Rheumatoid Arthritis

Key clinical point: The addition of iguratimod (IGU) can effectively reduce methotrexate (MTX) dose required by rheumatoid arthritis (RA) patients with long-term clinical remission.

Major finding: MTX dose could be reduced from 8.6±2.4 mg/week to 4.7±2.2 mg/week at 36 weeks. Despite MTX dose reduction, disease activity score 28-erythrocyte sedimentation rate was maintained at 1.48 at baseline and 1.69 at 36 weeks (P = .911). Other than drug discontinuation by 2 patients in the IGU addition group, no other adverse events were observed.

Study details: Findings are from a prospective analysis of 47 patients with RA who had sustained clinical remission with MTX for more than 24 weeks. Patients either continued constant MTX dose (n=25) or were treated with additional IGU and tapered MTX dose (n=22).

Disclosures: No source of funding was declared. The authors declared no conflicts of interest.

Source: Yoshikawa A et al. Mod Rheumatol. 2021 Mar 16. doi: 10.1080/14397595.2021.1892945.

Key clinical point: The addition of iguratimod (IGU) can effectively reduce methotrexate (MTX) dose required by rheumatoid arthritis (RA) patients with long-term clinical remission.

Major finding: MTX dose could be reduced from 8.6±2.4 mg/week to 4.7±2.2 mg/week at 36 weeks. Despite MTX dose reduction, disease activity score 28-erythrocyte sedimentation rate was maintained at 1.48 at baseline and 1.69 at 36 weeks (P = .911). Other than drug discontinuation by 2 patients in the IGU addition group, no other adverse events were observed.

Study details: Findings are from a prospective analysis of 47 patients with RA who had sustained clinical remission with MTX for more than 24 weeks. Patients either continued constant MTX dose (n=25) or were treated with additional IGU and tapered MTX dose (n=22).

Disclosures: No source of funding was declared. The authors declared no conflicts of interest.

Source: Yoshikawa A et al. Mod Rheumatol. 2021 Mar 16. doi: 10.1080/14397595.2021.1892945.

Key clinical point: The addition of iguratimod (IGU) can effectively reduce methotrexate (MTX) dose required by rheumatoid arthritis (RA) patients with long-term clinical remission.

Major finding: MTX dose could be reduced from 8.6±2.4 mg/week to 4.7±2.2 mg/week at 36 weeks. Despite MTX dose reduction, disease activity score 28-erythrocyte sedimentation rate was maintained at 1.48 at baseline and 1.69 at 36 weeks (P = .911). Other than drug discontinuation by 2 patients in the IGU addition group, no other adverse events were observed.

Study details: Findings are from a prospective analysis of 47 patients with RA who had sustained clinical remission with MTX for more than 24 weeks. Patients either continued constant MTX dose (n=25) or were treated with additional IGU and tapered MTX dose (n=22).

Disclosures: No source of funding was declared. The authors declared no conflicts of interest.

Source: Yoshikawa A et al. Mod Rheumatol. 2021 Mar 16. doi: 10.1080/14397595.2021.1892945.

Key clinical point: Janus kinase inhibitors (JAKis: baricitinib or tofacitinib) vs. rituximab for the treatment of rheumatoid arthritis (RA) in patients with concurrent interstitial lung disease (ILD) or bronchiectasis did not increase the rate of hospitalization or mortality because of a respiratory cause.

Major finding: Respiratory events were reported in 5 patients treated with JAKi (18%; 7 hospitalizations, 2 of whom died) and 4 patients treated with rituximab (21%; 4 hospitalizations, 1 of whom died). Respiratory event survival (hazard ratio [HR], 1.38; P = .64) and the rate of drug discontinuation HR, 1.9; P = .251) did not differ significantly between groups.

Study details: A retrospective analysis of patients with RA and concurrent ILD or bronchiectasis who received JAKis (n=28: baricitinib, n=26; tofacitinib, n=2) or rituximab (n=19) for a mean of 1.1 and 2.14 years, respectively.

Disclosures: The study did not receive any funding. The lead author received sponsorship from Lilly and Pfizer to attend educational conferences. The other authors declared no conflicts of interest.

Citation: Cronin O et al. Rheumatol Int. 2021 Mar 15. doi: 10.1007/s00296-021-04835-1.

Key clinical point: Janus kinase inhibitors (JAKis: baricitinib or tofacitinib) vs. rituximab for the treatment of rheumatoid arthritis (RA) in patients with concurrent interstitial lung disease (ILD) or bronchiectasis did not increase the rate of hospitalization or mortality because of a respiratory cause.

Major finding: Respiratory events were reported in 5 patients treated with JAKi (18%; 7 hospitalizations, 2 of whom died) and 4 patients treated with rituximab (21%; 4 hospitalizations, 1 of whom died). Respiratory event survival (hazard ratio [HR], 1.38; P = .64) and the rate of drug discontinuation HR, 1.9; P = .251) did not differ significantly between groups.

Study details: A retrospective analysis of patients with RA and concurrent ILD or bronchiectasis who received JAKis (n=28: baricitinib, n=26; tofacitinib, n=2) or rituximab (n=19) for a mean of 1.1 and 2.14 years, respectively.

Disclosures: The study did not receive any funding. The lead author received sponsorship from Lilly and Pfizer to attend educational conferences. The other authors declared no conflicts of interest.

Citation: Cronin O et al. Rheumatol Int. 2021 Mar 15. doi: 10.1007/s00296-021-04835-1.

Key clinical point: Janus kinase inhibitors (JAKis: baricitinib or tofacitinib) vs. rituximab for the treatment of rheumatoid arthritis (RA) in patients with concurrent interstitial lung disease (ILD) or bronchiectasis did not increase the rate of hospitalization or mortality because of a respiratory cause.

Major finding: Respiratory events were reported in 5 patients treated with JAKi (18%; 7 hospitalizations, 2 of whom died) and 4 patients treated with rituximab (21%; 4 hospitalizations, 1 of whom died). Respiratory event survival (hazard ratio [HR], 1.38; P = .64) and the rate of drug discontinuation HR, 1.9; P = .251) did not differ significantly between groups.

Study details: A retrospective analysis of patients with RA and concurrent ILD or bronchiectasis who received JAKis (n=28: baricitinib, n=26; tofacitinib, n=2) or rituximab (n=19) for a mean of 1.1 and 2.14 years, respectively.

Disclosures: The study did not receive any funding. The lead author received sponsorship from Lilly and Pfizer to attend educational conferences. The other authors declared no conflicts of interest.

Citation: Cronin O et al. Rheumatol Int. 2021 Mar 15. doi: 10.1007/s00296-021-04835-1.

Key clinical point: Peficitinib (ASP015K) showed improvement in clinical outcomes, which was maintained throughout the treatment duration of 32 months along with a generally tolerable safety profile in patients with rheumatoid arthritis (RA).

Major finding: The American College of Rheumatology (ACR)20, ACR50, and ACR70 response rates were maintained throughout from baseline (71.6%, 52.1%, and 34.7%, respectively) to the end of treatment (78.7%, 63.3%, and 44.1%, respectively). Treatment-emergent adverse events, mostly grade 1 or 2 in severity, were experienced by 94.4% of patients, leading to drug discontinuation in 16.6% of patients. 

Study details: Findings are from the final analysis of an open-label long-term extension study involving 843 Asian patients with RA who previously completed phase 2b and phase 3 studies of peficitinib.

Disclosures: This work was funded by the Astellas Pharma, Inc. The authors including the lead author reported receiving grants, speaker’s fees, consultancy fees, personal fees, and/or honoraria from various sources including Astellas Pharma, Inc. Four of the authors reported being employees of Astellas Pharma, Inc.

Source: Takeuchi T et al. Rheumatol Ther. 2021 Mar 3. doi: 10.1007/s40744-021-00280-5.

Key clinical point: Peficitinib (ASP015K) showed improvement in clinical outcomes, which was maintained throughout the treatment duration of 32 months along with a generally tolerable safety profile in patients with rheumatoid arthritis (RA).

Major finding: The American College of Rheumatology (ACR)20, ACR50, and ACR70 response rates were maintained throughout from baseline (71.6%, 52.1%, and 34.7%, respectively) to the end of treatment (78.7%, 63.3%, and 44.1%, respectively). Treatment-emergent adverse events, mostly grade 1 or 2 in severity, were experienced by 94.4% of patients, leading to drug discontinuation in 16.6% of patients. 

Study details: Findings are from the final analysis of an open-label long-term extension study involving 843 Asian patients with RA who previously completed phase 2b and phase 3 studies of peficitinib.

Disclosures: This work was funded by the Astellas Pharma, Inc. The authors including the lead author reported receiving grants, speaker’s fees, consultancy fees, personal fees, and/or honoraria from various sources including Astellas Pharma, Inc. Four of the authors reported being employees of Astellas Pharma, Inc.

Source: Takeuchi T et al. Rheumatol Ther. 2021 Mar 3. doi: 10.1007/s40744-021-00280-5.

Key clinical point: Peficitinib (ASP015K) showed improvement in clinical outcomes, which was maintained throughout the treatment duration of 32 months along with a generally tolerable safety profile in patients with rheumatoid arthritis (RA).

Major finding: The American College of Rheumatology (ACR)20, ACR50, and ACR70 response rates were maintained throughout from baseline (71.6%, 52.1%, and 34.7%, respectively) to the end of treatment (78.7%, 63.3%, and 44.1%, respectively). Treatment-emergent adverse events, mostly grade 1 or 2 in severity, were experienced by 94.4% of patients, leading to drug discontinuation in 16.6% of patients. 

Study details: Findings are from the final analysis of an open-label long-term extension study involving 843 Asian patients with RA who previously completed phase 2b and phase 3 studies of peficitinib.

Disclosures: This work was funded by the Astellas Pharma, Inc. The authors including the lead author reported receiving grants, speaker’s fees, consultancy fees, personal fees, and/or honoraria from various sources including Astellas Pharma, Inc. Four of the authors reported being employees of Astellas Pharma, Inc.

Source: Takeuchi T et al. Rheumatol Ther. 2021 Mar 3. doi: 10.1007/s40744-021-00280-5.

Key clinical point: Patients with early rheumatoid arthritis (RA) who initiated biological vs. triple therapy after inadequate response to methotrexate (MTX) were more likely to achieve sustained remission (SR).

Major finding: Patients initiating biological vs. triple therapy were more likely to achieve short-term and long-term SR at 1 year (adjusted odds ratio [aOR], 1.79; 95% confidence interval [CI], 1.18-2.71 and aOR, 1.86; 95% CI, 1.00-3.48, respectively) and 2 years (aOR, 1.92; 95% CI, 1.21-3.06 and aOR, 1.62; 95% CI, 0.94-2.79, respectively) from treatment initiation.

Study details: Findings are from an analysis of 1,502 patients with relatively early RA who initiated biological (biological disease-modifying antirheumatic drugs+MTX; n=1,155) or triple (MTX+sulfasalazine+hydroxychloroquine/chloroquine; n=347) therapy as the first treatment strategy after inadequate response to MTX monotherapy.

Disclosures: This work funded by the Swedish Rheumatism Association, the Medical Faculty of Lund University, Alfred Österlund ́s Foundation, Greta and Johan Kock ́s foundation, the King Gustaf V Foundation, Lund University Hospital, Professor Nanna Svartz Foundation, and Anna-Greta Crafoord Foundation. The authors declared no conflicts of interest.

Source: Källmark H et al. Arthritis Rheumatol. 2021 Mar 7. doi: 10.1002/art.41720.

Key clinical point: Patients with early rheumatoid arthritis (RA) who initiated biological vs. triple therapy after inadequate response to methotrexate (MTX) were more likely to achieve sustained remission (SR).

Major finding: Patients initiating biological vs. triple therapy were more likely to achieve short-term and long-term SR at 1 year (adjusted odds ratio [aOR], 1.79; 95% confidence interval [CI], 1.18-2.71 and aOR, 1.86; 95% CI, 1.00-3.48, respectively) and 2 years (aOR, 1.92; 95% CI, 1.21-3.06 and aOR, 1.62; 95% CI, 0.94-2.79, respectively) from treatment initiation.

Study details: Findings are from an analysis of 1,502 patients with relatively early RA who initiated biological (biological disease-modifying antirheumatic drugs+MTX; n=1,155) or triple (MTX+sulfasalazine+hydroxychloroquine/chloroquine; n=347) therapy as the first treatment strategy after inadequate response to MTX monotherapy.

Disclosures: This work funded by the Swedish Rheumatism Association, the Medical Faculty of Lund University, Alfred Österlund ́s Foundation, Greta and Johan Kock ́s foundation, the King Gustaf V Foundation, Lund University Hospital, Professor Nanna Svartz Foundation, and Anna-Greta Crafoord Foundation. The authors declared no conflicts of interest.

Source: Källmark H et al. Arthritis Rheumatol. 2021 Mar 7. doi: 10.1002/art.41720.

Key clinical point: Patients with early rheumatoid arthritis (RA) who initiated biological vs. triple therapy after inadequate response to methotrexate (MTX) were more likely to achieve sustained remission (SR).

Major finding: Patients initiating biological vs. triple therapy were more likely to achieve short-term and long-term SR at 1 year (adjusted odds ratio [aOR], 1.79; 95% confidence interval [CI], 1.18-2.71 and aOR, 1.86; 95% CI, 1.00-3.48, respectively) and 2 years (aOR, 1.92; 95% CI, 1.21-3.06 and aOR, 1.62; 95% CI, 0.94-2.79, respectively) from treatment initiation.

Study details: Findings are from an analysis of 1,502 patients with relatively early RA who initiated biological (biological disease-modifying antirheumatic drugs+MTX; n=1,155) or triple (MTX+sulfasalazine+hydroxychloroquine/chloroquine; n=347) therapy as the first treatment strategy after inadequate response to MTX monotherapy.

Disclosures: This work funded by the Swedish Rheumatism Association, the Medical Faculty of Lund University, Alfred Österlund ́s Foundation, Greta and Johan Kock ́s foundation, the King Gustaf V Foundation, Lund University Hospital, Professor Nanna Svartz Foundation, and Anna-Greta Crafoord Foundation. The authors declared no conflicts of interest.

Source: Källmark H et al. Arthritis Rheumatol. 2021 Mar 7. doi: 10.1002/art.41720.

Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.

peterschreiber_media/iStock/Getty Images

In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.

The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.

Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.

None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.

“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.

Antibody responses

In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.

The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.

Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.

The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.

Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.

Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.

peterschreiber_media/iStock/Getty Images

In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.

The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.

Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.

None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.

“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.

Antibody responses

In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.

The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.

Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.

The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.

Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.

Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.

peterschreiber_media/iStock/Getty Images

In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.

The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.

Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.

None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.

“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.

Antibody responses

In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.

The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.

Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.

The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.

Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.

The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.

In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.

“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”

The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.

The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”

jevans@mdedge.com

The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.

In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.

“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”

The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.

The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”

jevans@mdedge.com

The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.

In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.

“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”

The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.

The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”

jevans@mdedge.com

Macrophages are among the most important inflammatory cells in the synovium of patients with rheumatoid arthritis, according to research discussed at the Canadian Arthritis Research Conference: Research with Impact.

Work conducted as part of the Accelerating Medicines Partnership (AMP) Rheumatoid Arthritis and Systemic Lupus Erythematosus (RA/SLE) Network suggests that not only do macrophages play an inflammatory role, but there may also be a subset of macrophages that have a predominantly anti-inflammatory effect.

“These are cells that are really activated and can produce a lot of proinflammatory cytokines, including TNF [tumor necrosis factor],” said Jennifer Howitt Anolik, MD, PhD, associate professor of medicine at the University of Rochester (N.Y.) and cochair of the AMP RA/SLE Network.

“In addition to inflammatory mediators there’s an anti-inflammatory population which may control the disease,” she added, at the virtual meeting, which was sponsored by The Arthritis Society, the Canadian Rheumatology Association, and Canada’s Institute of Health and Arthritis.

There are up to 15 different populations of macrophages found so far as part of a project by Fan Zhang of Brigham and Women’s Hospital and Harvard Medical School in Boston, Dr. Anolik revealed. Of these, three have been shown to be proinflammatory and five have been shown to be anti-inflammatory – including one of particular interest that expresses MERTK, which recent work suggests are lacking in people with RA, compared with a control population of people with osteoarthritis (OA).

Clearly, Dr. Anolik said, there is “lots more work to do to understand how those anti-inflammatory monocytes might work, understand the relationship to treatment response and treatment failure, and how to target them.”
 

AMP RA/SLE Network: Examining RA synovial tissue

What’s unique about the AMP’s work is that it is involving single-cell analytics in which individual cells derived from patients with RA are subjected to an array of RNA sequencing and molecular classification methods.

“If we’re able to define the cells that are driving the disease at the tissue level, this may lead to better therapeutics and more of like a precision medicine approach,” Dr. Anolik said. An important feature of the AMP’s work is that it is based on the use of existing and thus “very informative cohorts” for whom we know a lot about disease characteristics, she said.

The AMP RA/SLE Network officially formed in 2014 and is a public–private partnership between the National Institutes of Health, the Food and Drug Administration, several biopharmaceutical companies, and nonprofit organizations. The task was to try to accelerate discoveries that would lead to better patient care.

“The initial phase [Research Phase 0], was really about developing the procedures in a standardized way,” Dr. Anolik said. “Because we’re looking at patient joint tissue samples, we needed to access that tissue and that required developing needle biopsy approaches.” Synovial biopsy had been pioneered in the United Kingdom and become fairly standard to perform, she added, but this was not an approach that was routinely being used in the United States at the time.

In the next step, Research Phase I, researchers looked at the expression profiles of RA synovial cells in a small group of patients. In all, around 5,000 cells from the joints of up to 20 patients with RA were analyzed. What was apparent was that while there were fibroblasts, monocytes, T cells, and B cells all present to some degree, there was substantial heterogeneity among those subtypes.

“Within all the different immune cells and stromal cells, we found 18 different populations overall,” Dr. Anolik said, giving some of the top-level findings. Both single-cell RNA sequencing and mass cytometry revealed that there were greatly (16-fold) increased numbers of a population of sublining fibroblasts and a 3.3-fold increase in interleukin-1-beta-expressing proinflammatory monocytes. There was a threefold increase in a subset of B cells expressing CD11/T-bet, and a 2.4-fold increase in certain peripheral T cells.

“Interestingly, we were able to pinpoint which cells are making which kinds of inflammatory mediators like inflammatory cytokines,” Dr. Anolik said. Notably, one of the fibroblast populations and one of the B cells were prominent producers of interleukin-6.

The AMP RA/SLE Network is now in Research Phase II, looking at much greater numbers of cells (>5,000) in more than 100 samples from individual patients. It’s a “very comprehensive, big data look at RA,” according to Dr. Anolik.

Research Phase II will also see more rigorous groups of patients being examined, including those who have not had any or much exposure to disease-modifying antirheumatic drugs and those who have inadequately responded to methotrexate or anti-TNF drugs.

Recent AMP RA/SLE Network findings

Recent work by the AMP RA/SLE Network has shown that stromal fibroblasts can become highly inflammatory in RA.

“What’s becoming clear is that these are more than just lining of the joint or structure of the joint, they actually play an active role in the disease,” Dr. Anolik said.

There is a lot of diversity in these fibroblasts but they broadly fall into lining or sublining subtypes. Those that are proinflammatory tend to express markers such as HLA-DR and CD90, and one that is of notable interest is a subgroup of sublining fibroblasts that express Notch3. Indeed, it has been shown that the higher the number of Notch3-expressing fibroblasts there are in the joint, the greater the level of inflammation. Also, mice lacking Notch3 seem to get less arthritis than those with Notch3. This makes Notch3 an interesting potential target that no one had thought of before.

Dr. Anolik noted that some evolving concepts about T cells include evidence showing CD8-postive T cells are more abundant in the joint tissue than previously thought and, together with natural killer (NK) cells, are an important producer of interferon-gamma.

“There are some very interesting CD4 T-cell populations, including an expansion of T peripheral helper cells that may be very important in driving B-cell activation,” Dr. Anolik said. There are also many other clusters of T cells and NK cells that have unknown roles.

Over the past years, Dr. Anolik’s research had focused on the role B cells play in autoimmune disease, and one of the cells of interest are known as age-related B cells, or ABCs. High percentages of ABCs have been found in the RA synovium, and these seem to be related to disease activity as measured by the Disease Activity Score in 28 joints (DAS28). These cells also seem to cluster with some of the T helper cell populations found in the joint. Another interesting target could be B cells expressing a transcription factor known as T-bet. Work in mice suggests that the absence of T-bet B cells could be associated with reduced levels of arthritis.

“One of the things that we’re really interested in about B cells, in addition to their production of autoantibodies, is that they may be important for some of the structural damage that occurs with rheumatoid arthritis,” she said.

T-bet B cells seem to have an effect on both osteoclasts and osteoblasts – activating one while inhibiting the other to have a negative effect on bone overall, she explained. However, knocking out T-bet seems to resolve this, again suggesting that T-bet B cells may be another interesting subpopulation to target.

“Overall, the AMP has been a really interesting approach. This is a massive data set. We are putting the data together now to publish, and it will be available in the public domain,” Dr. Anolik said.

Members of the AMP RA/SLE Network include: AbbVie, the Arthritis Foundation, Bristol‐Myers Squibb, the Foundation for the NIH, the Lupus Foundation of America, the Lupus Research Alliance, Merck Sharp & Dohme, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer, the Rheumatology Research Foundation, Sanofi, and Takeda Pharmaceuticals International.

Dr. Anolik had no disclosures.

Macrophages are among the most important inflammatory cells in the synovium of patients with rheumatoid arthritis, according to research discussed at the Canadian Arthritis Research Conference: Research with Impact.

Work conducted as part of the Accelerating Medicines Partnership (AMP) Rheumatoid Arthritis and Systemic Lupus Erythematosus (RA/SLE) Network suggests that not only do macrophages play an inflammatory role, but there may also be a subset of macrophages that have a predominantly anti-inflammatory effect.

“These are cells that are really activated and can produce a lot of proinflammatory cytokines, including TNF [tumor necrosis factor],” said Jennifer Howitt Anolik, MD, PhD, associate professor of medicine at the University of Rochester (N.Y.) and cochair of the AMP RA/SLE Network.

“In addition to inflammatory mediators there’s an anti-inflammatory population which may control the disease,” she added, at the virtual meeting, which was sponsored by The Arthritis Society, the Canadian Rheumatology Association, and Canada’s Institute of Health and Arthritis.

There are up to 15 different populations of macrophages found so far as part of a project by Fan Zhang of Brigham and Women’s Hospital and Harvard Medical School in Boston, Dr. Anolik revealed. Of these, three have been shown to be proinflammatory and five have been shown to be anti-inflammatory – including one of particular interest that expresses MERTK, which recent work suggests are lacking in people with RA, compared with a control population of people with osteoarthritis (OA).

Clearly, Dr. Anolik said, there is “lots more work to do to understand how those anti-inflammatory monocytes might work, understand the relationship to treatment response and treatment failure, and how to target them.”
 

AMP RA/SLE Network: Examining RA synovial tissue

What’s unique about the AMP’s work is that it is involving single-cell analytics in which individual cells derived from patients with RA are subjected to an array of RNA sequencing and molecular classification methods.

“If we’re able to define the cells that are driving the disease at the tissue level, this may lead to better therapeutics and more of like a precision medicine approach,” Dr. Anolik said. An important feature of the AMP’s work is that it is based on the use of existing and thus “very informative cohorts” for whom we know a lot about disease characteristics, she said.

The AMP RA/SLE Network officially formed in 2014 and is a public–private partnership between the National Institutes of Health, the Food and Drug Administration, several biopharmaceutical companies, and nonprofit organizations. The task was to try to accelerate discoveries that would lead to better patient care.

“The initial phase [Research Phase 0], was really about developing the procedures in a standardized way,” Dr. Anolik said. “Because we’re looking at patient joint tissue samples, we needed to access that tissue and that required developing needle biopsy approaches.” Synovial biopsy had been pioneered in the United Kingdom and become fairly standard to perform, she added, but this was not an approach that was routinely being used in the United States at the time.

In the next step, Research Phase I, researchers looked at the expression profiles of RA synovial cells in a small group of patients. In all, around 5,000 cells from the joints of up to 20 patients with RA were analyzed. What was apparent was that while there were fibroblasts, monocytes, T cells, and B cells all present to some degree, there was substantial heterogeneity among those subtypes.

“Within all the different immune cells and stromal cells, we found 18 different populations overall,” Dr. Anolik said, giving some of the top-level findings. Both single-cell RNA sequencing and mass cytometry revealed that there were greatly (16-fold) increased numbers of a population of sublining fibroblasts and a 3.3-fold increase in interleukin-1-beta-expressing proinflammatory monocytes. There was a threefold increase in a subset of B cells expressing CD11/T-bet, and a 2.4-fold increase in certain peripheral T cells.

“Interestingly, we were able to pinpoint which cells are making which kinds of inflammatory mediators like inflammatory cytokines,” Dr. Anolik said. Notably, one of the fibroblast populations and one of the B cells were prominent producers of interleukin-6.

The AMP RA/SLE Network is now in Research Phase II, looking at much greater numbers of cells (>5,000) in more than 100 samples from individual patients. It’s a “very comprehensive, big data look at RA,” according to Dr. Anolik.

Research Phase II will also see more rigorous groups of patients being examined, including those who have not had any or much exposure to disease-modifying antirheumatic drugs and those who have inadequately responded to methotrexate or anti-TNF drugs.

Recent AMP RA/SLE Network findings

Recent work by the AMP RA/SLE Network has shown that stromal fibroblasts can become highly inflammatory in RA.

“What’s becoming clear is that these are more than just lining of the joint or structure of the joint, they actually play an active role in the disease,” Dr. Anolik said.

There is a lot of diversity in these fibroblasts but they broadly fall into lining or sublining subtypes. Those that are proinflammatory tend to express markers such as HLA-DR and CD90, and one that is of notable interest is a subgroup of sublining fibroblasts that express Notch3. Indeed, it has been shown that the higher the number of Notch3-expressing fibroblasts there are in the joint, the greater the level of inflammation. Also, mice lacking Notch3 seem to get less arthritis than those with Notch3. This makes Notch3 an interesting potential target that no one had thought of before.

Dr. Anolik noted that some evolving concepts about T cells include evidence showing CD8-postive T cells are more abundant in the joint tissue than previously thought and, together with natural killer (NK) cells, are an important producer of interferon-gamma.

“There are some very interesting CD4 T-cell populations, including an expansion of T peripheral helper cells that may be very important in driving B-cell activation,” Dr. Anolik said. There are also many other clusters of T cells and NK cells that have unknown roles.

Over the past years, Dr. Anolik’s research had focused on the role B cells play in autoimmune disease, and one of the cells of interest are known as age-related B cells, or ABCs. High percentages of ABCs have been found in the RA synovium, and these seem to be related to disease activity as measured by the Disease Activity Score in 28 joints (DAS28). These cells also seem to cluster with some of the T helper cell populations found in the joint. Another interesting target could be B cells expressing a transcription factor known as T-bet. Work in mice suggests that the absence of T-bet B cells could be associated with reduced levels of arthritis.

“One of the things that we’re really interested in about B cells, in addition to their production of autoantibodies, is that they may be important for some of the structural damage that occurs with rheumatoid arthritis,” she said.

T-bet B cells seem to have an effect on both osteoclasts and osteoblasts – activating one while inhibiting the other to have a negative effect on bone overall, she explained. However, knocking out T-bet seems to resolve this, again suggesting that T-bet B cells may be another interesting subpopulation to target.

“Overall, the AMP has been a really interesting approach. This is a massive data set. We are putting the data together now to publish, and it will be available in the public domain,” Dr. Anolik said.

Members of the AMP RA/SLE Network include: AbbVie, the Arthritis Foundation, Bristol‐Myers Squibb, the Foundation for the NIH, the Lupus Foundation of America, the Lupus Research Alliance, Merck Sharp & Dohme, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer, the Rheumatology Research Foundation, Sanofi, and Takeda Pharmaceuticals International.

Dr. Anolik had no disclosures.

Macrophages are among the most important inflammatory cells in the synovium of patients with rheumatoid arthritis, according to research discussed at the Canadian Arthritis Research Conference: Research with Impact.

Work conducted as part of the Accelerating Medicines Partnership (AMP) Rheumatoid Arthritis and Systemic Lupus Erythematosus (RA/SLE) Network suggests that not only do macrophages play an inflammatory role, but there may also be a subset of macrophages that have a predominantly anti-inflammatory effect.

“These are cells that are really activated and can produce a lot of proinflammatory cytokines, including TNF [tumor necrosis factor],” said Jennifer Howitt Anolik, MD, PhD, associate professor of medicine at the University of Rochester (N.Y.) and cochair of the AMP RA/SLE Network.

“In addition to inflammatory mediators there’s an anti-inflammatory population which may control the disease,” she added, at the virtual meeting, which was sponsored by The Arthritis Society, the Canadian Rheumatology Association, and Canada’s Institute of Health and Arthritis.

There are up to 15 different populations of macrophages found so far as part of a project by Fan Zhang of Brigham and Women’s Hospital and Harvard Medical School in Boston, Dr. Anolik revealed. Of these, three have been shown to be proinflammatory and five have been shown to be anti-inflammatory – including one of particular interest that expresses MERTK, which recent work suggests are lacking in people with RA, compared with a control population of people with osteoarthritis (OA).

Clearly, Dr. Anolik said, there is “lots more work to do to understand how those anti-inflammatory monocytes might work, understand the relationship to treatment response and treatment failure, and how to target them.”
 

AMP RA/SLE Network: Examining RA synovial tissue

What’s unique about the AMP’s work is that it is involving single-cell analytics in which individual cells derived from patients with RA are subjected to an array of RNA sequencing and molecular classification methods.

“If we’re able to define the cells that are driving the disease at the tissue level, this may lead to better therapeutics and more of like a precision medicine approach,” Dr. Anolik said. An important feature of the AMP’s work is that it is based on the use of existing and thus “very informative cohorts” for whom we know a lot about disease characteristics, she said.

The AMP RA/SLE Network officially formed in 2014 and is a public–private partnership between the National Institutes of Health, the Food and Drug Administration, several biopharmaceutical companies, and nonprofit organizations. The task was to try to accelerate discoveries that would lead to better patient care.

“The initial phase [Research Phase 0], was really about developing the procedures in a standardized way,” Dr. Anolik said. “Because we’re looking at patient joint tissue samples, we needed to access that tissue and that required developing needle biopsy approaches.” Synovial biopsy had been pioneered in the United Kingdom and become fairly standard to perform, she added, but this was not an approach that was routinely being used in the United States at the time.

In the next step, Research Phase I, researchers looked at the expression profiles of RA synovial cells in a small group of patients. In all, around 5,000 cells from the joints of up to 20 patients with RA were analyzed. What was apparent was that while there were fibroblasts, monocytes, T cells, and B cells all present to some degree, there was substantial heterogeneity among those subtypes.

“Within all the different immune cells and stromal cells, we found 18 different populations overall,” Dr. Anolik said, giving some of the top-level findings. Both single-cell RNA sequencing and mass cytometry revealed that there were greatly (16-fold) increased numbers of a population of sublining fibroblasts and a 3.3-fold increase in interleukin-1-beta-expressing proinflammatory monocytes. There was a threefold increase in a subset of B cells expressing CD11/T-bet, and a 2.4-fold increase in certain peripheral T cells.

“Interestingly, we were able to pinpoint which cells are making which kinds of inflammatory mediators like inflammatory cytokines,” Dr. Anolik said. Notably, one of the fibroblast populations and one of the B cells were prominent producers of interleukin-6.

The AMP RA/SLE Network is now in Research Phase II, looking at much greater numbers of cells (>5,000) in more than 100 samples from individual patients. It’s a “very comprehensive, big data look at RA,” according to Dr. Anolik.

Research Phase II will also see more rigorous groups of patients being examined, including those who have not had any or much exposure to disease-modifying antirheumatic drugs and those who have inadequately responded to methotrexate or anti-TNF drugs.

Recent AMP RA/SLE Network findings

Recent work by the AMP RA/SLE Network has shown that stromal fibroblasts can become highly inflammatory in RA.

“What’s becoming clear is that these are more than just lining of the joint or structure of the joint, they actually play an active role in the disease,” Dr. Anolik said.

There is a lot of diversity in these fibroblasts but they broadly fall into lining or sublining subtypes. Those that are proinflammatory tend to express markers such as HLA-DR and CD90, and one that is of notable interest is a subgroup of sublining fibroblasts that express Notch3. Indeed, it has been shown that the higher the number of Notch3-expressing fibroblasts there are in the joint, the greater the level of inflammation. Also, mice lacking Notch3 seem to get less arthritis than those with Notch3. This makes Notch3 an interesting potential target that no one had thought of before.

Dr. Anolik noted that some evolving concepts about T cells include evidence showing CD8-postive T cells are more abundant in the joint tissue than previously thought and, together with natural killer (NK) cells, are an important producer of interferon-gamma.

“There are some very interesting CD4 T-cell populations, including an expansion of T peripheral helper cells that may be very important in driving B-cell activation,” Dr. Anolik said. There are also many other clusters of T cells and NK cells that have unknown roles.

Over the past years, Dr. Anolik’s research had focused on the role B cells play in autoimmune disease, and one of the cells of interest are known as age-related B cells, or ABCs. High percentages of ABCs have been found in the RA synovium, and these seem to be related to disease activity as measured by the Disease Activity Score in 28 joints (DAS28). These cells also seem to cluster with some of the T helper cell populations found in the joint. Another interesting target could be B cells expressing a transcription factor known as T-bet. Work in mice suggests that the absence of T-bet B cells could be associated with reduced levels of arthritis.

“One of the things that we’re really interested in about B cells, in addition to their production of autoantibodies, is that they may be important for some of the structural damage that occurs with rheumatoid arthritis,” she said.

T-bet B cells seem to have an effect on both osteoclasts and osteoblasts – activating one while inhibiting the other to have a negative effect on bone overall, she explained. However, knocking out T-bet seems to resolve this, again suggesting that T-bet B cells may be another interesting subpopulation to target.

“Overall, the AMP has been a really interesting approach. This is a massive data set. We are putting the data together now to publish, and it will be available in the public domain,” Dr. Anolik said.

Members of the AMP RA/SLE Network include: AbbVie, the Arthritis Foundation, Bristol‐Myers Squibb, the Foundation for the NIH, the Lupus Foundation of America, the Lupus Research Alliance, Merck Sharp & Dohme, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer, the Rheumatology Research Foundation, Sanofi, and Takeda Pharmaceuticals International.

Dr. Anolik had no disclosures.

Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.

“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.

This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.

Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.

Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.

This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
 

Delayed onset and resolution of rheumatologic immune-related adverse events

“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.

Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.

Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
 

Flares of preexisting rheumatic diseases

These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.

Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.

“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.

He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.

“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.

Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.

bjancin@mdedge.com

Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.

“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.

This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.

Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.

Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.

This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
 

Delayed onset and resolution of rheumatologic immune-related adverse events

“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.

Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.

Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
 

Flares of preexisting rheumatic diseases

These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.

Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.

“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.

He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.

“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.

Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.

bjancin@mdedge.com

Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.

“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.

This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.

Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.

Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.

This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
 

Delayed onset and resolution of rheumatologic immune-related adverse events

“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.

Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.

Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
 

Flares of preexisting rheumatic diseases

These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.

Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.

“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.

He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.

“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.

Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.

bjancin@mdedge.com

Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.

Bruce Jancin/MDedge News

But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.

He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.

Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
 

RA improvement on an ITIS diet

Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.

However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.

The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.

As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.

At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.

Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.

The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.

Biqi is big in China, gaining ground in the U.S.

Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.

“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.

If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.

In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.

“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.

American RA patients embrace turmeric

Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.

Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.

Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
 

What about osteoarthritis?

Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.

Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.

Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.

Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
 

bjancin@mdedge.com

Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.

Bruce Jancin/MDedge News

But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.

He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.

Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
 

RA improvement on an ITIS diet

Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.

However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.

The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.

As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.

At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.

Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.

The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.

Biqi is big in China, gaining ground in the U.S.

Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.

“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.

If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.

In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.

“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.

American RA patients embrace turmeric

Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.

Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.

Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
 

What about osteoarthritis?

Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.

Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.

Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.

Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
 

bjancin@mdedge.com

Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.

Bruce Jancin/MDedge News

But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.

He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.

Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
 

RA improvement on an ITIS diet

Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.

However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.

The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.

As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.

At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.

Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.

The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.

Biqi is big in China, gaining ground in the U.S.

Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.

“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.

If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.

In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.

“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.

American RA patients embrace turmeric

Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.

Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.

Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
 

What about osteoarthritis?

Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.

Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.

Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.

Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
 

bjancin@mdedge.com

It’s been a banner year for treatment advances in systemic lupus erythematosus (SLE), with two drugs gaining approval for lupus nephritis while other promising molecules with novel mechanisms of action advanced smartly through the developmental pipeline, speakers agreed at the 2021 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“I think the most important thing in rheumatology in the last year is where we are now with lupus. With two drugs being approved for lupus nephritis, I think that’s really huge as we talk about treat-to-target,” said Alvin F. Wells, MD, PhD, a rheumatologist in Franklin, Wisc.

Martin Bergman, MD, concurred.

“Lupus has been blowing up in the past year. We have two new medications for lupus nephritis, we have two or three new mechanisms of action for therapy. I think that was one of the biggest things in rheumatology in the past year,” said Dr. Bergman, a rheumatologist at Drexel University in Philadelphia and in private practice in Ridley Park, Pa.

Together with Roy Fleischmann, MD, Dr. Wells spotlighted promising new molecules for the treatment of SLE, giant cell arteritis, vasculitis, rheumatoid arthritis, and osteoarthritis.
 

SLE

The two drugs approved in recent months specifically for lupus nephritis are voclosporin (Lupkynis) and belimumab (Benlysta), which has been approved for lupus for a decade. Voclosporin, an oral calcineurin inhibitor, is a modification of cyclosporine offering significant advantages over the older drug: It’s more potent, requires no dose titration, has a better safety profile, and is metabolized more quickly.

“A safer and easier-to-use calcineurin inhibitor is going to be huge,” Dr. Wells predicted.

Up for Food and Drug Administration review in the coming year on the basis of the positive phase 3 TULIP-1 and TULIP-2 trials is anifrolumab, a monoclonal antibody that binds to the type 1 interferon receptor subunit 1d. At 52 weeks in the pooled analysis, one or more SLE flares occurred in 33.6% of patients on anifrolumab and 42.9% of placebo-treated controls.

“This is not a blockbuster, but it’s a worthwhile addition, like belimumab,” according to Dr. Fleischmann, a rheumatologist at the University of Texas, Dallas.

Dr. Wells concurred, with a reservation: In a subgroup analysis of the TULIP trials, anifrolumab wasn’t significantly better than placebo in black patients, who tend to have more severe and tough-to-treat renal disease.

“Anifrolumab doesn’t look as effective as some other agents, and I’d be disinclined to give it to my black patients,” the rheumatologist said.

Dr. Fleischmann was far more enthusiastic about obinutuzumab (Gazyva), a humanized anti-CD20 monoclonal antibody already approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma.

Bruce Jancin/MDedge News

A humanized monoclonal antibody known for now as BIIB059 demonstrated efficacy and was well tolerated in the phase 2 LILAC trial. BIIB059 binds to blood dendritic cell antigen 2 (BDCA2), a receptor specific to plasmacytoid dendritic cells, resulting in decreased production of type 1 interferon and other inflammatory cytokines. The LILAC trial included 132 SLE patients with active arthritis and skin disease who received subcutaneous injections of BIIB059 at 450 mg or placebo every 4 weeks, with an extra dose at week 2. The primary endpoint was met, with an absolute 15-joint reduction in the total number of tender or swollen joints from baseline to week 24 in the BIIB059 group, compared to an 11.6-joint reduction with placebo. In addition, the likelihood of an SRI-4 response at week 24 was 3.49-fold greater with BIIB059 than with placebo.

Dr. Wells noted that the BIIB059 group showed continued improvement from week 12 to week 24, unlike the response pattern seen with many biologics for rheumatoid arthritis, where a plateau is reached by 8-12 weeks.

Vasculitis

The positive results for the C5a receptor inhibitor avacopan for treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the phase-3 ADVOCATE trial have been hailed by some rheumatologists as a major breakthrough, but Dr. Fleischmann isn’t so sure.

The trial randomized 331 patients to oral avacopan at 30 mg twice daily or oral prednisone, with all patients on either cyclophosphamide or rituximab. Avacopan was noninferior to prednisone in terms of remission at week 26, but superior to prednisone for sustained taper at week 52. The rate of serious adverse events was 45.1% with prednisone and 42.2% in the avacopan arm.

“This is a drug that’s going to be much, much more expensive than prednisone. There were people in our group who were ecstatic that this drug is going to come, but how much it’s going to be used, I don’t know,” Dr. Fleischmann said.

Dr. Wells said cost-benefit analyses will be needed in order to learn if avacopan’s anticipated high sticker price is offset by the cost of serious corticosteroid side effects such as avascular necrosis.
 

Giant cell arteritis

Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony stimulating factor receptor alpha. It demonstrated impressive efficacy in a phase 2, double-blind, randomized, placebo-controlled trial conducted in 70 patients with biopsy-confirmed giant cell arteritis. Participants were on corticosteroids until they went into remission and were then randomized to mavrilimumab or placebo, with the steroids stopped. By week 26, 19% of patients in the mavrilimumab arm had flared, as compared to 46.4% of controls.

“This is a game changer,” Dr. Wells declared. “I struggle with these patients because I can’t get the IL-6 drugs approved for them. I need something else.”

Dr. Fleischmann has a good idea how he’ll use mavrilimumab, if it wins approval: “I think this is clearly a drug you would use in a patient you can’t get off steroids and you’re having all the steroid toxicity. I don’t know that you’d use it right away.”

Osteoarthritis

Dr. Fleischmann predicted that tanezumab, a monoclonal antibody directed against nerve growth factor, will win FDA approval in 2021 for the treatment of osteoarthritis pain in patients with an inadequate response or intolerance to standard-of-care NSAIDs and opioids. But he cautioned his colleagues not to expect too much from the biologic, which has a long and checkered developmental history.

“It works better than placebo. It does not work better than an NSAID or an opioid. So it should be reasonable in patients who cannot take an NSAID or cannot or will not take an opioid,” he said.

There are safety issues to be aware of with tanezumab, he added: clinically significant increased risks of peripheral neuropathy and joint space narrowing.
 

Rheumatoid arthritis

Dr. Wells thought one of the most interesting novel therapies for RA in the past year didn’t involve a pharmaceutical, but rather noninvasive auricular branch stimulation of the vagus nerve. He cited an open-label, 12-week, uncontrolled study in 27 patients with active RA who wore an ear clip for vagal nerve stimulation for 12 weeks. The mean Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) – the primary study endpoint – improved from 6.30 at baseline to 3.76 at week 12. The number of tender joints dropped from 12.17 to 4.7, while the swollen joint count went from 7.0 to 3.44. Pain scores improved from 75.23 to 43.3. Scores on the Health Assessment Questionnaire Disability Index improved from 1.59 to 1.05. There was no significant change in CRP. All in all, a modest clinical effect achieved noninvasively.

“The thing that did it for me was the effect on MRI from baseline: decreased synovitis, osteitis, and bone erosion scores,” Dr. Wells said. “This is noninvasive, so patients who want to do medical marijuana or CBD can put an earring on their auricular nerve.”

Dr. Fleischmann scoffed. “An open-label study, 27 patients? Let me see the real study,” he quipped.

Dr. Fleischmann reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Wells serves as a consultant to MiCare Path.

bjancin@mdedge.com

It’s been a banner year for treatment advances in systemic lupus erythematosus (SLE), with two drugs gaining approval for lupus nephritis while other promising molecules with novel mechanisms of action advanced smartly through the developmental pipeline, speakers agreed at the 2021 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“I think the most important thing in rheumatology in the last year is where we are now with lupus. With two drugs being approved for lupus nephritis, I think that’s really huge as we talk about treat-to-target,” said Alvin F. Wells, MD, PhD, a rheumatologist in Franklin, Wisc.

Martin Bergman, MD, concurred.

“Lupus has been blowing up in the past year. We have two new medications for lupus nephritis, we have two or three new mechanisms of action for therapy. I think that was one of the biggest things in rheumatology in the past year,” said Dr. Bergman, a rheumatologist at Drexel University in Philadelphia and in private practice in Ridley Park, Pa.

Together with Roy Fleischmann, MD, Dr. Wells spotlighted promising new molecules for the treatment of SLE, giant cell arteritis, vasculitis, rheumatoid arthritis, and osteoarthritis.
 

SLE

The two drugs approved in recent months specifically for lupus nephritis are voclosporin (Lupkynis) and belimumab (Benlysta), which has been approved for lupus for a decade. Voclosporin, an oral calcineurin inhibitor, is a modification of cyclosporine offering significant advantages over the older drug: It’s more potent, requires no dose titration, has a better safety profile, and is metabolized more quickly.

“A safer and easier-to-use calcineurin inhibitor is going to be huge,” Dr. Wells predicted.

Up for Food and Drug Administration review in the coming year on the basis of the positive phase 3 TULIP-1 and TULIP-2 trials is anifrolumab, a monoclonal antibody that binds to the type 1 interferon receptor subunit 1d. At 52 weeks in the pooled analysis, one or more SLE flares occurred in 33.6% of patients on anifrolumab and 42.9% of placebo-treated controls.

“This is not a blockbuster, but it’s a worthwhile addition, like belimumab,” according to Dr. Fleischmann, a rheumatologist at the University of Texas, Dallas.

Dr. Wells concurred, with a reservation: In a subgroup analysis of the TULIP trials, anifrolumab wasn’t significantly better than placebo in black patients, who tend to have more severe and tough-to-treat renal disease.

“Anifrolumab doesn’t look as effective as some other agents, and I’d be disinclined to give it to my black patients,” the rheumatologist said.

Dr. Fleischmann was far more enthusiastic about obinutuzumab (Gazyva), a humanized anti-CD20 monoclonal antibody already approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma.

Bruce Jancin/MDedge News

A humanized monoclonal antibody known for now as BIIB059 demonstrated efficacy and was well tolerated in the phase 2 LILAC trial. BIIB059 binds to blood dendritic cell antigen 2 (BDCA2), a receptor specific to plasmacytoid dendritic cells, resulting in decreased production of type 1 interferon and other inflammatory cytokines. The LILAC trial included 132 SLE patients with active arthritis and skin disease who received subcutaneous injections of BIIB059 at 450 mg or placebo every 4 weeks, with an extra dose at week 2. The primary endpoint was met, with an absolute 15-joint reduction in the total number of tender or swollen joints from baseline to week 24 in the BIIB059 group, compared to an 11.6-joint reduction with placebo. In addition, the likelihood of an SRI-4 response at week 24 was 3.49-fold greater with BIIB059 than with placebo.

Dr. Wells noted that the BIIB059 group showed continued improvement from week 12 to week 24, unlike the response pattern seen with many biologics for rheumatoid arthritis, where a plateau is reached by 8-12 weeks.

Vasculitis

The positive results for the C5a receptor inhibitor avacopan for treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the phase-3 ADVOCATE trial have been hailed by some rheumatologists as a major breakthrough, but Dr. Fleischmann isn’t so sure.

The trial randomized 331 patients to oral avacopan at 30 mg twice daily or oral prednisone, with all patients on either cyclophosphamide or rituximab. Avacopan was noninferior to prednisone in terms of remission at week 26, but superior to prednisone for sustained taper at week 52. The rate of serious adverse events was 45.1% with prednisone and 42.2% in the avacopan arm.

“This is a drug that’s going to be much, much more expensive than prednisone. There were people in our group who were ecstatic that this drug is going to come, but how much it’s going to be used, I don’t know,” Dr. Fleischmann said.

Dr. Wells said cost-benefit analyses will be needed in order to learn if avacopan’s anticipated high sticker price is offset by the cost of serious corticosteroid side effects such as avascular necrosis.
 

Giant cell arteritis

Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony stimulating factor receptor alpha. It demonstrated impressive efficacy in a phase 2, double-blind, randomized, placebo-controlled trial conducted in 70 patients with biopsy-confirmed giant cell arteritis. Participants were on corticosteroids until they went into remission and were then randomized to mavrilimumab or placebo, with the steroids stopped. By week 26, 19% of patients in the mavrilimumab arm had flared, as compared to 46.4% of controls.

“This is a game changer,” Dr. Wells declared. “I struggle with these patients because I can’t get the IL-6 drugs approved for them. I need something else.”

Dr. Fleischmann has a good idea how he’ll use mavrilimumab, if it wins approval: “I think this is clearly a drug you would use in a patient you can’t get off steroids and you’re having all the steroid toxicity. I don’t know that you’d use it right away.”

Osteoarthritis

Dr. Fleischmann predicted that tanezumab, a monoclonal antibody directed against nerve growth factor, will win FDA approval in 2021 for the treatment of osteoarthritis pain in patients with an inadequate response or intolerance to standard-of-care NSAIDs and opioids. But he cautioned his colleagues not to expect too much from the biologic, which has a long and checkered developmental history.

“It works better than placebo. It does not work better than an NSAID or an opioid. So it should be reasonable in patients who cannot take an NSAID or cannot or will not take an opioid,” he said.

There are safety issues to be aware of with tanezumab, he added: clinically significant increased risks of peripheral neuropathy and joint space narrowing.
 

Rheumatoid arthritis

Dr. Wells thought one of the most interesting novel therapies for RA in the past year didn’t involve a pharmaceutical, but rather noninvasive auricular branch stimulation of the vagus nerve. He cited an open-label, 12-week, uncontrolled study in 27 patients with active RA who wore an ear clip for vagal nerve stimulation for 12 weeks. The mean Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) – the primary study endpoint – improved from 6.30 at baseline to 3.76 at week 12. The number of tender joints dropped from 12.17 to 4.7, while the swollen joint count went from 7.0 to 3.44. Pain scores improved from 75.23 to 43.3. Scores on the Health Assessment Questionnaire Disability Index improved from 1.59 to 1.05. There was no significant change in CRP. All in all, a modest clinical effect achieved noninvasively.

“The thing that did it for me was the effect on MRI from baseline: decreased synovitis, osteitis, and bone erosion scores,” Dr. Wells said. “This is noninvasive, so patients who want to do medical marijuana or CBD can put an earring on their auricular nerve.”

Dr. Fleischmann scoffed. “An open-label study, 27 patients? Let me see the real study,” he quipped.

Dr. Fleischmann reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Wells serves as a consultant to MiCare Path.

bjancin@mdedge.com

It’s been a banner year for treatment advances in systemic lupus erythematosus (SLE), with two drugs gaining approval for lupus nephritis while other promising molecules with novel mechanisms of action advanced smartly through the developmental pipeline, speakers agreed at the 2021 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“I think the most important thing in rheumatology in the last year is where we are now with lupus. With two drugs being approved for lupus nephritis, I think that’s really huge as we talk about treat-to-target,” said Alvin F. Wells, MD, PhD, a rheumatologist in Franklin, Wisc.

Martin Bergman, MD, concurred.

“Lupus has been blowing up in the past year. We have two new medications for lupus nephritis, we have two or three new mechanisms of action for therapy. I think that was one of the biggest things in rheumatology in the past year,” said Dr. Bergman, a rheumatologist at Drexel University in Philadelphia and in private practice in Ridley Park, Pa.

Together with Roy Fleischmann, MD, Dr. Wells spotlighted promising new molecules for the treatment of SLE, giant cell arteritis, vasculitis, rheumatoid arthritis, and osteoarthritis.
 

SLE

The two drugs approved in recent months specifically for lupus nephritis are voclosporin (Lupkynis) and belimumab (Benlysta), which has been approved for lupus for a decade. Voclosporin, an oral calcineurin inhibitor, is a modification of cyclosporine offering significant advantages over the older drug: It’s more potent, requires no dose titration, has a better safety profile, and is metabolized more quickly.

“A safer and easier-to-use calcineurin inhibitor is going to be huge,” Dr. Wells predicted.

Up for Food and Drug Administration review in the coming year on the basis of the positive phase 3 TULIP-1 and TULIP-2 trials is anifrolumab, a monoclonal antibody that binds to the type 1 interferon receptor subunit 1d. At 52 weeks in the pooled analysis, one or more SLE flares occurred in 33.6% of patients on anifrolumab and 42.9% of placebo-treated controls.

“This is not a blockbuster, but it’s a worthwhile addition, like belimumab,” according to Dr. Fleischmann, a rheumatologist at the University of Texas, Dallas.

Dr. Wells concurred, with a reservation: In a subgroup analysis of the TULIP trials, anifrolumab wasn’t significantly better than placebo in black patients, who tend to have more severe and tough-to-treat renal disease.

“Anifrolumab doesn’t look as effective as some other agents, and I’d be disinclined to give it to my black patients,” the rheumatologist said.

Dr. Fleischmann was far more enthusiastic about obinutuzumab (Gazyva), a humanized anti-CD20 monoclonal antibody already approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma.

Bruce Jancin/MDedge News

A humanized monoclonal antibody known for now as BIIB059 demonstrated efficacy and was well tolerated in the phase 2 LILAC trial. BIIB059 binds to blood dendritic cell antigen 2 (BDCA2), a receptor specific to plasmacytoid dendritic cells, resulting in decreased production of type 1 interferon and other inflammatory cytokines. The LILAC trial included 132 SLE patients with active arthritis and skin disease who received subcutaneous injections of BIIB059 at 450 mg or placebo every 4 weeks, with an extra dose at week 2. The primary endpoint was met, with an absolute 15-joint reduction in the total number of tender or swollen joints from baseline to week 24 in the BIIB059 group, compared to an 11.6-joint reduction with placebo. In addition, the likelihood of an SRI-4 response at week 24 was 3.49-fold greater with BIIB059 than with placebo.

Dr. Wells noted that the BIIB059 group showed continued improvement from week 12 to week 24, unlike the response pattern seen with many biologics for rheumatoid arthritis, where a plateau is reached by 8-12 weeks.

Vasculitis

The positive results for the C5a receptor inhibitor avacopan for treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the phase-3 ADVOCATE trial have been hailed by some rheumatologists as a major breakthrough, but Dr. Fleischmann isn’t so sure.

The trial randomized 331 patients to oral avacopan at 30 mg twice daily or oral prednisone, with all patients on either cyclophosphamide or rituximab. Avacopan was noninferior to prednisone in terms of remission at week 26, but superior to prednisone for sustained taper at week 52. The rate of serious adverse events was 45.1% with prednisone and 42.2% in the avacopan arm.

“This is a drug that’s going to be much, much more expensive than prednisone. There were people in our group who were ecstatic that this drug is going to come, but how much it’s going to be used, I don’t know,” Dr. Fleischmann said.

Dr. Wells said cost-benefit analyses will be needed in order to learn if avacopan’s anticipated high sticker price is offset by the cost of serious corticosteroid side effects such as avascular necrosis.
 

Giant cell arteritis

Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony stimulating factor receptor alpha. It demonstrated impressive efficacy in a phase 2, double-blind, randomized, placebo-controlled trial conducted in 70 patients with biopsy-confirmed giant cell arteritis. Participants were on corticosteroids until they went into remission and were then randomized to mavrilimumab or placebo, with the steroids stopped. By week 26, 19% of patients in the mavrilimumab arm had flared, as compared to 46.4% of controls.

“This is a game changer,” Dr. Wells declared. “I struggle with these patients because I can’t get the IL-6 drugs approved for them. I need something else.”

Dr. Fleischmann has a good idea how he’ll use mavrilimumab, if it wins approval: “I think this is clearly a drug you would use in a patient you can’t get off steroids and you’re having all the steroid toxicity. I don’t know that you’d use it right away.”

Osteoarthritis

Dr. Fleischmann predicted that tanezumab, a monoclonal antibody directed against nerve growth factor, will win FDA approval in 2021 for the treatment of osteoarthritis pain in patients with an inadequate response or intolerance to standard-of-care NSAIDs and opioids. But he cautioned his colleagues not to expect too much from the biologic, which has a long and checkered developmental history.

“It works better than placebo. It does not work better than an NSAID or an opioid. So it should be reasonable in patients who cannot take an NSAID or cannot or will not take an opioid,” he said.

There are safety issues to be aware of with tanezumab, he added: clinically significant increased risks of peripheral neuropathy and joint space narrowing.
 

Rheumatoid arthritis

Dr. Wells thought one of the most interesting novel therapies for RA in the past year didn’t involve a pharmaceutical, but rather noninvasive auricular branch stimulation of the vagus nerve. He cited an open-label, 12-week, uncontrolled study in 27 patients with active RA who wore an ear clip for vagal nerve stimulation for 12 weeks. The mean Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) – the primary study endpoint – improved from 6.30 at baseline to 3.76 at week 12. The number of tender joints dropped from 12.17 to 4.7, while the swollen joint count went from 7.0 to 3.44. Pain scores improved from 75.23 to 43.3. Scores on the Health Assessment Questionnaire Disability Index improved from 1.59 to 1.05. There was no significant change in CRP. All in all, a modest clinical effect achieved noninvasively.

“The thing that did it for me was the effect on MRI from baseline: decreased synovitis, osteitis, and bone erosion scores,” Dr. Wells said. “This is noninvasive, so patients who want to do medical marijuana or CBD can put an earring on their auricular nerve.”

Dr. Fleischmann scoffed. “An open-label study, 27 patients? Let me see the real study,” he quipped.

Dr. Fleischmann reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Wells serves as a consultant to MiCare Path.

bjancin@mdedge.com