Key clinical point: Stimulation with IL-33 showed an increase in several mast cell lines in RA patients compared to controls, suggesting that inhibiting mast cells might be a therapeutic strategy to prevent joint deterioration in RA patients.

Major finding: Synovial tissues in RA patients showed more more c-kit- and FcεRI-positive mast cells, which are producers of both tryptase and chymase, compared to controls after stimulation with IL-33. In addition, IL-33-stimulated mast cells promoted more osteoclast differentiation than non-stimulated mast cells.

Study details: The data come from synovial fluid samples collected from 20 RA patients and 20 patients with osteoarthritis of knee joints who served as controls. 

Disclosures: The study was supported in part by grants from the National Research Foundation of Korea. The researchers had no financial conflicts to disclose.  

Source: Kim K-W et al. Arthritis Res Ther. 2021 Apr 21. doi: 10.1186/s13075-021-02491-1.

Key clinical point: Stimulation with IL-33 showed an increase in several mast cell lines in RA patients compared to controls, suggesting that inhibiting mast cells might be a therapeutic strategy to prevent joint deterioration in RA patients.

Major finding: Synovial tissues in RA patients showed more more c-kit- and FcεRI-positive mast cells, which are producers of both tryptase and chymase, compared to controls after stimulation with IL-33. In addition, IL-33-stimulated mast cells promoted more osteoclast differentiation than non-stimulated mast cells.

Study details: The data come from synovial fluid samples collected from 20 RA patients and 20 patients with osteoarthritis of knee joints who served as controls. 

Disclosures: The study was supported in part by grants from the National Research Foundation of Korea. The researchers had no financial conflicts to disclose.  

Source: Kim K-W et al. Arthritis Res Ther. 2021 Apr 21. doi: 10.1186/s13075-021-02491-1.

Key clinical point: Stimulation with IL-33 showed an increase in several mast cell lines in RA patients compared to controls, suggesting that inhibiting mast cells might be a therapeutic strategy to prevent joint deterioration in RA patients.

Major finding: Synovial tissues in RA patients showed more more c-kit- and FcεRI-positive mast cells, which are producers of both tryptase and chymase, compared to controls after stimulation with IL-33. In addition, IL-33-stimulated mast cells promoted more osteoclast differentiation than non-stimulated mast cells.

Study details: The data come from synovial fluid samples collected from 20 RA patients and 20 patients with osteoarthritis of knee joints who served as controls. 

Disclosures: The study was supported in part by grants from the National Research Foundation of Korea. The researchers had no financial conflicts to disclose.  

Source: Kim K-W et al. Arthritis Res Ther. 2021 Apr 21. doi: 10.1186/s13075-021-02491-1.

Key clinical point: In an analysis of blood-derived CD19+ B cells, miRNAs may have regulatory functions in RA patients treated with methotrexate.

Major finding: Differences in expression were noted for 27 microRNAs between methotrexate patients and controls, but no significant differences between newly diagnosed patients and controls. Some of the differentially expressed miRNAs were dysregulated in RA patients including miR-223-3p, miR-486-3p and miR-23a-3p. 

Study details: The data come from small RNA sequencing of 10 newly diagnosed untreated RA patients (n=10), 18 successfully methotrexate (MTX) treated RA patients in remission, and 9 healthy controls.

Disclosures: The study was supported in part by Helse Sør-Øst Grants. The researchers had no financial conflicts to disclose.

Source: Heinicke F et al. Front Immunol. 2021 Apr 9. doi: 10.3389/fimmu.2021.663736.

Key clinical point: In an analysis of blood-derived CD19+ B cells, miRNAs may have regulatory functions in RA patients treated with methotrexate.

Major finding: Differences in expression were noted for 27 microRNAs between methotrexate patients and controls, but no significant differences between newly diagnosed patients and controls. Some of the differentially expressed miRNAs were dysregulated in RA patients including miR-223-3p, miR-486-3p and miR-23a-3p. 

Study details: The data come from small RNA sequencing of 10 newly diagnosed untreated RA patients (n=10), 18 successfully methotrexate (MTX) treated RA patients in remission, and 9 healthy controls.

Disclosures: The study was supported in part by Helse Sør-Øst Grants. The researchers had no financial conflicts to disclose.

Source: Heinicke F et al. Front Immunol. 2021 Apr 9. doi: 10.3389/fimmu.2021.663736.

Key clinical point: In an analysis of blood-derived CD19+ B cells, miRNAs may have regulatory functions in RA patients treated with methotrexate.

Major finding: Differences in expression were noted for 27 microRNAs between methotrexate patients and controls, but no significant differences between newly diagnosed patients and controls. Some of the differentially expressed miRNAs were dysregulated in RA patients including miR-223-3p, miR-486-3p and miR-23a-3p. 

Study details: The data come from small RNA sequencing of 10 newly diagnosed untreated RA patients (n=10), 18 successfully methotrexate (MTX) treated RA patients in remission, and 9 healthy controls.

Disclosures: The study was supported in part by Helse Sør-Øst Grants. The researchers had no financial conflicts to disclose.

Source: Heinicke F et al. Front Immunol. 2021 Apr 9. doi: 10.3389/fimmu.2021.663736.

Key clinical point: Rheumatoid arthritis patients taking a combination of methotrexate and JAKi showed no increased risk of malignancy compared to RA patients on methotrexate alone.

Major finding: No significant differences in overall malignancy appeared between methotrexate /JAKi combination patients compared to methotrexate-only patients (risk ratio 1.42); no differences appeared between the groups for nonmelanoma skin cancer (RR 1.44), malignancies excluding nonmelanoma skin cancer (RR 1.12), serious adverse events (RR 1.15), or deaths (RR 1.99).

Study details: The data come from a meta-analysis of 13 randomized, controlled trials with a total of 6,911 RA patients who received methotrexate and Janus kinase inhibitors (JAKi) 

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Solipuram V et al. Auto Immune Highlights. 2021 Apr 28. doi: 10.1186/s13317-021-00153-5.

Key clinical point: Rheumatoid arthritis patients taking a combination of methotrexate and JAKi showed no increased risk of malignancy compared to RA patients on methotrexate alone.

Major finding: No significant differences in overall malignancy appeared between methotrexate /JAKi combination patients compared to methotrexate-only patients (risk ratio 1.42); no differences appeared between the groups for nonmelanoma skin cancer (RR 1.44), malignancies excluding nonmelanoma skin cancer (RR 1.12), serious adverse events (RR 1.15), or deaths (RR 1.99).

Study details: The data come from a meta-analysis of 13 randomized, controlled trials with a total of 6,911 RA patients who received methotrexate and Janus kinase inhibitors (JAKi) 

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Solipuram V et al. Auto Immune Highlights. 2021 Apr 28. doi: 10.1186/s13317-021-00153-5.

Key clinical point: Rheumatoid arthritis patients taking a combination of methotrexate and JAKi showed no increased risk of malignancy compared to RA patients on methotrexate alone.

Major finding: No significant differences in overall malignancy appeared between methotrexate /JAKi combination patients compared to methotrexate-only patients (risk ratio 1.42); no differences appeared between the groups for nonmelanoma skin cancer (RR 1.44), malignancies excluding nonmelanoma skin cancer (RR 1.12), serious adverse events (RR 1.15), or deaths (RR 1.99).

Study details: The data come from a meta-analysis of 13 randomized, controlled trials with a total of 6,911 RA patients who received methotrexate and Janus kinase inhibitors (JAKi) 

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Solipuram V et al. Auto Immune Highlights. 2021 Apr 28. doi: 10.1186/s13317-021-00153-5.

Key clinical point: Current smoking was an independent predictor of inadequate response to methotrexate in treatment-naïve rheumatoid arthritis patients.

Major finding: Inadequate response to methotrexate, demonstrated by failure to achieve low disease activity, was significantly associated with current smoking (adjusted odds ratio 1.79). Lack of EULAR response also was significantly associated with current smoking (aOR 2.04).

Study details: The data come from a retrospective cohort study of 294 rheumatoid arthritis patients (60.5% women) who were naïve to disease modifying anti-rheumatic drugs.  

Disclosures: The study was supported by an unconditioned research grant from Pfizer. The researchers had no financial conflicts to disclose.

Source: Floris A et al. Medicine. 2021 Apr 30. doi: 10.1097/MD.0000000000025481.

Key clinical point: Current smoking was an independent predictor of inadequate response to methotrexate in treatment-naïve rheumatoid arthritis patients.

Major finding: Inadequate response to methotrexate, demonstrated by failure to achieve low disease activity, was significantly associated with current smoking (adjusted odds ratio 1.79). Lack of EULAR response also was significantly associated with current smoking (aOR 2.04).

Study details: The data come from a retrospective cohort study of 294 rheumatoid arthritis patients (60.5% women) who were naïve to disease modifying anti-rheumatic drugs.  

Disclosures: The study was supported by an unconditioned research grant from Pfizer. The researchers had no financial conflicts to disclose.

Source: Floris A et al. Medicine. 2021 Apr 30. doi: 10.1097/MD.0000000000025481.

Key clinical point: Current smoking was an independent predictor of inadequate response to methotrexate in treatment-naïve rheumatoid arthritis patients.

Major finding: Inadequate response to methotrexate, demonstrated by failure to achieve low disease activity, was significantly associated with current smoking (adjusted odds ratio 1.79). Lack of EULAR response also was significantly associated with current smoking (aOR 2.04).

Study details: The data come from a retrospective cohort study of 294 rheumatoid arthritis patients (60.5% women) who were naïve to disease modifying anti-rheumatic drugs.  

Disclosures: The study was supported by an unconditioned research grant from Pfizer. The researchers had no financial conflicts to disclose.

Source: Floris A et al. Medicine. 2021 Apr 30. doi: 10.1097/MD.0000000000025481.

Key clinical point: Diagnostic delay was an independent predictor of mortality in RA patients with interstitial lung disease in a multivariate analysis.

Major finding: Diagnostic delay was significantly associated with increased risk of mortality in adults with RA and interstitial lung disease (hazard ratio 1.11), along with age, severe oxygen desaturation on effort (SatO2) and diffusion capacity for carbon monoxide (DLCO); with hazard ratios of 1.33, 0.85, and 0.62, respectively.   

Study details: The data come from a multicenter study of 106 consecutive adults with rheumatoid arthritis and interstitial lung disease.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Cano-Jiménez E et al. Sci Rep. 2021 Apr 28. doi: 10.1038/s41598-021-88734-2.

Key clinical point: Diagnostic delay was an independent predictor of mortality in RA patients with interstitial lung disease in a multivariate analysis.

Major finding: Diagnostic delay was significantly associated with increased risk of mortality in adults with RA and interstitial lung disease (hazard ratio 1.11), along with age, severe oxygen desaturation on effort (SatO2) and diffusion capacity for carbon monoxide (DLCO); with hazard ratios of 1.33, 0.85, and 0.62, respectively.   

Study details: The data come from a multicenter study of 106 consecutive adults with rheumatoid arthritis and interstitial lung disease.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Cano-Jiménez E et al. Sci Rep. 2021 Apr 28. doi: 10.1038/s41598-021-88734-2.

Key clinical point: Diagnostic delay was an independent predictor of mortality in RA patients with interstitial lung disease in a multivariate analysis.

Major finding: Diagnostic delay was significantly associated with increased risk of mortality in adults with RA and interstitial lung disease (hazard ratio 1.11), along with age, severe oxygen desaturation on effort (SatO2) and diffusion capacity for carbon monoxide (DLCO); with hazard ratios of 1.33, 0.85, and 0.62, respectively.   

Study details: The data come from a multicenter study of 106 consecutive adults with rheumatoid arthritis and interstitial lung disease.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Cano-Jiménez E et al. Sci Rep. 2021 Apr 28. doi: 10.1038/s41598-021-88734-2.

Key clinical point: Rheumatic immune-related adverse events occurred in approximately one-third of cancer patients on immune checkpoint inhibitor (ICI) therapy.

Major finding: A total of 37.3% of patients on ICI therapy experienced at least one immune-related adverse event; 4.3% of patients experienced at least one rheumatic immune-related adverse event (rh-irAEs) and 3 of these patients had pre-existing rheumatic disease.

Study details: The data come from 437 adult cancer patients who were treated with ipilimumab and/or nivolumab, or pembrolizumab at a single center between January 2014 and December 2018.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Verspohl SH et al. Ther Adv Musculoskelet Dis. 2021 Apr 12. doi: 10.1177/1759720X211006963.

Key clinical point: Rheumatic immune-related adverse events occurred in approximately one-third of cancer patients on immune checkpoint inhibitor (ICI) therapy.

Major finding: A total of 37.3% of patients on ICI therapy experienced at least one immune-related adverse event; 4.3% of patients experienced at least one rheumatic immune-related adverse event (rh-irAEs) and 3 of these patients had pre-existing rheumatic disease.

Study details: The data come from 437 adult cancer patients who were treated with ipilimumab and/or nivolumab, or pembrolizumab at a single center between January 2014 and December 2018.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Verspohl SH et al. Ther Adv Musculoskelet Dis. 2021 Apr 12. doi: 10.1177/1759720X211006963.

Key clinical point: Rheumatic immune-related adverse events occurred in approximately one-third of cancer patients on immune checkpoint inhibitor (ICI) therapy.

Major finding: A total of 37.3% of patients on ICI therapy experienced at least one immune-related adverse event; 4.3% of patients experienced at least one rheumatic immune-related adverse event (rh-irAEs) and 3 of these patients had pre-existing rheumatic disease.

Study details: The data come from 437 adult cancer patients who were treated with ipilimumab and/or nivolumab, or pembrolizumab at a single center between January 2014 and December 2018.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Verspohl SH et al. Ther Adv Musculoskelet Dis. 2021 Apr 12. doi: 10.1177/1759720X211006963.

Key clinical point: The Internet-based Worry and Sadness program improved mental health in adults with rheumatoid arthritis over 3 months.

Major finding: At 3 months’ follow-up, measures of anxiety, depression, and emotional distress  improved significantly from baseline with effect sizes ranging from small to large; 44% of participants had normal scores for anxiety (medium effect size).

Study details: The data come from 28 adults (mean age 57 years, 86% women) with rheumatoid arthritis who completed an Internet-based cognitive-behavioral therapy intervention.

Disclosures: The study was supported in part by a University of Manitoba Graduate Fellowship and The Arthritis Society 2016 PhD Salary Award to lead author Dr. Blaney, and by the CIHR Chronic Pain SPOR Network and Health Sciences Centre. The researchers had no financial conflicts to disclose.

Source: Blaney C et al. Internet Interv. 2021 Mar 26. doi: 10.1016/j.invent.2021.100385.

Key clinical point: The Internet-based Worry and Sadness program improved mental health in adults with rheumatoid arthritis over 3 months.

Major finding: At 3 months’ follow-up, measures of anxiety, depression, and emotional distress  improved significantly from baseline with effect sizes ranging from small to large; 44% of participants had normal scores for anxiety (medium effect size).

Study details: The data come from 28 adults (mean age 57 years, 86% women) with rheumatoid arthritis who completed an Internet-based cognitive-behavioral therapy intervention.

Disclosures: The study was supported in part by a University of Manitoba Graduate Fellowship and The Arthritis Society 2016 PhD Salary Award to lead author Dr. Blaney, and by the CIHR Chronic Pain SPOR Network and Health Sciences Centre. The researchers had no financial conflicts to disclose.

Source: Blaney C et al. Internet Interv. 2021 Mar 26. doi: 10.1016/j.invent.2021.100385.

Key clinical point: The Internet-based Worry and Sadness program improved mental health in adults with rheumatoid arthritis over 3 months.

Major finding: At 3 months’ follow-up, measures of anxiety, depression, and emotional distress  improved significantly from baseline with effect sizes ranging from small to large; 44% of participants had normal scores for anxiety (medium effect size).

Study details: The data come from 28 adults (mean age 57 years, 86% women) with rheumatoid arthritis who completed an Internet-based cognitive-behavioral therapy intervention.

Disclosures: The study was supported in part by a University of Manitoba Graduate Fellowship and The Arthritis Society 2016 PhD Salary Award to lead author Dr. Blaney, and by the CIHR Chronic Pain SPOR Network and Health Sciences Centre. The researchers had no financial conflicts to disclose.

Source: Blaney C et al. Internet Interv. 2021 Mar 26. doi: 10.1016/j.invent.2021.100385.

Key clinical point: Use of beta blockers was significantly associated with remission in RA based on the Simplified Disease Activity Index and Clinical Disease Activity Index.

Major finding: Approximately 11% of the RA patients were using systemic beta blockers, and beta blocker use was associated with less frequent remission, both in the total study cohort and the cohort of patients with cardiovascular disease (adjusted hazard ratios 0.70 and 0.75, respectively).

Study details: The data come from a pooled cohort analysis of five randomized trials of tocilizumab and/or csDMARDs including 5,502 RA patients.

Disclosures: The study received no outside funding. Two researchers were supported by Beat Cancer Research Fellowships from Cancer Council South Australia and a Postdoctoral Fellowship from the National Breast Cancer Foundation, Australia. The lead author and other researchers had no financial conflicts to disclose. 

Source: Abuhelwa AY. Ther Adv Musculoskelet Dis. 2021 Apr 12. doi: 10.1177/1759720X211009020.

Key clinical point: Use of beta blockers was significantly associated with remission in RA based on the Simplified Disease Activity Index and Clinical Disease Activity Index.

Major finding: Approximately 11% of the RA patients were using systemic beta blockers, and beta blocker use was associated with less frequent remission, both in the total study cohort and the cohort of patients with cardiovascular disease (adjusted hazard ratios 0.70 and 0.75, respectively).

Study details: The data come from a pooled cohort analysis of five randomized trials of tocilizumab and/or csDMARDs including 5,502 RA patients.

Disclosures: The study received no outside funding. Two researchers were supported by Beat Cancer Research Fellowships from Cancer Council South Australia and a Postdoctoral Fellowship from the National Breast Cancer Foundation, Australia. The lead author and other researchers had no financial conflicts to disclose. 

Source: Abuhelwa AY. Ther Adv Musculoskelet Dis. 2021 Apr 12. doi: 10.1177/1759720X211009020.

Key clinical point: Use of beta blockers was significantly associated with remission in RA based on the Simplified Disease Activity Index and Clinical Disease Activity Index.

Major finding: Approximately 11% of the RA patients were using systemic beta blockers, and beta blocker use was associated with less frequent remission, both in the total study cohort and the cohort of patients with cardiovascular disease (adjusted hazard ratios 0.70 and 0.75, respectively).

Study details: The data come from a pooled cohort analysis of five randomized trials of tocilizumab and/or csDMARDs including 5,502 RA patients.

Disclosures: The study received no outside funding. Two researchers were supported by Beat Cancer Research Fellowships from Cancer Council South Australia and a Postdoctoral Fellowship from the National Breast Cancer Foundation, Australia. The lead author and other researchers had no financial conflicts to disclose. 

Source: Abuhelwa AY. Ther Adv Musculoskelet Dis. 2021 Apr 12. doi: 10.1177/1759720X211009020.

Key clinical point: Treatment of irradiated peripheral blood mononuclear cells (PBMCs) with filgotinib in particular correlated with enhanced foci in vitro; the study was a rare comparison of all four JAKis approved for RA: tofacitinib, baricitinib, and upadacitinib, and filgotinib.

Major finding: Lymphocyte proliferation was similar for tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib was two orders of magnitude higher when these JAKis were added to peripheral blood mononuclear cells from healthy donors.

Study details: The data come from an in vitro study of four JAK inhibitors currently approved for the treatment of RA: tofacitinib, baricitinib, upadacitinib, and filgotinib, in which increasing concentrations of the JAKis or methotrexate were added to peripheral blood mononuclear cells from healthy volunteers.

Disclosures: The study was supported by the European Union Program Regional Development Fund of the Ministry of Economy, Science and Digitalisation in Saxony-Anhalt. Lead author Dr. Reddig had no financial conflicts to disclose.

Source: Reddig A et al. J Clin Med. 2021 Apr 1. doi: 103390/jcm10071431.

Key clinical point: Treatment of irradiated peripheral blood mononuclear cells (PBMCs) with filgotinib in particular correlated with enhanced foci in vitro; the study was a rare comparison of all four JAKis approved for RA: tofacitinib, baricitinib, and upadacitinib, and filgotinib.

Major finding: Lymphocyte proliferation was similar for tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib was two orders of magnitude higher when these JAKis were added to peripheral blood mononuclear cells from healthy donors.

Study details: The data come from an in vitro study of four JAK inhibitors currently approved for the treatment of RA: tofacitinib, baricitinib, upadacitinib, and filgotinib, in which increasing concentrations of the JAKis or methotrexate were added to peripheral blood mononuclear cells from healthy volunteers.

Disclosures: The study was supported by the European Union Program Regional Development Fund of the Ministry of Economy, Science and Digitalisation in Saxony-Anhalt. Lead author Dr. Reddig had no financial conflicts to disclose.

Source: Reddig A et al. J Clin Med. 2021 Apr 1. doi: 103390/jcm10071431.

Key clinical point: Treatment of irradiated peripheral blood mononuclear cells (PBMCs) with filgotinib in particular correlated with enhanced foci in vitro; the study was a rare comparison of all four JAKis approved for RA: tofacitinib, baricitinib, and upadacitinib, and filgotinib.

Major finding: Lymphocyte proliferation was similar for tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib was two orders of magnitude higher when these JAKis were added to peripheral blood mononuclear cells from healthy donors.

Study details: The data come from an in vitro study of four JAK inhibitors currently approved for the treatment of RA: tofacitinib, baricitinib, upadacitinib, and filgotinib, in which increasing concentrations of the JAKis or methotrexate were added to peripheral blood mononuclear cells from healthy volunteers.

Disclosures: The study was supported by the European Union Program Regional Development Fund of the Ministry of Economy, Science and Digitalisation in Saxony-Anhalt. Lead author Dr. Reddig had no financial conflicts to disclose.

Source: Reddig A et al. J Clin Med. 2021 Apr 1. doi: 103390/jcm10071431.

The association of RA and cardiovascular disease has been extensively described. Beta adrenergic receptors are not known to be involved in RA, though Abuhelwa et al. suggest a potential role in “immunologic balance” in their study of beta blocker use and RA remission. In a pooled analysis of five tocilizumab trials, use of beta blockers was associated with lower proportions of CDAI remission. However, without information on beta blocker dose or duration of therapy as well as potential confounding by indication, the significance of this finding is uncertain.

Another known association of RA and its treatment is malignancy, perhaps due to decrease in immunosurveillance; it remains a concern in choice of therapy and long-term effects. Solipuram et al. performed a systematic review of combination JAK inhibitor and methotrexate therapy in RA to evaluate the evidence regarding malignancy risk. Among the 13 trials included for analysis, 40 cases of malignancy were reported for over 3,600 patient-years in patients receiving combination therapy, compared to 7 cases among nearly 1,000 patient-years in patients receiving methotrexate alone; no change in relative risk was seen in non-melanomatous skin cancer or other cancers. While this information is reassuring, it does not eliminate the possibility of increased malignancy given variations in duration of followup in different studies.  There is also a need for longer follow-up because of a potential latency period before the development of cancer. Ideally, long-term extension studies could help better define this risk, though those studies tend to be single-armed and without a control.

Though different JAK inhibitors generally are thought to have similar efficacy and class-associated side effects, few studies have compared immunomodulatory effects of the medications. Reddig et al compared the effects of baricitinib, upadicitinib, filgotinib, tofacitinib, and methotrexate on cell proliferation, cell activation, and apoptosis, as well as induction of DNA damage and repair in an in vitro study. The study authors used human peripheral blood monocytes treated with phytohemagglutinin to activate T cells and induce proliferation. Tofacitinib, baricitinib, and upadicitinib were associated with comparable dose-dependent inhibition of lymphocyte activation and proliferation. Higher doses of filgotinib were required to obtain the same effect. Filgotinib at high concentrations also were associated with higher levels of DNA damage markers. These findings are interesting as to the shared mechanism of action of JAK inhibitors, regardless of JAK specificity. However, given the lack of “universal” patterns in vitro, their clinical importance or relevance in distinguishing between the medications is unclear.

Kim et al. investigates the pathogenesis of RA in their in vitro study of mast cells. Though previously identified in RA synovial fluid and tissue and not in OA synovium, their role is not entirely clear. Though normally associated with allergic responses, mast cells have been postulated to have pro- and anti-inflammatory effects, and release inflammatory cytokines and mediators, such as histamine. Synovial fluid and serum samples from RA and OA patients, as well as healthy volunteers, were analyzed for tryptase, chymase, and histamine; serum levels of all three were higher in RA than in OA patients and healthy volunteers. Synovial fluid levels of histamine were higher in RA. Cell culture studies were performed using IL-33 to activate human mast cells, causing an increase in tryptase –positive cells, as well as an increased expression of RANKL and MMP-9. This suggests a role for mast cells in osteoclastogenesis and tissue degradation. In addition to providing more information about the involvement of mast cells in RA pathogenesis, these findings suggest mast cells as a potential therapeutic target.

The association of RA and cardiovascular disease has been extensively described. Beta adrenergic receptors are not known to be involved in RA, though Abuhelwa et al. suggest a potential role in “immunologic balance” in their study of beta blocker use and RA remission. In a pooled analysis of five tocilizumab trials, use of beta blockers was associated with lower proportions of CDAI remission. However, without information on beta blocker dose or duration of therapy as well as potential confounding by indication, the significance of this finding is uncertain.

Another known association of RA and its treatment is malignancy, perhaps due to decrease in immunosurveillance; it remains a concern in choice of therapy and long-term effects. Solipuram et al. performed a systematic review of combination JAK inhibitor and methotrexate therapy in RA to evaluate the evidence regarding malignancy risk. Among the 13 trials included for analysis, 40 cases of malignancy were reported for over 3,600 patient-years in patients receiving combination therapy, compared to 7 cases among nearly 1,000 patient-years in patients receiving methotrexate alone; no change in relative risk was seen in non-melanomatous skin cancer or other cancers. While this information is reassuring, it does not eliminate the possibility of increased malignancy given variations in duration of followup in different studies.  There is also a need for longer follow-up because of a potential latency period before the development of cancer. Ideally, long-term extension studies could help better define this risk, though those studies tend to be single-armed and without a control.

Though different JAK inhibitors generally are thought to have similar efficacy and class-associated side effects, few studies have compared immunomodulatory effects of the medications. Reddig et al compared the effects of baricitinib, upadicitinib, filgotinib, tofacitinib, and methotrexate on cell proliferation, cell activation, and apoptosis, as well as induction of DNA damage and repair in an in vitro study. The study authors used human peripheral blood monocytes treated with phytohemagglutinin to activate T cells and induce proliferation. Tofacitinib, baricitinib, and upadicitinib were associated with comparable dose-dependent inhibition of lymphocyte activation and proliferation. Higher doses of filgotinib were required to obtain the same effect. Filgotinib at high concentrations also were associated with higher levels of DNA damage markers. These findings are interesting as to the shared mechanism of action of JAK inhibitors, regardless of JAK specificity. However, given the lack of “universal” patterns in vitro, their clinical importance or relevance in distinguishing between the medications is unclear.

Kim et al. investigates the pathogenesis of RA in their in vitro study of mast cells. Though previously identified in RA synovial fluid and tissue and not in OA synovium, their role is not entirely clear. Though normally associated with allergic responses, mast cells have been postulated to have pro- and anti-inflammatory effects, and release inflammatory cytokines and mediators, such as histamine. Synovial fluid and serum samples from RA and OA patients, as well as healthy volunteers, were analyzed for tryptase, chymase, and histamine; serum levels of all three were higher in RA than in OA patients and healthy volunteers. Synovial fluid levels of histamine were higher in RA. Cell culture studies were performed using IL-33 to activate human mast cells, causing an increase in tryptase –positive cells, as well as an increased expression of RANKL and MMP-9. This suggests a role for mast cells in osteoclastogenesis and tissue degradation. In addition to providing more information about the involvement of mast cells in RA pathogenesis, these findings suggest mast cells as a potential therapeutic target.

The association of RA and cardiovascular disease has been extensively described. Beta adrenergic receptors are not known to be involved in RA, though Abuhelwa et al. suggest a potential role in “immunologic balance” in their study of beta blocker use and RA remission. In a pooled analysis of five tocilizumab trials, use of beta blockers was associated with lower proportions of CDAI remission. However, without information on beta blocker dose or duration of therapy as well as potential confounding by indication, the significance of this finding is uncertain.

Another known association of RA and its treatment is malignancy, perhaps due to decrease in immunosurveillance; it remains a concern in choice of therapy and long-term effects. Solipuram et al. performed a systematic review of combination JAK inhibitor and methotrexate therapy in RA to evaluate the evidence regarding malignancy risk. Among the 13 trials included for analysis, 40 cases of malignancy were reported for over 3,600 patient-years in patients receiving combination therapy, compared to 7 cases among nearly 1,000 patient-years in patients receiving methotrexate alone; no change in relative risk was seen in non-melanomatous skin cancer or other cancers. While this information is reassuring, it does not eliminate the possibility of increased malignancy given variations in duration of followup in different studies.  There is also a need for longer follow-up because of a potential latency period before the development of cancer. Ideally, long-term extension studies could help better define this risk, though those studies tend to be single-armed and without a control.

Though different JAK inhibitors generally are thought to have similar efficacy and class-associated side effects, few studies have compared immunomodulatory effects of the medications. Reddig et al compared the effects of baricitinib, upadicitinib, filgotinib, tofacitinib, and methotrexate on cell proliferation, cell activation, and apoptosis, as well as induction of DNA damage and repair in an in vitro study. The study authors used human peripheral blood monocytes treated with phytohemagglutinin to activate T cells and induce proliferation. Tofacitinib, baricitinib, and upadicitinib were associated with comparable dose-dependent inhibition of lymphocyte activation and proliferation. Higher doses of filgotinib were required to obtain the same effect. Filgotinib at high concentrations also were associated with higher levels of DNA damage markers. These findings are interesting as to the shared mechanism of action of JAK inhibitors, regardless of JAK specificity. However, given the lack of “universal” patterns in vitro, their clinical importance or relevance in distinguishing between the medications is unclear.

Kim et al. investigates the pathogenesis of RA in their in vitro study of mast cells. Though previously identified in RA synovial fluid and tissue and not in OA synovium, their role is not entirely clear. Though normally associated with allergic responses, mast cells have been postulated to have pro- and anti-inflammatory effects, and release inflammatory cytokines and mediators, such as histamine. Synovial fluid and serum samples from RA and OA patients, as well as healthy volunteers, were analyzed for tryptase, chymase, and histamine; serum levels of all three were higher in RA than in OA patients and healthy volunteers. Synovial fluid levels of histamine were higher in RA. Cell culture studies were performed using IL-33 to activate human mast cells, causing an increase in tryptase –positive cells, as well as an increased expression of RANKL and MMP-9. This suggests a role for mast cells in osteoclastogenesis and tissue degradation. In addition to providing more information about the involvement of mast cells in RA pathogenesis, these findings suggest mast cells as a potential therapeutic target.