of pain and should use nonpharmacologic methods when possible.

“If a pharmacological treatment is needed and NSAIDs are contraindicated, the lowest possible dose of weak opioids can be used for a very limited time for acute pain only,” she said.
 

Pain despite disease control

Even when their disease is well controlled, approximately 60% of patients with RA still report pain. NSAIDs are commonly used to treat pain in patients with RA, but they are associated with modest increases in risk for cardiovascular disease (CVD), gastrointestinal bleeding, renal injury, and hypertension.

Some providers are leery of NSAIDs and will instead prescribe either regular or intermittent opioids for pain control in their patients.

Disease-modifying antirheumatic drugs have only minimal pain-relieving benefits, “and even worse, opioids can delay initiation of DMARDs in RA,” Dr. Ozen said.

Opioids have been shown to increase oxidative stress, platelet aggregation, and myocardial fibrosis, as well as hypogonadism, weight gain, and CVD risk factors.

There is little evidence, however, on whether opioids are associated with cardiovascular events in patients with RA. This dearth of data prompted Dr. Ozen and colleagues to study the relative risks for MACE in patients with RA starting on opioids or NSAIDs for pain.

Matched cohorts

They used data from FORWARD, a joint Canadian and U.S. databank for rheumatic diseases, to conduct a new-user active comparator cohort study. The cohort included adults with RA without cancer who participated in FORWARD for a minimum of 1 year between 1998 and 2021.

The patients were followed either from drug initiation until 3 months after the end of treatment, defined as either discontinuation or a switch to a different analgesic, end of study follow-up, or the development of a MACE outcome.

The investigators used propensity score matching to compare each opioid initiator with two NSAID initiators. The participants were matched by age, sex, body mass index, smoking, alcohol, RA duration, disease activity, Health Assessment Questionnaire, visual analog scale for pain, joint surgeries, prior CVD and VTE, hypertension, diabetes, rheumatic diseases comorbidity index, osteoporosis/fractures, thyroid, chronic liver, kidney, lung and mental health diseases, hospitalizations, 36-Item Short Form Health Survey scores, and sleep scores.

The two groups were well matched, except for a slightly higher incidence of VTE in opioid initiators, although incidence rates were low in both groups (0.9% vs. 0.6% of NSAID initiators).
 

Higher death rate in opioid users

The incidence rate of MACE among opioid initiators was 20.6% versus18.9% among NSAID initiators, a difference that was not statistically significant. There were also no significant differences in incidence rates of the individual components of the MACE composite outcome: myocardial infarction, stroke, heart failure, CVD death, or VTE.

There were, however, significantly more deaths from any cause among patients in the opioid group, with an incidence rate of 13.5% versus 10.8% in the NSAID group.

An analysis of the associaion of drug type with outcomes, adjusted for propensity score weight and prior VTE showed that patients on opioids had a statistically significant hazard ratio for death from any cause of 1.33 (95% confidence interval, 1.06-1.67).

The increased risk for all-cause mortality occurred both in patients starting on weak opioids (hydrocodone, tramadol, codeine, pentazocine, and propoxyphene) and on strong opioids (hydromorphone, dihydromorphinone, oxymorphone, butorphanol, methadone, morphine, oxycodone, meperidine, and fentanyl).

As noted before, there was a trend toward an increased risk for VTE among opioid initiators, but this was not statistically significant.

The increase in risk was higher among patients on strong versus weak opioids, suggesting a dose-dependent relationship, Dr. Ozen said.

A comparison of opioid-associated risk for all-cause mortality vs. NSAIDs according to type (nonselective or selective) showed that most of the increase in risk was relative to selective cycloxygenase-2 inhibitors.

‘Beautiful’ analysis

“This is a beautiful piece of analysis on a really difficult question to address because the confounding is really hard to unpick,” commented James Galloway, MBBS, deputy head of the center for rheumatic diseases at King’s College London and consulting rheumatologist at King’s College Hospital, also in London.

“The headline message is that there didn’t appear to be a clear signal that NSAIDs were worse, which is what I thought the preexisting view might have been. And so, people may have paradoxically prescribed opioids in favor of NSAIDs in a person with cardiovascular risk,” he said in an interview. Dr. Galloway attended the oral abstract session but was not involved in the study.

The study was supported by a grant to Dr. Ozen from the Rheumatology Research Foundation. Dr. Galloway reported having no relevant disclosures.

PHILADELPHIA – For patients with rheumatoid arthritis who are already at increased risk for major adverse cardiovascular events (MACE), NSAIDs may be safer than opioids, results of a new-user active comparator study suggest.

Among 6,866 patients with RA who started on opioids and 13,698 patients who started on NSAIDs for pain, the use of both weak and strong opioids was associated with a 33% increase in risk for all-cause mortality and a trend toward higher rates of venous thromboembolism (VTE), compared with NSAID use, reported Gulsen Ozen, MD, of the University of Nebraska Medical Center, Omaha.

Neil Osterweil/MDedge News

“Pain in RA is a very complex process, and we know that it’s not solely dependent on the disease activity, but there is no evidence that opioids have any benefit in long-term pain management, and it can even cause hyperalgesia. And as we show, it’s not safer than NSAIDs,” she said in an oral abstract session at the annual meeting of the American College of Rheumatology.

She stressed that patients should be assessed for non-RA causes of pain and should use nonpharmacologic methods when possible.

“If a pharmacological treatment is needed and NSAIDs are contraindicated, the lowest possible dose of weak opioids can be used for a very limited time for acute pain only,” she said.
 

Pain despite disease control

Even when their disease is well controlled, approximately 60% of patients with RA still report pain. NSAIDs are commonly used to treat pain in patients with RA, but they are associated with modest increases in risk for cardiovascular disease (CVD), gastrointestinal bleeding, renal injury, and hypertension.

Some providers are leery of NSAIDs and will instead prescribe either regular or intermittent opioids for pain control in their patients.

Disease-modifying antirheumatic drugs have only minimal pain-relieving benefits, “and even worse, opioids can delay initiation of DMARDs in RA,” Dr. Ozen said.

Opioids have been shown to increase oxidative stress, platelet aggregation, and myocardial fibrosis, as well as hypogonadism, weight gain, and CVD risk factors.

There is little evidence, however, on whether opioids are associated with cardiovascular events in patients with RA. This dearth of data prompted Dr. Ozen and colleagues to study the relative risks for MACE in patients with RA starting on opioids or NSAIDs for pain.

Matched cohorts

They used data from FORWARD, a joint Canadian and U.S. databank for rheumatic diseases, to conduct a new-user active comparator cohort study. The cohort included adults with RA without cancer who participated in FORWARD for a minimum of 1 year between 1998 and 2021.

The patients were followed either from drug initiation until 3 months after the end of treatment, defined as either discontinuation or a switch to a different analgesic, end of study follow-up, or the development of a MACE outcome.

The investigators used propensity score matching to compare each opioid initiator with two NSAID initiators. The participants were matched by age, sex, body mass index, smoking, alcohol, RA duration, disease activity, Health Assessment Questionnaire, visual analog scale for pain, joint surgeries, prior CVD and VTE, hypertension, diabetes, rheumatic diseases comorbidity index, osteoporosis/fractures, thyroid, chronic liver, kidney, lung and mental health diseases, hospitalizations, 36-Item Short Form Health Survey scores, and sleep scores.

The two groups were well matched, except for a slightly higher incidence of VTE in opioid initiators, although incidence rates were low in both groups (0.9% vs. 0.6% of NSAID initiators).
 

Higher death rate in opioid users

The incidence rate of MACE among opioid initiators was 20.6% versus18.9% among NSAID initiators, a difference that was not statistically significant. There were also no significant differences in incidence rates of the individual components of the MACE composite outcome: myocardial infarction, stroke, heart failure, CVD death, or VTE.

There were, however, significantly more deaths from any cause among patients in the opioid group, with an incidence rate of 13.5% versus 10.8% in the NSAID group.

An analysis of the associaion of drug type with outcomes, adjusted for propensity score weight and prior VTE showed that patients on opioids had a statistically significant hazard ratio for death from any cause of 1.33 (95% confidence interval, 1.06-1.67).

The increased risk for all-cause mortality occurred both in patients starting on weak opioids (hydrocodone, tramadol, codeine, pentazocine, and propoxyphene) and on strong opioids (hydromorphone, dihydromorphinone, oxymorphone, butorphanol, methadone, morphine, oxycodone, meperidine, and fentanyl).

As noted before, there was a trend toward an increased risk for VTE among opioid initiators, but this was not statistically significant.

The increase in risk was higher among patients on strong versus weak opioids, suggesting a dose-dependent relationship, Dr. Ozen said.

A comparison of opioid-associated risk for all-cause mortality vs. NSAIDs according to type (nonselective or selective) showed that most of the increase in risk was relative to selective cycloxygenase-2 inhibitors.

‘Beautiful’ analysis

“This is a beautiful piece of analysis on a really difficult question to address because the confounding is really hard to unpick,” commented James Galloway, MBBS, deputy head of the center for rheumatic diseases at King’s College London and consulting rheumatologist at King’s College Hospital, also in London.

“The headline message is that there didn’t appear to be a clear signal that NSAIDs were worse, which is what I thought the preexisting view might have been. And so, people may have paradoxically prescribed opioids in favor of NSAIDs in a person with cardiovascular risk,” he said in an interview. Dr. Galloway attended the oral abstract session but was not involved in the study.

The study was supported by a grant to Dr. Ozen from the Rheumatology Research Foundation. Dr. Galloway reported having no relevant disclosures.

Boston dietitian Katarina Mollo, MEd, RDN, LDN, has virtually no memory of life without celiac disease (CD). Diagnosed at age 4, Dr. Mollo has been on a gluten-free diet for 41 years, which she says has kept her healthy and may also be why she hasn’t developed other autoimmune diseases. It’s also played a part in her thinking about screening patients with CD.

“I think [physicians] should definitely be screening people with celiac disease for autoimmune disorders, especially if they see things like anemia or if a child has dropped on the growth chart and has nutrient deficiencies,” said Dr. Mollo, whose daughter also has the disease. “I would recommend that they see someone who specializes in celiac disease so they can get monitored and have regular follow-up checks for nutrient deficiencies and other autoimmune disorders.”

Dr. Mollo’s views on screening are echoed by many CD specialists and physicians, who cite multiple studies that have found that people with the disease face higher risks for diabetes, thyroid conditions, arthritis, and other autoimmune disorders.

Gastroenterologist Alessio Fasano, MD, with Massachusetts General Hospital, Boston, said there has been a “shift in the paradigm in thinking” about cross-screening for CD and autoimmune disorders. As result, he believes the answer to the question of whether to routinely do so is a no-brainer.

“The bottom line is, if you have CD, it [should be] routine that during your annual follow-ups you check for the possibility of the onset of other autoimmune disease. And people with other autoimmune diseases, like type 1 diabetes, should also be screened for CD because of the comorbidity,” said Dr. Fasano, professor of pediatrics and gastroenterology at Harvard Medical School and professor of nutrition at the Harvard School of Public Health, both in Boston. “This is what we call good clinical practice.”
 

Screening, despite lack of consensus guidelines

Other CD specialists differ on the need for universal cross-screening but agree that, at least in some cases, people with one autoimmune disorder should be tested for others.

Jolanda Denham, MD, a pediatric gastroenterologist affiliated with Nemours Children’s Hospital in Orlando, routinely recommends that her patients with CD be screened for certain autoimmune disorders – such as type 1 diabetes and autoimmune thyroid and liver diseases – even though medical organizations have not developed clear consensus or standard guidelines on cross-screening.

“There currently is no evidence to support the screening of celiac patients for all autoimmune and rheumatologic disorders,” she said. “It is true that celiac disease is an autoimmune disorder, and as such, there is a definite increased risk of these disorders in patients with celiac disease and vice versa.”

Echoing Dr. Denham, New York–based gastroenterologist Benjamin Lebwohl, MD, president of the Society for the Study of Celiac Disease, urges physicians to look beyond consensus guidelines and to err on the side of caution and make the best decisions for their patients on a case-by-case basis.

“Given the increased risk of certain autoimmune conditions in people with celiac disease, it behooves physicians to have a low threshold to evaluate for these conditions if any suggestive symptoms are present,” said Dr. Lebwohl, director of clinical research at the Celiac Disease Center at Columbia University, New York.

“Whether to screen for these conditions among people who are entirely without symptoms is less certain, and there is no consensus on that. But it is reasonable and common to include some basic tests with annual blood work, such as thyroid function and a liver profile, since both autoimmune thyroid disease and autoimmune liver disease can be silent early on and the patient would potentially benefit from identification and treatment of these conditions,” he said.

The American Diabetes Association and the International Society of Pediatric and Adolescent Diabetes do recommend that people with diabetes be screened for CD years after diagnosis, noted Robert Rapaport, MD, a pediatric endocrinologist, with Kravis Children’s Hospital, New York. But in a study published in 2021, he and colleagues found that this wasn’t occurring, which prompted them to recommend yearly screening.

“There is a consensus that in children with type 1 diabetes, we screen them for other autoimmune disorders, specifically for thyroid disease and celiac disease,” said Dr. Rapaport, who is also Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes at Icahn School of Medicine at Mount Sinai, New York. “But there is no consensus going the other way – for patients with celiac disease, what other autoimmune conditions they should be screened for.”

This hasn’t kept some doctors from extending cross-screening efforts to their patients.

“At our center, we screen ... for thyroid disease and autoimmune liver disease as part of routine healthcare maintenance for our celiac disease patients. We discuss symptoms of diabetes and send screening with [hemoglobin] A1c for anyone who has symptoms,” said Lui Edwin, MD, a pediatric gastroenterologist with Children’s Hospital Colorado, Aurora, and director of the Colorado Center for Celiac Disease, who delivered a lecture on CD-autoimmune screening at the International Celiac Disease Symposium in October.

“It is definitely worth screening for celiac disease in [those with] other autoimmune disorders,” Dr. Edwin added.

“The symptoms can be very heterogeneous. Diagnosing and treating celiac disease can make a huge impact with respect to symptoms, quality of life, and preventing disease-related complications,” he said.
 

Mounting evidence linking CD to autoimmune disorders

Many studies have linked CD to a variety of other autoimmune disorders. The association could be due to common genetic factors or because CD might lead to such conditions. Researchers have found that people diagnosed with CD later in life are more likely to develop other autoimmune disorders.

Going gluten free has preventive advantages

In a landmark 2012 study, researchers with the Celiac Disease Center at Columbia University stopped short of recommending routine screening for the general public or asymptomatic individuals in high-prevalence groups. But they concluded that more screening of symptomatic individuals – and close relatives – would speed treatment for those with more than one autoimmune disorder.

They also noted that some studies have found that a gluten-free diet might help prevent the development of other autoimmune disorders.

Marisa Gallant Stahl, MD, a gastroenterologist with Children’s Hospital Colorado, agreed that it is important that physicians keep gluten-free diets in mind when determining which patients to cross-screen.

“The literature is mixed, but some studies suggest that treating celiac disease with a gluten-free diet actually augments the treatment and control of other autoimmune disorders [and] adherence to a gluten-free diet does reduce the risk of cancer associated with celiac disease,” she said.

Dr. Denham agreed. “Strict adherence to a gluten-free diet definitely protects against the development of enteropathy-associated T-cell lymphoma but may be protective against non-Hodgkin’s lymphoma and adenocarcinoma of the small intestine as well. All three are associated with long-term nonadherence to a gluten-free diet.”

She also noted that a gluten-free diet may help people with CD manage other autoimmune disorders, which can be complicated by CD.

“Good control of celiac disease will help prevent complications that can worsen symptoms and outcomes of concomitant autoimmune and rheumatologic disorders,” she said.
 

Other factors to consider

Dr. Fasano added that autoimmune disorders can be complicated by CD in cases in which oral medications or healthful foods are not properly absorbed in the intestines.

“For example, with Hashimoto’s disease, if you have hormone replacement with oral treatments and your intestines are not 100% functional because you have inflammation, then you may have a problem [with] the absorption of medications like levothyroxine,” he said.

“It’s the same story with diabetes. You don’t take insulin by mouth, but glucose [control] strongly depends on several factors, mostly what comes from the diet, and if it’s erratic, that can be a problem. ... So, the treatment of autoimmune diseases can be influenced by celiac disease,” he said.

In addition, Dr. Fasano and others believe that people with CD and other autoimmune disorders should be managed by a team of experts who can personalize the care on the basis of specific needs of the individual patient. These should include specialists, dietitians, mental health counselors, and family social workers.

“It has to be a multidisciplinary approach to maintain the good health of an individual,” Dr. Fasano said. “Celiac disease is the quintessential example in which the primary care physician needs to be the quarterback of the team, the patient is active in his or her health, and [specialists] not only deliver personalized care but also preventive intervention, particularly the prevention of comorbidities.”

Financial disclosures for those quoted in this article were not available at the time of publication.

A version of this article first appeared on Medscape.com.

Boston dietitian Katarina Mollo, MEd, RDN, LDN, has virtually no memory of life without celiac disease (CD). Diagnosed at age 4, Dr. Mollo has been on a gluten-free diet for 41 years, which she says has kept her healthy and may also be why she hasn’t developed other autoimmune diseases. It’s also played a part in her thinking about screening patients with CD.

“I think [physicians] should definitely be screening people with celiac disease for autoimmune disorders, especially if they see things like anemia or if a child has dropped on the growth chart and has nutrient deficiencies,” said Dr. Mollo, whose daughter also has the disease. “I would recommend that they see someone who specializes in celiac disease so they can get monitored and have regular follow-up checks for nutrient deficiencies and other autoimmune disorders.”

Dr. Mollo’s views on screening are echoed by many CD specialists and physicians, who cite multiple studies that have found that people with the disease face higher risks for diabetes, thyroid conditions, arthritis, and other autoimmune disorders.

Gastroenterologist Alessio Fasano, MD, with Massachusetts General Hospital, Boston, said there has been a “shift in the paradigm in thinking” about cross-screening for CD and autoimmune disorders. As result, he believes the answer to the question of whether to routinely do so is a no-brainer.

“The bottom line is, if you have CD, it [should be] routine that during your annual follow-ups you check for the possibility of the onset of other autoimmune disease. And people with other autoimmune diseases, like type 1 diabetes, should also be screened for CD because of the comorbidity,” said Dr. Fasano, professor of pediatrics and gastroenterology at Harvard Medical School and professor of nutrition at the Harvard School of Public Health, both in Boston. “This is what we call good clinical practice.”
 

Screening, despite lack of consensus guidelines

Other CD specialists differ on the need for universal cross-screening but agree that, at least in some cases, people with one autoimmune disorder should be tested for others.

Jolanda Denham, MD, a pediatric gastroenterologist affiliated with Nemours Children’s Hospital in Orlando, routinely recommends that her patients with CD be screened for certain autoimmune disorders – such as type 1 diabetes and autoimmune thyroid and liver diseases – even though medical organizations have not developed clear consensus or standard guidelines on cross-screening.

“There currently is no evidence to support the screening of celiac patients for all autoimmune and rheumatologic disorders,” she said. “It is true that celiac disease is an autoimmune disorder, and as such, there is a definite increased risk of these disorders in patients with celiac disease and vice versa.”

Echoing Dr. Denham, New York–based gastroenterologist Benjamin Lebwohl, MD, president of the Society for the Study of Celiac Disease, urges physicians to look beyond consensus guidelines and to err on the side of caution and make the best decisions for their patients on a case-by-case basis.

“Given the increased risk of certain autoimmune conditions in people with celiac disease, it behooves physicians to have a low threshold to evaluate for these conditions if any suggestive symptoms are present,” said Dr. Lebwohl, director of clinical research at the Celiac Disease Center at Columbia University, New York.

“Whether to screen for these conditions among people who are entirely without symptoms is less certain, and there is no consensus on that. But it is reasonable and common to include some basic tests with annual blood work, such as thyroid function and a liver profile, since both autoimmune thyroid disease and autoimmune liver disease can be silent early on and the patient would potentially benefit from identification and treatment of these conditions,” he said.

The American Diabetes Association and the International Society of Pediatric and Adolescent Diabetes do recommend that people with diabetes be screened for CD years after diagnosis, noted Robert Rapaport, MD, a pediatric endocrinologist, with Kravis Children’s Hospital, New York. But in a study published in 2021, he and colleagues found that this wasn’t occurring, which prompted them to recommend yearly screening.

“There is a consensus that in children with type 1 diabetes, we screen them for other autoimmune disorders, specifically for thyroid disease and celiac disease,” said Dr. Rapaport, who is also Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes at Icahn School of Medicine at Mount Sinai, New York. “But there is no consensus going the other way – for patients with celiac disease, what other autoimmune conditions they should be screened for.”

This hasn’t kept some doctors from extending cross-screening efforts to their patients.

“At our center, we screen ... for thyroid disease and autoimmune liver disease as part of routine healthcare maintenance for our celiac disease patients. We discuss symptoms of diabetes and send screening with [hemoglobin] A1c for anyone who has symptoms,” said Lui Edwin, MD, a pediatric gastroenterologist with Children’s Hospital Colorado, Aurora, and director of the Colorado Center for Celiac Disease, who delivered a lecture on CD-autoimmune screening at the International Celiac Disease Symposium in October.

“It is definitely worth screening for celiac disease in [those with] other autoimmune disorders,” Dr. Edwin added.

“The symptoms can be very heterogeneous. Diagnosing and treating celiac disease can make a huge impact with respect to symptoms, quality of life, and preventing disease-related complications,” he said.
 

Mounting evidence linking CD to autoimmune disorders

Many studies have linked CD to a variety of other autoimmune disorders. The association could be due to common genetic factors or because CD might lead to such conditions. Researchers have found that people diagnosed with CD later in life are more likely to develop other autoimmune disorders.

Going gluten free has preventive advantages

In a landmark 2012 study, researchers with the Celiac Disease Center at Columbia University stopped short of recommending routine screening for the general public or asymptomatic individuals in high-prevalence groups. But they concluded that more screening of symptomatic individuals – and close relatives – would speed treatment for those with more than one autoimmune disorder.

They also noted that some studies have found that a gluten-free diet might help prevent the development of other autoimmune disorders.

Marisa Gallant Stahl, MD, a gastroenterologist with Children’s Hospital Colorado, agreed that it is important that physicians keep gluten-free diets in mind when determining which patients to cross-screen.

“The literature is mixed, but some studies suggest that treating celiac disease with a gluten-free diet actually augments the treatment and control of other autoimmune disorders [and] adherence to a gluten-free diet does reduce the risk of cancer associated with celiac disease,” she said.

Dr. Denham agreed. “Strict adherence to a gluten-free diet definitely protects against the development of enteropathy-associated T-cell lymphoma but may be protective against non-Hodgkin’s lymphoma and adenocarcinoma of the small intestine as well. All three are associated with long-term nonadherence to a gluten-free diet.”

She also noted that a gluten-free diet may help people with CD manage other autoimmune disorders, which can be complicated by CD.

“Good control of celiac disease will help prevent complications that can worsen symptoms and outcomes of concomitant autoimmune and rheumatologic disorders,” she said.
 

Other factors to consider

Dr. Fasano added that autoimmune disorders can be complicated by CD in cases in which oral medications or healthful foods are not properly absorbed in the intestines.

“For example, with Hashimoto’s disease, if you have hormone replacement with oral treatments and your intestines are not 100% functional because you have inflammation, then you may have a problem [with] the absorption of medications like levothyroxine,” he said.

“It’s the same story with diabetes. You don’t take insulin by mouth, but glucose [control] strongly depends on several factors, mostly what comes from the diet, and if it’s erratic, that can be a problem. ... So, the treatment of autoimmune diseases can be influenced by celiac disease,” he said.

In addition, Dr. Fasano and others believe that people with CD and other autoimmune disorders should be managed by a team of experts who can personalize the care on the basis of specific needs of the individual patient. These should include specialists, dietitians, mental health counselors, and family social workers.

“It has to be a multidisciplinary approach to maintain the good health of an individual,” Dr. Fasano said. “Celiac disease is the quintessential example in which the primary care physician needs to be the quarterback of the team, the patient is active in his or her health, and [specialists] not only deliver personalized care but also preventive intervention, particularly the prevention of comorbidities.”

Financial disclosures for those quoted in this article were not available at the time of publication.

A version of this article first appeared on Medscape.com.

Boston dietitian Katarina Mollo, MEd, RDN, LDN, has virtually no memory of life without celiac disease (CD). Diagnosed at age 4, Dr. Mollo has been on a gluten-free diet for 41 years, which she says has kept her healthy and may also be why she hasn’t developed other autoimmune diseases. It’s also played a part in her thinking about screening patients with CD.

“I think [physicians] should definitely be screening people with celiac disease for autoimmune disorders, especially if they see things like anemia or if a child has dropped on the growth chart and has nutrient deficiencies,” said Dr. Mollo, whose daughter also has the disease. “I would recommend that they see someone who specializes in celiac disease so they can get monitored and have regular follow-up checks for nutrient deficiencies and other autoimmune disorders.”

Dr. Mollo’s views on screening are echoed by many CD specialists and physicians, who cite multiple studies that have found that people with the disease face higher risks for diabetes, thyroid conditions, arthritis, and other autoimmune disorders.

Gastroenterologist Alessio Fasano, MD, with Massachusetts General Hospital, Boston, said there has been a “shift in the paradigm in thinking” about cross-screening for CD and autoimmune disorders. As result, he believes the answer to the question of whether to routinely do so is a no-brainer.

“The bottom line is, if you have CD, it [should be] routine that during your annual follow-ups you check for the possibility of the onset of other autoimmune disease. And people with other autoimmune diseases, like type 1 diabetes, should also be screened for CD because of the comorbidity,” said Dr. Fasano, professor of pediatrics and gastroenterology at Harvard Medical School and professor of nutrition at the Harvard School of Public Health, both in Boston. “This is what we call good clinical practice.”
 

Screening, despite lack of consensus guidelines

Other CD specialists differ on the need for universal cross-screening but agree that, at least in some cases, people with one autoimmune disorder should be tested for others.

Jolanda Denham, MD, a pediatric gastroenterologist affiliated with Nemours Children’s Hospital in Orlando, routinely recommends that her patients with CD be screened for certain autoimmune disorders – such as type 1 diabetes and autoimmune thyroid and liver diseases – even though medical organizations have not developed clear consensus or standard guidelines on cross-screening.

“There currently is no evidence to support the screening of celiac patients for all autoimmune and rheumatologic disorders,” she said. “It is true that celiac disease is an autoimmune disorder, and as such, there is a definite increased risk of these disorders in patients with celiac disease and vice versa.”

Echoing Dr. Denham, New York–based gastroenterologist Benjamin Lebwohl, MD, president of the Society for the Study of Celiac Disease, urges physicians to look beyond consensus guidelines and to err on the side of caution and make the best decisions for their patients on a case-by-case basis.

“Given the increased risk of certain autoimmune conditions in people with celiac disease, it behooves physicians to have a low threshold to evaluate for these conditions if any suggestive symptoms are present,” said Dr. Lebwohl, director of clinical research at the Celiac Disease Center at Columbia University, New York.

“Whether to screen for these conditions among people who are entirely without symptoms is less certain, and there is no consensus on that. But it is reasonable and common to include some basic tests with annual blood work, such as thyroid function and a liver profile, since both autoimmune thyroid disease and autoimmune liver disease can be silent early on and the patient would potentially benefit from identification and treatment of these conditions,” he said.

The American Diabetes Association and the International Society of Pediatric and Adolescent Diabetes do recommend that people with diabetes be screened for CD years after diagnosis, noted Robert Rapaport, MD, a pediatric endocrinologist, with Kravis Children’s Hospital, New York. But in a study published in 2021, he and colleagues found that this wasn’t occurring, which prompted them to recommend yearly screening.

“There is a consensus that in children with type 1 diabetes, we screen them for other autoimmune disorders, specifically for thyroid disease and celiac disease,” said Dr. Rapaport, who is also Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes at Icahn School of Medicine at Mount Sinai, New York. “But there is no consensus going the other way – for patients with celiac disease, what other autoimmune conditions they should be screened for.”

This hasn’t kept some doctors from extending cross-screening efforts to their patients.

“At our center, we screen ... for thyroid disease and autoimmune liver disease as part of routine healthcare maintenance for our celiac disease patients. We discuss symptoms of diabetes and send screening with [hemoglobin] A1c for anyone who has symptoms,” said Lui Edwin, MD, a pediatric gastroenterologist with Children’s Hospital Colorado, Aurora, and director of the Colorado Center for Celiac Disease, who delivered a lecture on CD-autoimmune screening at the International Celiac Disease Symposium in October.

“It is definitely worth screening for celiac disease in [those with] other autoimmune disorders,” Dr. Edwin added.

“The symptoms can be very heterogeneous. Diagnosing and treating celiac disease can make a huge impact with respect to symptoms, quality of life, and preventing disease-related complications,” he said.
 

Mounting evidence linking CD to autoimmune disorders

Many studies have linked CD to a variety of other autoimmune disorders. The association could be due to common genetic factors or because CD might lead to such conditions. Researchers have found that people diagnosed with CD later in life are more likely to develop other autoimmune disorders.

Going gluten free has preventive advantages

In a landmark 2012 study, researchers with the Celiac Disease Center at Columbia University stopped short of recommending routine screening for the general public or asymptomatic individuals in high-prevalence groups. But they concluded that more screening of symptomatic individuals – and close relatives – would speed treatment for those with more than one autoimmune disorder.

They also noted that some studies have found that a gluten-free diet might help prevent the development of other autoimmune disorders.

Marisa Gallant Stahl, MD, a gastroenterologist with Children’s Hospital Colorado, agreed that it is important that physicians keep gluten-free diets in mind when determining which patients to cross-screen.

“The literature is mixed, but some studies suggest that treating celiac disease with a gluten-free diet actually augments the treatment and control of other autoimmune disorders [and] adherence to a gluten-free diet does reduce the risk of cancer associated with celiac disease,” she said.

Dr. Denham agreed. “Strict adherence to a gluten-free diet definitely protects against the development of enteropathy-associated T-cell lymphoma but may be protective against non-Hodgkin’s lymphoma and adenocarcinoma of the small intestine as well. All three are associated with long-term nonadherence to a gluten-free diet.”

She also noted that a gluten-free diet may help people with CD manage other autoimmune disorders, which can be complicated by CD.

“Good control of celiac disease will help prevent complications that can worsen symptoms and outcomes of concomitant autoimmune and rheumatologic disorders,” she said.
 

Other factors to consider

Dr. Fasano added that autoimmune disorders can be complicated by CD in cases in which oral medications or healthful foods are not properly absorbed in the intestines.

“For example, with Hashimoto’s disease, if you have hormone replacement with oral treatments and your intestines are not 100% functional because you have inflammation, then you may have a problem [with] the absorption of medications like levothyroxine,” he said.

“It’s the same story with diabetes. You don’t take insulin by mouth, but glucose [control] strongly depends on several factors, mostly what comes from the diet, and if it’s erratic, that can be a problem. ... So, the treatment of autoimmune diseases can be influenced by celiac disease,” he said.

In addition, Dr. Fasano and others believe that people with CD and other autoimmune disorders should be managed by a team of experts who can personalize the care on the basis of specific needs of the individual patient. These should include specialists, dietitians, mental health counselors, and family social workers.

“It has to be a multidisciplinary approach to maintain the good health of an individual,” Dr. Fasano said. “Celiac disease is the quintessential example in which the primary care physician needs to be the quarterback of the team, the patient is active in his or her health, and [specialists] not only deliver personalized care but also preventive intervention, particularly the prevention of comorbidities.”

Financial disclosures for those quoted in this article were not available at the time of publication.

A version of this article first appeared on Medscape.com.

PHILADELPHIA – When patients with inflammatory rheumatic diseases were switched from one biosimilar agent to another, treatment retention rates were high, investigators in Denmark reported.

The findings suggest patient-related factors rather than drug-related factors appear to determine whether patients will stay on the new drug, the researchers said.

One year after a Danish government-mandated switch from one infliximab (Remicade) biosimilar to another equally efficacious but less costly biosimilar, 83% of patients who had started therapy on a biosimilar (so-called “originator-naive” patients) stayed on the newly assigned therapy. And so did 92% of patients who had started on the original infliximab (“originator experienced”) before they were switched to one biosimilar and then another.

Neil Osterweil/MDedge News

“In regards to potential baseline predictors, we found that treatment withdrawal was more frequent among originator-naive switchers and patients with higher baseline disease activity, especially [in] patient-reported outcomes, which may indicate that treatment-related outcomes may be more affected by patient-related rather than drug-related factors,” said lead author Hafsah Nabi, MD from the Danish biosimilar registry DANBIO and a PhD candidate at the Copenhagen Center for Arthritis Research.

Dr. Nabi reported the results in an oral abstract session at the annual meeting of the American College of Rheumatology.
 

Annual review of biologic agents

In Denmark, health authorities issue annual recommendations for the use of biologic agents. “And since patients receive this treatment free from the hospital, based on the tax system, the switches are made due to these cost considerations,” Dr. Nabi said in an interview.

Neil Osterweil/MDedge News

To get the nod from Danish pharmaceutical regulators, pharmaceutical manufacturers submit drugs that have already been approved by the European Medicines Agency for consideration for treatment of specific indications, explained coauthor Merete Lund Hetland, MD, PhD, DMSc, from Rigshospitalet in Copenhagen.

“Those drugs that are then considered equally safe and effective are invited to this process where they will give their bid, and then the cheapest one will win,” she said.

The winning formulation will be able to capture about 80% of prescriptions for that indication for the coming year.
 

Awake at the switch

Dr. Nabi, Dr. Hetland, and colleagues studied how one such recent government-mandated switch from one biosimilar to another affected efficacy and patterns of care among patients with rheumatoid arthritis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA).

To identify prior comorbidities, they drew data from the DANBIO registry, which is linked to patient specific but anonymous data from other comprehensive birth-to-death patient registries in Denmark.

They looked at all patients with RA, PsA, or axSpA who were switched from CT-P13 (Remsira, Inflectra) to GP1111 (Zessly) from April 1, 2019, to Feb. 1, 2020.

They identified a total of 1,605 patients, including 685 with RA, 314 with PsA, and 606 with axSpa. The median disease duration was 9 years, and 37% of all patients were in remission according to Clinical Disease Activity Index or Ankylosing Spondylitis Disease Activity Scale.

Of this group, 1,171 had started therapy on a biosimilar.

As noted above, 83% of patients who had never received original infliximab, and 92% of those who were originator experienced were still on the new biosimilar 1 year after the switch.

In a multivariate analysis controlling for demographic and clinical factors at baseline, the variables significantly associated with treatment withdrawal from the new biosimilar (GP11110) included previous Remicade exposure (hazard ratio, 0.36), methotrexate use (HR, 0.60), and patient-reported global visual analog scale (HR, 1.02).

Among all patients, disease activity was stable 6 months before and after the switch, Dr. Nabi said, although she did not show data to support it.
 

Patient education benefit

During the session, Jonathan Kay, MD, professor of rheumatology and chair of the division of rheumatology at the University of Massachusetts, Worcester, who was not involved the study, asked Dr. Nabi whether patients were educated about equivalent efficacy and safety of biosimilars prior to the switch. He noted that education prior to switching led to a much lower patient withdrawal rate in a similar switching study conducted in The Netherlands.

“In this study, we haven’t looked more specifically into the education and which strategies have been used prior to switching, and we also conclude in the study that there may be the presence of a nocebo effect, which can be handled by better educating the patients,” she replied.

The nocebo effect refers to the phenomenon in which a patient’s belief that a specific intervention may cause harm actually can lead to negative outcomes – in other words, the opposite of the placebo effect.

In an interview, Dr. Kay said that he is confident about the efficacy, safety, and equivalency of approved biosimilar agents.

“A biosimilar that has been reviewed and approved by a regulatory agency such as the [Food and Drug Administration or the [European Medicines Agency] should be equivalent in efficacy and comparable in safety and immunogenicity. I would be fully confident in switching from the reference product to the biosimilar,” he said.

Dr. Nabi reported that the study was partly funded by a research grant from Sandoz, the maker of GP1111. Dr. Hetland has disclosed grants from various companies, not including Sandoz. Dr. Kay disclosed consulting fees from various companies, not including Sandoz.

PHILADELPHIA – When patients with inflammatory rheumatic diseases were switched from one biosimilar agent to another, treatment retention rates were high, investigators in Denmark reported.

The findings suggest patient-related factors rather than drug-related factors appear to determine whether patients will stay on the new drug, the researchers said.

One year after a Danish government-mandated switch from one infliximab (Remicade) biosimilar to another equally efficacious but less costly biosimilar, 83% of patients who had started therapy on a biosimilar (so-called “originator-naive” patients) stayed on the newly assigned therapy. And so did 92% of patients who had started on the original infliximab (“originator experienced”) before they were switched to one biosimilar and then another.

Neil Osterweil/MDedge News

“In regards to potential baseline predictors, we found that treatment withdrawal was more frequent among originator-naive switchers and patients with higher baseline disease activity, especially [in] patient-reported outcomes, which may indicate that treatment-related outcomes may be more affected by patient-related rather than drug-related factors,” said lead author Hafsah Nabi, MD from the Danish biosimilar registry DANBIO and a PhD candidate at the Copenhagen Center for Arthritis Research.

Dr. Nabi reported the results in an oral abstract session at the annual meeting of the American College of Rheumatology.
 

Annual review of biologic agents

In Denmark, health authorities issue annual recommendations for the use of biologic agents. “And since patients receive this treatment free from the hospital, based on the tax system, the switches are made due to these cost considerations,” Dr. Nabi said in an interview.

Neil Osterweil/MDedge News

To get the nod from Danish pharmaceutical regulators, pharmaceutical manufacturers submit drugs that have already been approved by the European Medicines Agency for consideration for treatment of specific indications, explained coauthor Merete Lund Hetland, MD, PhD, DMSc, from Rigshospitalet in Copenhagen.

“Those drugs that are then considered equally safe and effective are invited to this process where they will give their bid, and then the cheapest one will win,” she said.

The winning formulation will be able to capture about 80% of prescriptions for that indication for the coming year.
 

Awake at the switch

Dr. Nabi, Dr. Hetland, and colleagues studied how one such recent government-mandated switch from one biosimilar to another affected efficacy and patterns of care among patients with rheumatoid arthritis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA).

To identify prior comorbidities, they drew data from the DANBIO registry, which is linked to patient specific but anonymous data from other comprehensive birth-to-death patient registries in Denmark.

They looked at all patients with RA, PsA, or axSpA who were switched from CT-P13 (Remsira, Inflectra) to GP1111 (Zessly) from April 1, 2019, to Feb. 1, 2020.

They identified a total of 1,605 patients, including 685 with RA, 314 with PsA, and 606 with axSpa. The median disease duration was 9 years, and 37% of all patients were in remission according to Clinical Disease Activity Index or Ankylosing Spondylitis Disease Activity Scale.

Of this group, 1,171 had started therapy on a biosimilar.

As noted above, 83% of patients who had never received original infliximab, and 92% of those who were originator experienced were still on the new biosimilar 1 year after the switch.

In a multivariate analysis controlling for demographic and clinical factors at baseline, the variables significantly associated with treatment withdrawal from the new biosimilar (GP11110) included previous Remicade exposure (hazard ratio, 0.36), methotrexate use (HR, 0.60), and patient-reported global visual analog scale (HR, 1.02).

Among all patients, disease activity was stable 6 months before and after the switch, Dr. Nabi said, although she did not show data to support it.
 

Patient education benefit

During the session, Jonathan Kay, MD, professor of rheumatology and chair of the division of rheumatology at the University of Massachusetts, Worcester, who was not involved the study, asked Dr. Nabi whether patients were educated about equivalent efficacy and safety of biosimilars prior to the switch. He noted that education prior to switching led to a much lower patient withdrawal rate in a similar switching study conducted in The Netherlands.

“In this study, we haven’t looked more specifically into the education and which strategies have been used prior to switching, and we also conclude in the study that there may be the presence of a nocebo effect, which can be handled by better educating the patients,” she replied.

The nocebo effect refers to the phenomenon in which a patient’s belief that a specific intervention may cause harm actually can lead to negative outcomes – in other words, the opposite of the placebo effect.

In an interview, Dr. Kay said that he is confident about the efficacy, safety, and equivalency of approved biosimilar agents.

“A biosimilar that has been reviewed and approved by a regulatory agency such as the [Food and Drug Administration or the [European Medicines Agency] should be equivalent in efficacy and comparable in safety and immunogenicity. I would be fully confident in switching from the reference product to the biosimilar,” he said.

Dr. Nabi reported that the study was partly funded by a research grant from Sandoz, the maker of GP1111. Dr. Hetland has disclosed grants from various companies, not including Sandoz. Dr. Kay disclosed consulting fees from various companies, not including Sandoz.

PHILADELPHIA – When patients with inflammatory rheumatic diseases were switched from one biosimilar agent to another, treatment retention rates were high, investigators in Denmark reported.

The findings suggest patient-related factors rather than drug-related factors appear to determine whether patients will stay on the new drug, the researchers said.

One year after a Danish government-mandated switch from one infliximab (Remicade) biosimilar to another equally efficacious but less costly biosimilar, 83% of patients who had started therapy on a biosimilar (so-called “originator-naive” patients) stayed on the newly assigned therapy. And so did 92% of patients who had started on the original infliximab (“originator experienced”) before they were switched to one biosimilar and then another.

Neil Osterweil/MDedge News

“In regards to potential baseline predictors, we found that treatment withdrawal was more frequent among originator-naive switchers and patients with higher baseline disease activity, especially [in] patient-reported outcomes, which may indicate that treatment-related outcomes may be more affected by patient-related rather than drug-related factors,” said lead author Hafsah Nabi, MD from the Danish biosimilar registry DANBIO and a PhD candidate at the Copenhagen Center for Arthritis Research.

Dr. Nabi reported the results in an oral abstract session at the annual meeting of the American College of Rheumatology.
 

Annual review of biologic agents

In Denmark, health authorities issue annual recommendations for the use of biologic agents. “And since patients receive this treatment free from the hospital, based on the tax system, the switches are made due to these cost considerations,” Dr. Nabi said in an interview.

Neil Osterweil/MDedge News

To get the nod from Danish pharmaceutical regulators, pharmaceutical manufacturers submit drugs that have already been approved by the European Medicines Agency for consideration for treatment of specific indications, explained coauthor Merete Lund Hetland, MD, PhD, DMSc, from Rigshospitalet in Copenhagen.

“Those drugs that are then considered equally safe and effective are invited to this process where they will give their bid, and then the cheapest one will win,” she said.

The winning formulation will be able to capture about 80% of prescriptions for that indication for the coming year.
 

Awake at the switch

Dr. Nabi, Dr. Hetland, and colleagues studied how one such recent government-mandated switch from one biosimilar to another affected efficacy and patterns of care among patients with rheumatoid arthritis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA).

To identify prior comorbidities, they drew data from the DANBIO registry, which is linked to patient specific but anonymous data from other comprehensive birth-to-death patient registries in Denmark.

They looked at all patients with RA, PsA, or axSpA who were switched from CT-P13 (Remsira, Inflectra) to GP1111 (Zessly) from April 1, 2019, to Feb. 1, 2020.

They identified a total of 1,605 patients, including 685 with RA, 314 with PsA, and 606 with axSpa. The median disease duration was 9 years, and 37% of all patients were in remission according to Clinical Disease Activity Index or Ankylosing Spondylitis Disease Activity Scale.

Of this group, 1,171 had started therapy on a biosimilar.

As noted above, 83% of patients who had never received original infliximab, and 92% of those who were originator experienced were still on the new biosimilar 1 year after the switch.

In a multivariate analysis controlling for demographic and clinical factors at baseline, the variables significantly associated with treatment withdrawal from the new biosimilar (GP11110) included previous Remicade exposure (hazard ratio, 0.36), methotrexate use (HR, 0.60), and patient-reported global visual analog scale (HR, 1.02).

Among all patients, disease activity was stable 6 months before and after the switch, Dr. Nabi said, although she did not show data to support it.
 

Patient education benefit

During the session, Jonathan Kay, MD, professor of rheumatology and chair of the division of rheumatology at the University of Massachusetts, Worcester, who was not involved the study, asked Dr. Nabi whether patients were educated about equivalent efficacy and safety of biosimilars prior to the switch. He noted that education prior to switching led to a much lower patient withdrawal rate in a similar switching study conducted in The Netherlands.

“In this study, we haven’t looked more specifically into the education and which strategies have been used prior to switching, and we also conclude in the study that there may be the presence of a nocebo effect, which can be handled by better educating the patients,” she replied.

The nocebo effect refers to the phenomenon in which a patient’s belief that a specific intervention may cause harm actually can lead to negative outcomes – in other words, the opposite of the placebo effect.

In an interview, Dr. Kay said that he is confident about the efficacy, safety, and equivalency of approved biosimilar agents.

“A biosimilar that has been reviewed and approved by a regulatory agency such as the [Food and Drug Administration or the [European Medicines Agency] should be equivalent in efficacy and comparable in safety and immunogenicity. I would be fully confident in switching from the reference product to the biosimilar,” he said.

Dr. Nabi reported that the study was partly funded by a research grant from Sandoz, the maker of GP1111. Dr. Hetland has disclosed grants from various companies, not including Sandoz. Dr. Kay disclosed consulting fees from various companies, not including Sandoz.

Exercise tops the list of 28 recommendations in a guideline for integrative interventions in patients with rheumatoid arthritis developed by the American College of Rheumatology.

The guideline is specific to RA and presents integrative interventions to accompany treatment with disease-modifying antirheumatic drugs (DMARDs), according to a summary statement issued by the ACR. The summary was approved by the ACR Board of Directors on Oct. 31, and the recommendations are part of a manuscript that will be submitted for publication in both Arthritis & Rheumatology and Arthritis Care & Research.

Consistent engagement in exercise earned the only strong recommendation; the other 27 were conditional. In the exercise category, the authors offered conditional recommendations for aerobic exercise, aquatic exercise, resistance exercise, and mind-body exercise.

Three recommendations focused on diet. Notably, the recommended diet is Mediterranean style. Two other recommendations were specifically against any other formal diet and against the use of dietary supplements. “The conditional recommendation for adhering to a Mediterranean-style diet, but not other formally defined diets, to improve RA-specific outcomes may be surprising to some clinicians,” said Bryant R. England, MD, PhD, of the University of Nebraska Medical Center, Omaha, and one of the guideline’s coprincipal investigators, in a press release. “The voting panel acknowledged, however, that other health indications may exist for alternative diet and dietary supplements, which makes it crucial for clinicians and patients to engage in shared decision-making,” Dr. England said.

Nearly half of the 28 recommendations (13) focused on rehabilitation, but all were conditional. These included comprehensive occupational and physical therapy and hand therapy, as well as the use of splinting, orthoses, compression, bracing, and taping of affected areas. Other conditional recommendations supported the use of joint protection techniques, assistive devices, adaptive equipment, and/or environmental adaptations. The authors also included a conditional recommendation for vocational rehabilitation and work-site evaluations and/or modifications.

A category of additional integrative interventions included recommendations against both electrotherapy and chiropractic care. However, conditional recommendations were positive for acupuncture, massage therapy, and thermal modalities. Conditional recommendations also supported cognitive-behavioral therapy and/or mind-body strategies, and a standardized self-management program.

The guideline was developed by an interprofessional voting panel of 20 individuals with expertise in epidemiology, exercise physiology, GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology, integrative medicine, nursing, nutrition, occupational therapy, physical therapy, rheumatology, and social work, as well as three individuals who have RA. The panel developed questions, conducted a literature review, and used the GRADE approach to rate the certainty of evidence.

“These recommendations are specific to RA management, understanding that other medical indications and general health benefits may exist for many of these interventions,” the authors write in the summary statement.

The range of interventions shows both the importance of an interprofessional team–based approach to RA management and the need to engage patients in shared decision-making, they said.

A version of this article first appeared on Medscape.com.

Exercise tops the list of 28 recommendations in a guideline for integrative interventions in patients with rheumatoid arthritis developed by the American College of Rheumatology.

The guideline is specific to RA and presents integrative interventions to accompany treatment with disease-modifying antirheumatic drugs (DMARDs), according to a summary statement issued by the ACR. The summary was approved by the ACR Board of Directors on Oct. 31, and the recommendations are part of a manuscript that will be submitted for publication in both Arthritis & Rheumatology and Arthritis Care & Research.

Consistent engagement in exercise earned the only strong recommendation; the other 27 were conditional. In the exercise category, the authors offered conditional recommendations for aerobic exercise, aquatic exercise, resistance exercise, and mind-body exercise.

Three recommendations focused on diet. Notably, the recommended diet is Mediterranean style. Two other recommendations were specifically against any other formal diet and against the use of dietary supplements. “The conditional recommendation for adhering to a Mediterranean-style diet, but not other formally defined diets, to improve RA-specific outcomes may be surprising to some clinicians,” said Bryant R. England, MD, PhD, of the University of Nebraska Medical Center, Omaha, and one of the guideline’s coprincipal investigators, in a press release. “The voting panel acknowledged, however, that other health indications may exist for alternative diet and dietary supplements, which makes it crucial for clinicians and patients to engage in shared decision-making,” Dr. England said.

Nearly half of the 28 recommendations (13) focused on rehabilitation, but all were conditional. These included comprehensive occupational and physical therapy and hand therapy, as well as the use of splinting, orthoses, compression, bracing, and taping of affected areas. Other conditional recommendations supported the use of joint protection techniques, assistive devices, adaptive equipment, and/or environmental adaptations. The authors also included a conditional recommendation for vocational rehabilitation and work-site evaluations and/or modifications.

A category of additional integrative interventions included recommendations against both electrotherapy and chiropractic care. However, conditional recommendations were positive for acupuncture, massage therapy, and thermal modalities. Conditional recommendations also supported cognitive-behavioral therapy and/or mind-body strategies, and a standardized self-management program.

The guideline was developed by an interprofessional voting panel of 20 individuals with expertise in epidemiology, exercise physiology, GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology, integrative medicine, nursing, nutrition, occupational therapy, physical therapy, rheumatology, and social work, as well as three individuals who have RA. The panel developed questions, conducted a literature review, and used the GRADE approach to rate the certainty of evidence.

“These recommendations are specific to RA management, understanding that other medical indications and general health benefits may exist for many of these interventions,” the authors write in the summary statement.

The range of interventions shows both the importance of an interprofessional team–based approach to RA management and the need to engage patients in shared decision-making, they said.

A version of this article first appeared on Medscape.com.

Exercise tops the list of 28 recommendations in a guideline for integrative interventions in patients with rheumatoid arthritis developed by the American College of Rheumatology.

The guideline is specific to RA and presents integrative interventions to accompany treatment with disease-modifying antirheumatic drugs (DMARDs), according to a summary statement issued by the ACR. The summary was approved by the ACR Board of Directors on Oct. 31, and the recommendations are part of a manuscript that will be submitted for publication in both Arthritis & Rheumatology and Arthritis Care & Research.

Consistent engagement in exercise earned the only strong recommendation; the other 27 were conditional. In the exercise category, the authors offered conditional recommendations for aerobic exercise, aquatic exercise, resistance exercise, and mind-body exercise.

Three recommendations focused on diet. Notably, the recommended diet is Mediterranean style. Two other recommendations were specifically against any other formal diet and against the use of dietary supplements. “The conditional recommendation for adhering to a Mediterranean-style diet, but not other formally defined diets, to improve RA-specific outcomes may be surprising to some clinicians,” said Bryant R. England, MD, PhD, of the University of Nebraska Medical Center, Omaha, and one of the guideline’s coprincipal investigators, in a press release. “The voting panel acknowledged, however, that other health indications may exist for alternative diet and dietary supplements, which makes it crucial for clinicians and patients to engage in shared decision-making,” Dr. England said.

Nearly half of the 28 recommendations (13) focused on rehabilitation, but all were conditional. These included comprehensive occupational and physical therapy and hand therapy, as well as the use of splinting, orthoses, compression, bracing, and taping of affected areas. Other conditional recommendations supported the use of joint protection techniques, assistive devices, adaptive equipment, and/or environmental adaptations. The authors also included a conditional recommendation for vocational rehabilitation and work-site evaluations and/or modifications.

A category of additional integrative interventions included recommendations against both electrotherapy and chiropractic care. However, conditional recommendations were positive for acupuncture, massage therapy, and thermal modalities. Conditional recommendations also supported cognitive-behavioral therapy and/or mind-body strategies, and a standardized self-management program.

The guideline was developed by an interprofessional voting panel of 20 individuals with expertise in epidemiology, exercise physiology, GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology, integrative medicine, nursing, nutrition, occupational therapy, physical therapy, rheumatology, and social work, as well as three individuals who have RA. The panel developed questions, conducted a literature review, and used the GRADE approach to rate the certainty of evidence.

“These recommendations are specific to RA management, understanding that other medical indications and general health benefits may exist for many of these interventions,” the authors write in the summary statement.

The range of interventions shows both the importance of an interprofessional team–based approach to RA management and the need to engage patients in shared decision-making, they said.

A version of this article first appeared on Medscape.com.

The incidence of dementia in patients with rheumatoid arthritis who took either a biologic disease-modifying antirheumatic drug (bDMARD) or targeted synthetic DMARD (tsDMARD) was significantly lower than the rate observed in patients who take only a conventional synthetic DMARD (csDMARD) in a national database study.

The work builds on previous research indicating a higher risk of Alzheimer’s disease and related dementias in people with RA. While joint pain and swelling are the cardinal symptoms of RA, its systemic inflammation leads to multiple systemic manifestations, offering biologically plausible links with cognitive decline. In addition, patients with RA have high prevalence of cardiovascular disease, diabetes, depression, disability, and physical inactivity, all of which are risk factors for dementia.

Chronic neuroinflammation secondary to either intrinsic or systemic stimuli is thought to play a key role in dementia development, especially Alzheimer’s dementia (AD). Research showing a role of tumor necrosis factor–alpha (TNF-alpha) in the development of dementia has piqued interest in a potential protective effect of TNF inhibitors. “TNF-alpha is thought to have an important role in different stages of the pathophysiology and disease progression of Alzheimer’s disease,” study first author Sebastian E. Sattui, MD, assistant professor of medicine at the University of Pittsburgh and director of the University of Pittsburgh Vasculitis Center, said in an interview. “Animal models have shown that TNF inhibition reduces microgliosis, neuronal loss, and tau phosphorylation. Cognitive improvement has been seen in two trials with Alzheimer’s disease patients, but were not in rheumatoid arthritis patients.”

In the newest study, published online in Seminars in Arthritis and Rheumatism, Dr. Sattui and colleagues suggest that a lower risk for dementia seen with bDMARDs and tsDMARDs may be attributable to an overall greater decrease in inflammation rather than any mechanism of action specific to these drugs.

In the study of Centers for Medicare & Medicaid Services claims during 2006-2017 for 141,326 adult patients with RA, the crude incident rates were 2.0 per 100 person-years (95% confidence interval, 1.9-2.1) for patients on csDMARDs and 1.3 (95% CI, 1.2-1.4) for patients on any b/tsDMARD. There were 3,794 cases of incident dementia during follow-up among 233,271 initiations of any DMARD. The adjusted risk for dementia among users of bDMARDs or tsDMARDs was 19% lower than the adjusted risk for patients on csDMARDs (hazard ratio, 0.81; 95% CI, 0.76-0.87). No significant differences were found between classes of bDMARDs or tsDMARDs.

Dr. Sattui and coauthors’ investigation included adults aged at least 40 years with two RA diagnoses by a rheumatologist more than 7 and less than 365 days apart. Those with prior dementia diagnoses were excluded. Their analysis found the risk of incident dementia to be comparable between patients receiving TNF inhibitors (HR, 0.86; 95% CI, 0.80-0.93), non-TNFi bDMARDs (HR, 0.76; 95% CI, 0.70-0.83), and tsDMARDs (HR, 0.69; 95% CI, 0.53-0.90), with csDMARDs as the referent. A second subgroup analysis looking at patients with prior methotrexate use who were taking bDMARDs or tsDMARDs revealed similar decreases in risk of incident dementia, compared with patients taking bDMARDs or tsDMARDs along with methotrexate at baseline.

“NSAIDs and glucocorticoids have been studied in RCTs [randomized, controlled trials],” Dr. Sattui said in the interview. “Despite initial observational data that showed some signal for improvement, no benefit was observed in either of the RCTs. Other agents with possible anti-inflammatory effects and more benign profiles, such as curcumin, are being studied. There are also ongoing trials looking into the use of JAK [Janus kinase] inhibitors or [interleukin]-1 inhibition in dementia.”

He added: “There is a need to better study the association between cognition and disease activity, as well as treat-to-target strategies, prospectively in patients with RA. It is important to also acknowledge that any of these findings might be just specific for RA, so extrapolation to non-RA individuals might be limited.”

In commenting on the findings of the study, Rishi J. Desai, PhD, assistant professor of medicine in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston, said that “superior inflammation control with biologics or targeted DMARDs is an interesting hypothesis explaining the observed findings. It merits further investigation and replication in diverse populations.” He added: “It should be noted that a key challenge in evaluating this hypothesis using insurance claims data is unavailability of some important factors such as socioeconomic status and patient frailty. These may be driving treatment selection between conventional DMARDs, which are cheaper with more benign adverse-event profiles, and biologic or targeted DMARDs, which are more expensive with a less favorable adverse-event profile.”
 

Prior research

Several studies have investigated the effect of DMARDs, including bDMARDs like tumor necrosis factor inhibitors, on incident dementia in patients with RA.

Among this research is a study by Dr. Desai and colleagues that looked at comparative risk of AD and related dementia in 22,569 Medicare beneficiaries receiving tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors in comparison with abatacept (a T-cell activation inhibitor). No differentiating risk associations were found in this cohort study.

Other past studies include:

• A study comparing about 21,000 patients with RA and a non-RA cohort of about 62,000 found a 37% reduction in dementia development among RA patients receiving DMARDs. The effect was dose dependent, greater with high cumulative dosages, and was found in both men and women and in subgroups younger and older than 65 years.
• A retrospective study of electronic health records from 56 million adult patients identified a subset of patients with RA, psoriasis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease in whom systemic inflammation increased risk for AD through a mechanism involving TNF. The risk for AD in patients was lowered by treatment with etanercept, adalimumab, infliximab, or methotrexate, with larger reductions observed in younger patients than in older patients receiving TNF blockers.
• A propensity score–matched retrospective cohort study in 2,510 U.S. veterans with RA found that use of a TNF inhibitor reduced the risk of dementia by 36%, compared with control patients (HR, 0.64; 95% CI, 0.52-0.80), and the effect was consistent over 5-20 years post RA diagnosis.
• In a retrospective, multinational, matched, case-control study of patients older than 50 years with RA, prior methotrexate use was associated with lower dementia risk (OR, 0.71; 95% CI, 0.52-0.98). Use of methotrexate longer than 4 years demonstrated the lowest dementia risk (odds ratio, 0.37; 95% CI, 0.17-0.79).

These past studies, Dr. Sattui and colleagues pointed out, have multiple shortcomings, including case-control design, different definitions of exposure or outcomes, and inadequate control of confounders, underscoring the need for more rigorous studies.

Several authors of the CMS claims study disclosed research support, grants, and consulting fees from pharmaceutical companies. The research was supported by a grant from the National Institutes of Health. Dr. Desai disclosed that he has received funding from the National Institute on Aging for drug repurposing studies of dementia.

The incidence of dementia in patients with rheumatoid arthritis who took either a biologic disease-modifying antirheumatic drug (bDMARD) or targeted synthetic DMARD (tsDMARD) was significantly lower than the rate observed in patients who take only a conventional synthetic DMARD (csDMARD) in a national database study.

The work builds on previous research indicating a higher risk of Alzheimer’s disease and related dementias in people with RA. While joint pain and swelling are the cardinal symptoms of RA, its systemic inflammation leads to multiple systemic manifestations, offering biologically plausible links with cognitive decline. In addition, patients with RA have high prevalence of cardiovascular disease, diabetes, depression, disability, and physical inactivity, all of which are risk factors for dementia.

Chronic neuroinflammation secondary to either intrinsic or systemic stimuli is thought to play a key role in dementia development, especially Alzheimer’s dementia (AD). Research showing a role of tumor necrosis factor–alpha (TNF-alpha) in the development of dementia has piqued interest in a potential protective effect of TNF inhibitors. “TNF-alpha is thought to have an important role in different stages of the pathophysiology and disease progression of Alzheimer’s disease,” study first author Sebastian E. Sattui, MD, assistant professor of medicine at the University of Pittsburgh and director of the University of Pittsburgh Vasculitis Center, said in an interview. “Animal models have shown that TNF inhibition reduces microgliosis, neuronal loss, and tau phosphorylation. Cognitive improvement has been seen in two trials with Alzheimer’s disease patients, but were not in rheumatoid arthritis patients.”

In the newest study, published online in Seminars in Arthritis and Rheumatism, Dr. Sattui and colleagues suggest that a lower risk for dementia seen with bDMARDs and tsDMARDs may be attributable to an overall greater decrease in inflammation rather than any mechanism of action specific to these drugs.

In the study of Centers for Medicare & Medicaid Services claims during 2006-2017 for 141,326 adult patients with RA, the crude incident rates were 2.0 per 100 person-years (95% confidence interval, 1.9-2.1) for patients on csDMARDs and 1.3 (95% CI, 1.2-1.4) for patients on any b/tsDMARD. There were 3,794 cases of incident dementia during follow-up among 233,271 initiations of any DMARD. The adjusted risk for dementia among users of bDMARDs or tsDMARDs was 19% lower than the adjusted risk for patients on csDMARDs (hazard ratio, 0.81; 95% CI, 0.76-0.87). No significant differences were found between classes of bDMARDs or tsDMARDs.

Dr. Sattui and coauthors’ investigation included adults aged at least 40 years with two RA diagnoses by a rheumatologist more than 7 and less than 365 days apart. Those with prior dementia diagnoses were excluded. Their analysis found the risk of incident dementia to be comparable between patients receiving TNF inhibitors (HR, 0.86; 95% CI, 0.80-0.93), non-TNFi bDMARDs (HR, 0.76; 95% CI, 0.70-0.83), and tsDMARDs (HR, 0.69; 95% CI, 0.53-0.90), with csDMARDs as the referent. A second subgroup analysis looking at patients with prior methotrexate use who were taking bDMARDs or tsDMARDs revealed similar decreases in risk of incident dementia, compared with patients taking bDMARDs or tsDMARDs along with methotrexate at baseline.

“NSAIDs and glucocorticoids have been studied in RCTs [randomized, controlled trials],” Dr. Sattui said in the interview. “Despite initial observational data that showed some signal for improvement, no benefit was observed in either of the RCTs. Other agents with possible anti-inflammatory effects and more benign profiles, such as curcumin, are being studied. There are also ongoing trials looking into the use of JAK [Janus kinase] inhibitors or [interleukin]-1 inhibition in dementia.”

He added: “There is a need to better study the association between cognition and disease activity, as well as treat-to-target strategies, prospectively in patients with RA. It is important to also acknowledge that any of these findings might be just specific for RA, so extrapolation to non-RA individuals might be limited.”

In commenting on the findings of the study, Rishi J. Desai, PhD, assistant professor of medicine in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston, said that “superior inflammation control with biologics or targeted DMARDs is an interesting hypothesis explaining the observed findings. It merits further investigation and replication in diverse populations.” He added: “It should be noted that a key challenge in evaluating this hypothesis using insurance claims data is unavailability of some important factors such as socioeconomic status and patient frailty. These may be driving treatment selection between conventional DMARDs, which are cheaper with more benign adverse-event profiles, and biologic or targeted DMARDs, which are more expensive with a less favorable adverse-event profile.”
 

Prior research

Several studies have investigated the effect of DMARDs, including bDMARDs like tumor necrosis factor inhibitors, on incident dementia in patients with RA.

Among this research is a study by Dr. Desai and colleagues that looked at comparative risk of AD and related dementia in 22,569 Medicare beneficiaries receiving tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors in comparison with abatacept (a T-cell activation inhibitor). No differentiating risk associations were found in this cohort study.

Other past studies include:

• A study comparing about 21,000 patients with RA and a non-RA cohort of about 62,000 found a 37% reduction in dementia development among RA patients receiving DMARDs. The effect was dose dependent, greater with high cumulative dosages, and was found in both men and women and in subgroups younger and older than 65 years.
• A retrospective study of electronic health records from 56 million adult patients identified a subset of patients with RA, psoriasis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease in whom systemic inflammation increased risk for AD through a mechanism involving TNF. The risk for AD in patients was lowered by treatment with etanercept, adalimumab, infliximab, or methotrexate, with larger reductions observed in younger patients than in older patients receiving TNF blockers.
• A propensity score–matched retrospective cohort study in 2,510 U.S. veterans with RA found that use of a TNF inhibitor reduced the risk of dementia by 36%, compared with control patients (HR, 0.64; 95% CI, 0.52-0.80), and the effect was consistent over 5-20 years post RA diagnosis.
• In a retrospective, multinational, matched, case-control study of patients older than 50 years with RA, prior methotrexate use was associated with lower dementia risk (OR, 0.71; 95% CI, 0.52-0.98). Use of methotrexate longer than 4 years demonstrated the lowest dementia risk (odds ratio, 0.37; 95% CI, 0.17-0.79).

These past studies, Dr. Sattui and colleagues pointed out, have multiple shortcomings, including case-control design, different definitions of exposure or outcomes, and inadequate control of confounders, underscoring the need for more rigorous studies.

Several authors of the CMS claims study disclosed research support, grants, and consulting fees from pharmaceutical companies. The research was supported by a grant from the National Institutes of Health. Dr. Desai disclosed that he has received funding from the National Institute on Aging for drug repurposing studies of dementia.

The incidence of dementia in patients with rheumatoid arthritis who took either a biologic disease-modifying antirheumatic drug (bDMARD) or targeted synthetic DMARD (tsDMARD) was significantly lower than the rate observed in patients who take only a conventional synthetic DMARD (csDMARD) in a national database study.

The work builds on previous research indicating a higher risk of Alzheimer’s disease and related dementias in people with RA. While joint pain and swelling are the cardinal symptoms of RA, its systemic inflammation leads to multiple systemic manifestations, offering biologically plausible links with cognitive decline. In addition, patients with RA have high prevalence of cardiovascular disease, diabetes, depression, disability, and physical inactivity, all of which are risk factors for dementia.

Chronic neuroinflammation secondary to either intrinsic or systemic stimuli is thought to play a key role in dementia development, especially Alzheimer’s dementia (AD). Research showing a role of tumor necrosis factor–alpha (TNF-alpha) in the development of dementia has piqued interest in a potential protective effect of TNF inhibitors. “TNF-alpha is thought to have an important role in different stages of the pathophysiology and disease progression of Alzheimer’s disease,” study first author Sebastian E. Sattui, MD, assistant professor of medicine at the University of Pittsburgh and director of the University of Pittsburgh Vasculitis Center, said in an interview. “Animal models have shown that TNF inhibition reduces microgliosis, neuronal loss, and tau phosphorylation. Cognitive improvement has been seen in two trials with Alzheimer’s disease patients, but were not in rheumatoid arthritis patients.”

In the newest study, published online in Seminars in Arthritis and Rheumatism, Dr. Sattui and colleagues suggest that a lower risk for dementia seen with bDMARDs and tsDMARDs may be attributable to an overall greater decrease in inflammation rather than any mechanism of action specific to these drugs.

In the study of Centers for Medicare & Medicaid Services claims during 2006-2017 for 141,326 adult patients with RA, the crude incident rates were 2.0 per 100 person-years (95% confidence interval, 1.9-2.1) for patients on csDMARDs and 1.3 (95% CI, 1.2-1.4) for patients on any b/tsDMARD. There were 3,794 cases of incident dementia during follow-up among 233,271 initiations of any DMARD. The adjusted risk for dementia among users of bDMARDs or tsDMARDs was 19% lower than the adjusted risk for patients on csDMARDs (hazard ratio, 0.81; 95% CI, 0.76-0.87). No significant differences were found between classes of bDMARDs or tsDMARDs.

Dr. Sattui and coauthors’ investigation included adults aged at least 40 years with two RA diagnoses by a rheumatologist more than 7 and less than 365 days apart. Those with prior dementia diagnoses were excluded. Their analysis found the risk of incident dementia to be comparable between patients receiving TNF inhibitors (HR, 0.86; 95% CI, 0.80-0.93), non-TNFi bDMARDs (HR, 0.76; 95% CI, 0.70-0.83), and tsDMARDs (HR, 0.69; 95% CI, 0.53-0.90), with csDMARDs as the referent. A second subgroup analysis looking at patients with prior methotrexate use who were taking bDMARDs or tsDMARDs revealed similar decreases in risk of incident dementia, compared with patients taking bDMARDs or tsDMARDs along with methotrexate at baseline.

“NSAIDs and glucocorticoids have been studied in RCTs [randomized, controlled trials],” Dr. Sattui said in the interview. “Despite initial observational data that showed some signal for improvement, no benefit was observed in either of the RCTs. Other agents with possible anti-inflammatory effects and more benign profiles, such as curcumin, are being studied. There are also ongoing trials looking into the use of JAK [Janus kinase] inhibitors or [interleukin]-1 inhibition in dementia.”

He added: “There is a need to better study the association between cognition and disease activity, as well as treat-to-target strategies, prospectively in patients with RA. It is important to also acknowledge that any of these findings might be just specific for RA, so extrapolation to non-RA individuals might be limited.”

In commenting on the findings of the study, Rishi J. Desai, PhD, assistant professor of medicine in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston, said that “superior inflammation control with biologics or targeted DMARDs is an interesting hypothesis explaining the observed findings. It merits further investigation and replication in diverse populations.” He added: “It should be noted that a key challenge in evaluating this hypothesis using insurance claims data is unavailability of some important factors such as socioeconomic status and patient frailty. These may be driving treatment selection between conventional DMARDs, which are cheaper with more benign adverse-event profiles, and biologic or targeted DMARDs, which are more expensive with a less favorable adverse-event profile.”
 

Prior research

Several studies have investigated the effect of DMARDs, including bDMARDs like tumor necrosis factor inhibitors, on incident dementia in patients with RA.

Among this research is a study by Dr. Desai and colleagues that looked at comparative risk of AD and related dementia in 22,569 Medicare beneficiaries receiving tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors in comparison with abatacept (a T-cell activation inhibitor). No differentiating risk associations were found in this cohort study.

Other past studies include:

• A study comparing about 21,000 patients with RA and a non-RA cohort of about 62,000 found a 37% reduction in dementia development among RA patients receiving DMARDs. The effect was dose dependent, greater with high cumulative dosages, and was found in both men and women and in subgroups younger and older than 65 years.
• A retrospective study of electronic health records from 56 million adult patients identified a subset of patients with RA, psoriasis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease in whom systemic inflammation increased risk for AD through a mechanism involving TNF. The risk for AD in patients was lowered by treatment with etanercept, adalimumab, infliximab, or methotrexate, with larger reductions observed in younger patients than in older patients receiving TNF blockers.
• A propensity score–matched retrospective cohort study in 2,510 U.S. veterans with RA found that use of a TNF inhibitor reduced the risk of dementia by 36%, compared with control patients (HR, 0.64; 95% CI, 0.52-0.80), and the effect was consistent over 5-20 years post RA diagnosis.
• In a retrospective, multinational, matched, case-control study of patients older than 50 years with RA, prior methotrexate use was associated with lower dementia risk (OR, 0.71; 95% CI, 0.52-0.98). Use of methotrexate longer than 4 years demonstrated the lowest dementia risk (odds ratio, 0.37; 95% CI, 0.17-0.79).

These past studies, Dr. Sattui and colleagues pointed out, have multiple shortcomings, including case-control design, different definitions of exposure or outcomes, and inadequate control of confounders, underscoring the need for more rigorous studies.

Several authors of the CMS claims study disclosed research support, grants, and consulting fees from pharmaceutical companies. The research was supported by a grant from the National Institutes of Health. Dr. Desai disclosed that he has received funding from the National Institute on Aging for drug repurposing studies of dementia.

Therapeutic drug monitoring allowed patients with rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis to reduce their dosage of tumor necrosis factor–alpha (TNF) inhibitors, based on data from 239 individuals.

Use of TNF-alpha inhibitors improves treatment response for many arthritis patients but dosage is rarely adjusted on an individual level, which may lead to unnecessary overdosing in some patients, Mogens Pfeiffer-Jensen, MD, of Aarhus (Denmark) University Hospital, and colleagues wrote.

Data from previous studies suggest that therapeutic drug monitoring (TDM) based on serum trough levels may allow for dose optimization and dose reduction in inflammatory bowel disease patients, but data in patients with arthritis are lacking, they wrote.

In a study published in the Scandinavian Journal of Rheumatology, the researchers recruited 99 patients with RA, 48 with psoriatic arthritis (PsA), and 92 with spondyloarthritis (SpA). The participants were randomized to standard care or standard care plus TDM. Serum trough levels were assessed at baseline and at every 4 months, and prescription changes or drug switches were implemented based on these levels. At baseline, 81 patients were being treated with infliximab (Remicade and biosimilars), 79 with etanercept (Enbrel), and 79 with adalimumab (Humira).

The primary endpoint was reduced drug prescription after 48 weeks.

Overall, TDM significantly reduced prescription of infliximab by 12% (P = .001) and prescription of etanercept by 15% (P = .01), compared with standard care. TDM also prolonged the interdosing intervals of etanercept by 235% (P = .02) and of adalimumab by 28% (P = .04), compared with standard care.

TDM patients taking infliximab had more frequent dose reduction and less frequent dose increases during and after the study when compared with patients who stayed with standard care; similar trends were seen with adalimumab. TDM also accelerated the switch to other biologics for patients on all three medications.

No significant differences occurred in adverse events or hospitalizations between the TDM and standard care patients.

Clinical composite scores (Disease Activity Score based on 28 joints with C-reactive protein) were reduced in patients with RA and PsA who were taking adalimumab and randomized to TDM, but no other clinical outcome differences were noted. Scores on the Health Assessment Questionnaire and global Visual Analog Scale for pain were significantly lower in patients in the TDM group who were taking infliximab and adalimumab, “indicating equally or superior sustained remission across diagnoses,” the researchers emphasized.

The findings were limited by several factors, including the variations in pathophysiology and open-label design. “However, since the TDM was based on an objective serum value and decision procedures were clear, we do not consider the potential of unconscious bias to outweigh the benefits of dose-changing abilities,” they wrote.

The researchers expressed surprise that the reduced use of TNF-alpha inhibitors did not significantly reduce adverse events or serious adverse events, compared with standard care, but they proposed that standard of care may have taken adverse events into account, because all patients had received prescriptions at least 3 months before the study.

As for clinical implications, the current costs of the biochemical assays necessary for TDM may be a barrier to implementing TDM as a standard part of daily clinical practice, the researchers added. However, the study was strengthened by the inclusion of patients with RA, PsA, and SpA, and is the first known to include patients receiving etanercept or adalimumab in an examination of TDM.

“Our data support TDM based solely on serum trough levels in [TNF-alpha inhibitors] with different pharmacokinetics as a future key player in personalized medicine for chronic rheumatoid diseases treated with biologics,” they concluded.

The study was supported by Spydspidspuljen, Region Midt, Denmark, and Department of Rheumatology, Aarhus University Hospital. The researchers had no financial conflicts to disclose. 

Therapeutic drug monitoring allowed patients with rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis to reduce their dosage of tumor necrosis factor–alpha (TNF) inhibitors, based on data from 239 individuals.

Use of TNF-alpha inhibitors improves treatment response for many arthritis patients but dosage is rarely adjusted on an individual level, which may lead to unnecessary overdosing in some patients, Mogens Pfeiffer-Jensen, MD, of Aarhus (Denmark) University Hospital, and colleagues wrote.

Data from previous studies suggest that therapeutic drug monitoring (TDM) based on serum trough levels may allow for dose optimization and dose reduction in inflammatory bowel disease patients, but data in patients with arthritis are lacking, they wrote.

In a study published in the Scandinavian Journal of Rheumatology, the researchers recruited 99 patients with RA, 48 with psoriatic arthritis (PsA), and 92 with spondyloarthritis (SpA). The participants were randomized to standard care or standard care plus TDM. Serum trough levels were assessed at baseline and at every 4 months, and prescription changes or drug switches were implemented based on these levels. At baseline, 81 patients were being treated with infliximab (Remicade and biosimilars), 79 with etanercept (Enbrel), and 79 with adalimumab (Humira).

The primary endpoint was reduced drug prescription after 48 weeks.

Overall, TDM significantly reduced prescription of infliximab by 12% (P = .001) and prescription of etanercept by 15% (P = .01), compared with standard care. TDM also prolonged the interdosing intervals of etanercept by 235% (P = .02) and of adalimumab by 28% (P = .04), compared with standard care.

TDM patients taking infliximab had more frequent dose reduction and less frequent dose increases during and after the study when compared with patients who stayed with standard care; similar trends were seen with adalimumab. TDM also accelerated the switch to other biologics for patients on all three medications.

No significant differences occurred in adverse events or hospitalizations between the TDM and standard care patients.

Clinical composite scores (Disease Activity Score based on 28 joints with C-reactive protein) were reduced in patients with RA and PsA who were taking adalimumab and randomized to TDM, but no other clinical outcome differences were noted. Scores on the Health Assessment Questionnaire and global Visual Analog Scale for pain were significantly lower in patients in the TDM group who were taking infliximab and adalimumab, “indicating equally or superior sustained remission across diagnoses,” the researchers emphasized.

The findings were limited by several factors, including the variations in pathophysiology and open-label design. “However, since the TDM was based on an objective serum value and decision procedures were clear, we do not consider the potential of unconscious bias to outweigh the benefits of dose-changing abilities,” they wrote.

The researchers expressed surprise that the reduced use of TNF-alpha inhibitors did not significantly reduce adverse events or serious adverse events, compared with standard care, but they proposed that standard of care may have taken adverse events into account, because all patients had received prescriptions at least 3 months before the study.

As for clinical implications, the current costs of the biochemical assays necessary for TDM may be a barrier to implementing TDM as a standard part of daily clinical practice, the researchers added. However, the study was strengthened by the inclusion of patients with RA, PsA, and SpA, and is the first known to include patients receiving etanercept or adalimumab in an examination of TDM.

“Our data support TDM based solely on serum trough levels in [TNF-alpha inhibitors] with different pharmacokinetics as a future key player in personalized medicine for chronic rheumatoid diseases treated with biologics,” they concluded.

The study was supported by Spydspidspuljen, Region Midt, Denmark, and Department of Rheumatology, Aarhus University Hospital. The researchers had no financial conflicts to disclose. 

Therapeutic drug monitoring allowed patients with rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis to reduce their dosage of tumor necrosis factor–alpha (TNF) inhibitors, based on data from 239 individuals.

Use of TNF-alpha inhibitors improves treatment response for many arthritis patients but dosage is rarely adjusted on an individual level, which may lead to unnecessary overdosing in some patients, Mogens Pfeiffer-Jensen, MD, of Aarhus (Denmark) University Hospital, and colleagues wrote.

Data from previous studies suggest that therapeutic drug monitoring (TDM) based on serum trough levels may allow for dose optimization and dose reduction in inflammatory bowel disease patients, but data in patients with arthritis are lacking, they wrote.

In a study published in the Scandinavian Journal of Rheumatology, the researchers recruited 99 patients with RA, 48 with psoriatic arthritis (PsA), and 92 with spondyloarthritis (SpA). The participants were randomized to standard care or standard care plus TDM. Serum trough levels were assessed at baseline and at every 4 months, and prescription changes or drug switches were implemented based on these levels. At baseline, 81 patients were being treated with infliximab (Remicade and biosimilars), 79 with etanercept (Enbrel), and 79 with adalimumab (Humira).

The primary endpoint was reduced drug prescription after 48 weeks.

Overall, TDM significantly reduced prescription of infliximab by 12% (P = .001) and prescription of etanercept by 15% (P = .01), compared with standard care. TDM also prolonged the interdosing intervals of etanercept by 235% (P = .02) and of adalimumab by 28% (P = .04), compared with standard care.

TDM patients taking infliximab had more frequent dose reduction and less frequent dose increases during and after the study when compared with patients who stayed with standard care; similar trends were seen with adalimumab. TDM also accelerated the switch to other biologics for patients on all three medications.

No significant differences occurred in adverse events or hospitalizations between the TDM and standard care patients.

Clinical composite scores (Disease Activity Score based on 28 joints with C-reactive protein) were reduced in patients with RA and PsA who were taking adalimumab and randomized to TDM, but no other clinical outcome differences were noted. Scores on the Health Assessment Questionnaire and global Visual Analog Scale for pain were significantly lower in patients in the TDM group who were taking infliximab and adalimumab, “indicating equally or superior sustained remission across diagnoses,” the researchers emphasized.

The findings were limited by several factors, including the variations in pathophysiology and open-label design. “However, since the TDM was based on an objective serum value and decision procedures were clear, we do not consider the potential of unconscious bias to outweigh the benefits of dose-changing abilities,” they wrote.

The researchers expressed surprise that the reduced use of TNF-alpha inhibitors did not significantly reduce adverse events or serious adverse events, compared with standard care, but they proposed that standard of care may have taken adverse events into account, because all patients had received prescriptions at least 3 months before the study.

As for clinical implications, the current costs of the biochemical assays necessary for TDM may be a barrier to implementing TDM as a standard part of daily clinical practice, the researchers added. However, the study was strengthened by the inclusion of patients with RA, PsA, and SpA, and is the first known to include patients receiving etanercept or adalimumab in an examination of TDM.

“Our data support TDM based solely on serum trough levels in [TNF-alpha inhibitors] with different pharmacokinetics as a future key player in personalized medicine for chronic rheumatoid diseases treated with biologics,” they concluded.

The study was supported by Spydspidspuljen, Region Midt, Denmark, and Department of Rheumatology, Aarhus University Hospital. The researchers had no financial conflicts to disclose.