Arundathi Jayatilleke, MD

The association of rheumatoid arthritis (RA) with increased cancer risk compared with the general population has long been known, though the balance between risk related to RA disease activity compared with risk related to immunosuppressive medication has not been clear. This increased risk is seen primarily with lymphoma and lung cancer, and prior research has suggested a risk with biological disease-modifying antirheumatic drugs (bDMARD), such as anti–tumor necrosis factor (TNF) agents. Beydon and colleagues performed a cohort study using a French national claims database; they looked at patients seen for at least 1 year with treatment for RA and compared the incidence of cancer by type. In over 257,000 patients, nearly 24,000 cancer cases were found. The most common cancers were breast, colon, lung, and prostate. All-cancer risk was > 1.2 (standardized incidence ratio) compared with those without cancer, higher in men compared with women, and the risk was increased in patients who received conventional synthetic (cs) DMARD, TNF inhibitors (TNFi), abatacept, and rituximab, but not interleukin (IL)-6 inhibitors or Janus kinase inhibitors (JAKi). Given that the risk was most highly associated with exposure to rituximab, this may show a type of bias rendering the study difficult to interpret, as rituximab is considered "safe" in cancer, and treatments such as csDMARD may have been given because they were not contraindicated in patients with cancer. This renders the study’s other results, such as lower risk with JAKi or higher risk with abatacept, hard to interpret.

Hayashi and colleagues performed a "real-world" comparative study using data from the Japanese observational ANSWER registry database to compare effectiveness of different JAKi over 6 months, a question of high interest given the availability of several JAKi currently. Within the database of over 11,000 participants, only 622 patients were exposed to tofacitinib, baricitinib, peficitinib, or upadacitinib, with 361 included in the final analysis due to missing baseline data (later missing data were imputed). Treatment retention rates were similar among all four JAKi, and discontinuation rates due to adverse events and due to lack of efficacy were similar as well. There was no significant difference in Health Assessment Questionnaire (HAQ), Clinical Disease Activity Index (CDAI), or C-reactive protein after 6 months between the four JAKi. Baricitinib had higher rates of CDAI low disease activity and remission at 6 months when used as a first-line biologic/targeted synthetic (b/ts) DMARD. However, this and other specific findings related to individual JAKi may be affected by the relatively small number of patients included and exposed to each JAKi, and the relatively short duration of follow-up (in terms of drug discontinuation), thus countering the initial premise for the study.

Finally, another important real-world study, by Tageldin and colleagues, looked at tapering therapy in the Rheumatoid Arthritis Medication Tapering (RHEUMTAP) cohort of patients with RA in sustained disease remission or low disease activity for at least 6 months on stable medications (infused bDMARD excluded). This 2-year prospective cohort included reducing frequency, reducing dose, and stopping medication according to predefined regimens. Of 131 patients, 40% underwent tapering, with more flares in the taper group over > 400 days of follow-up; flare rates were much higher in those tapering b/tsDMARD compared with csDMARD. Though limited by small numbers in examining the three different tapering groups, this real-world study provides an important counterpoint to the notion that medication can be tapered easily in RA patients doing well. A more stringent definition or longer duration of disease remission may also affect this finding.

The association of rheumatoid arthritis (RA) with increased cancer risk compared with the general population has long been known, though the balance between risk related to RA disease activity compared with risk related to immunosuppressive medication has not been clear. This increased risk is seen primarily with lymphoma and lung cancer, and prior research has suggested a risk with biological disease-modifying antirheumatic drugs (bDMARD), such as anti–tumor necrosis factor (TNF) agents. Beydon and colleagues performed a cohort study using a French national claims database; they looked at patients seen for at least 1 year with treatment for RA and compared the incidence of cancer by type. In over 257,000 patients, nearly 24,000 cancer cases were found. The most common cancers were breast, colon, lung, and prostate. All-cancer risk was > 1.2 (standardized incidence ratio) compared with those without cancer, higher in men compared with women, and the risk was increased in patients who received conventional synthetic (cs) DMARD, TNF inhibitors (TNFi), abatacept, and rituximab, but not interleukin (IL)-6 inhibitors or Janus kinase inhibitors (JAKi). Given that the risk was most highly associated with exposure to rituximab, this may show a type of bias rendering the study difficult to interpret, as rituximab is considered "safe" in cancer, and treatments such as csDMARD may have been given because they were not contraindicated in patients with cancer. This renders the study’s other results, such as lower risk with JAKi or higher risk with abatacept, hard to interpret.

Hayashi and colleagues performed a "real-world" comparative study using data from the Japanese observational ANSWER registry database to compare effectiveness of different JAKi over 6 months, a question of high interest given the availability of several JAKi currently. Within the database of over 11,000 participants, only 622 patients were exposed to tofacitinib, baricitinib, peficitinib, or upadacitinib, with 361 included in the final analysis due to missing baseline data (later missing data were imputed). Treatment retention rates were similar among all four JAKi, and discontinuation rates due to adverse events and due to lack of efficacy were similar as well. There was no significant difference in Health Assessment Questionnaire (HAQ), Clinical Disease Activity Index (CDAI), or C-reactive protein after 6 months between the four JAKi. Baricitinib had higher rates of CDAI low disease activity and remission at 6 months when used as a first-line biologic/targeted synthetic (b/ts) DMARD. However, this and other specific findings related to individual JAKi may be affected by the relatively small number of patients included and exposed to each JAKi, and the relatively short duration of follow-up (in terms of drug discontinuation), thus countering the initial premise for the study.

Finally, another important real-world study, by Tageldin and colleagues, looked at tapering therapy in the Rheumatoid Arthritis Medication Tapering (RHEUMTAP) cohort of patients with RA in sustained disease remission or low disease activity for at least 6 months on stable medications (infused bDMARD excluded). This 2-year prospective cohort included reducing frequency, reducing dose, and stopping medication according to predefined regimens. Of 131 patients, 40% underwent tapering, with more flares in the taper group over > 400 days of follow-up; flare rates were much higher in those tapering b/tsDMARD compared with csDMARD. Though limited by small numbers in examining the three different tapering groups, this real-world study provides an important counterpoint to the notion that medication can be tapered easily in RA patients doing well. A more stringent definition or longer duration of disease remission may also affect this finding.

The association of rheumatoid arthritis (RA) with increased cancer risk compared with the general population has long been known, though the balance between risk related to RA disease activity compared with risk related to immunosuppressive medication has not been clear. This increased risk is seen primarily with lymphoma and lung cancer, and prior research has suggested a risk with biological disease-modifying antirheumatic drugs (bDMARD), such as anti–tumor necrosis factor (TNF) agents. Beydon and colleagues performed a cohort study using a French national claims database; they looked at patients seen for at least 1 year with treatment for RA and compared the incidence of cancer by type. In over 257,000 patients, nearly 24,000 cancer cases were found. The most common cancers were breast, colon, lung, and prostate. All-cancer risk was > 1.2 (standardized incidence ratio) compared with those without cancer, higher in men compared with women, and the risk was increased in patients who received conventional synthetic (cs) DMARD, TNF inhibitors (TNFi), abatacept, and rituximab, but not interleukin (IL)-6 inhibitors or Janus kinase inhibitors (JAKi). Given that the risk was most highly associated with exposure to rituximab, this may show a type of bias rendering the study difficult to interpret, as rituximab is considered "safe" in cancer, and treatments such as csDMARD may have been given because they were not contraindicated in patients with cancer. This renders the study’s other results, such as lower risk with JAKi or higher risk with abatacept, hard to interpret.

Hayashi and colleagues performed a "real-world" comparative study using data from the Japanese observational ANSWER registry database to compare effectiveness of different JAKi over 6 months, a question of high interest given the availability of several JAKi currently. Within the database of over 11,000 participants, only 622 patients were exposed to tofacitinib, baricitinib, peficitinib, or upadacitinib, with 361 included in the final analysis due to missing baseline data (later missing data were imputed). Treatment retention rates were similar among all four JAKi, and discontinuation rates due to adverse events and due to lack of efficacy were similar as well. There was no significant difference in Health Assessment Questionnaire (HAQ), Clinical Disease Activity Index (CDAI), or C-reactive protein after 6 months between the four JAKi. Baricitinib had higher rates of CDAI low disease activity and remission at 6 months when used as a first-line biologic/targeted synthetic (b/ts) DMARD. However, this and other specific findings related to individual JAKi may be affected by the relatively small number of patients included and exposed to each JAKi, and the relatively short duration of follow-up (in terms of drug discontinuation), thus countering the initial premise for the study.

Finally, another important real-world study, by Tageldin and colleagues, looked at tapering therapy in the Rheumatoid Arthritis Medication Tapering (RHEUMTAP) cohort of patients with RA in sustained disease remission or low disease activity for at least 6 months on stable medications (infused bDMARD excluded). This 2-year prospective cohort included reducing frequency, reducing dose, and stopping medication according to predefined regimens. Of 131 patients, 40% underwent tapering, with more flares in the taper group over > 400 days of follow-up; flare rates were much higher in those tapering b/tsDMARD compared with csDMARD. Though limited by small numbers in examining the three different tapering groups, this real-world study provides an important counterpoint to the notion that medication can be tapered easily in RA patients doing well. A more stringent definition or longer duration of disease remission may also affect this finding.

Given the frequency of autoimmune conditions in women, the possible effects of estrogen and hormonal therapy exposure over the lifespan on the development of rheumatoid arthritis (RA) has long been of interest. Prior studies have identified a potential increase in RA risk in older women taking estrogen replacement. Hadizadeh and colleagues used the UK Biobank to identify cases of RA among over 236,000 women taking oral contraceptives and over 102,000 women taking hormone replacement therapy. Oral contraceptive use was associated with lower risk for RA (hazard ratio [HR] 0.89), whereas hormone replacement therapy was associated with higher risk for RA (HR 1.16) compared with women who had never used these therapies. Exogenous estrogen exposure may affect the development of RA, but the potential mechanisms (including the effect on systemic inflammation) remain unclear.

Among the multitude of studies on a treat-to-target (T2T) strategy in RA, a recent cluster randomized trial by Bessette and colleagues compared use of abatacept in 284 patients treated by 44 physicians. Patients assigned to both T2T and routine care had significant improvement in RA disease activity (as measured by the Clinical Disease Activity Index) with abatacept, with close to 40% in low disease activity at 12 months. Those treated with routine care experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with slightly higher odds of low disease activity and a shorter time to Simplified Disease Activity Index remission (14 vs 19 months). With T2T being largely accepted as a standard of care on the basis of prior studies, this study raises the question of why little difference was seen between the two groups — perhaps it was related to the use of abatacept. It is unlikely to further change the standard of care to reduce use of disease activity measures.

To better understand refractory or difficult-to-treat (D2T) RA, Jung and colleagues used the KOBIO (KOrean College of Rheumatology BIOlogics) registry to compare characteristics of patients with D2T RA vs those who respond more readily to therapy. Of the 2321 patients included in the study, about 12% (271) had D2T RA. Patients with D2T RA tended to be younger and have longer disease duration, as well as a negative rheumatoid factor (RF); less use of conventional synthetic disease-modifying antirheumatic drugs (csDMARD); and, as expected, higher disease activity measures. Given that about 80% of patients were seropositive for RF and the fact that patients with D2T RA tended to have higher inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), it is not likely that patients were misclassified with RA. The reason why patients with D2T RA had less csDMARD use is not clear, but prior studies have supported early and aggressive use of csDMARD for best outcomes. The study did suggest that patients with D2T RA stayed on Janus kinase (JAK) inhibitor therapy the longest, and perhaps similar studies in future will help outline the best treatment strategy for patients with D2T RA and persistently high disease activity.

Finally, in a post hoc analysis of the ORAL Start trial of the JAK inhibitor tofacitinib vs methotrexate, Ciurea and colleagues looked at paired joint pathology scores (PJPS) — swollen and tender joint counts with left and right pooled — over the course of the 12-month study. Patients receiving tofacitinib had overall improved PJPS, though patients receiving methotrexate had more improvement in the foot. These findings, generally supporting those of the initial study, are unlikely to further change therapy.

Given the frequency of autoimmune conditions in women, the possible effects of estrogen and hormonal therapy exposure over the lifespan on the development of rheumatoid arthritis (RA) has long been of interest. Prior studies have identified a potential increase in RA risk in older women taking estrogen replacement. Hadizadeh and colleagues used the UK Biobank to identify cases of RA among over 236,000 women taking oral contraceptives and over 102,000 women taking hormone replacement therapy. Oral contraceptive use was associated with lower risk for RA (hazard ratio [HR] 0.89), whereas hormone replacement therapy was associated with higher risk for RA (HR 1.16) compared with women who had never used these therapies. Exogenous estrogen exposure may affect the development of RA, but the potential mechanisms (including the effect on systemic inflammation) remain unclear.

Among the multitude of studies on a treat-to-target (T2T) strategy in RA, a recent cluster randomized trial by Bessette and colleagues compared use of abatacept in 284 patients treated by 44 physicians. Patients assigned to both T2T and routine care had significant improvement in RA disease activity (as measured by the Clinical Disease Activity Index) with abatacept, with close to 40% in low disease activity at 12 months. Those treated with routine care experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with slightly higher odds of low disease activity and a shorter time to Simplified Disease Activity Index remission (14 vs 19 months). With T2T being largely accepted as a standard of care on the basis of prior studies, this study raises the question of why little difference was seen between the two groups — perhaps it was related to the use of abatacept. It is unlikely to further change the standard of care to reduce use of disease activity measures.

To better understand refractory or difficult-to-treat (D2T) RA, Jung and colleagues used the KOBIO (KOrean College of Rheumatology BIOlogics) registry to compare characteristics of patients with D2T RA vs those who respond more readily to therapy. Of the 2321 patients included in the study, about 12% (271) had D2T RA. Patients with D2T RA tended to be younger and have longer disease duration, as well as a negative rheumatoid factor (RF); less use of conventional synthetic disease-modifying antirheumatic drugs (csDMARD); and, as expected, higher disease activity measures. Given that about 80% of patients were seropositive for RF and the fact that patients with D2T RA tended to have higher inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), it is not likely that patients were misclassified with RA. The reason why patients with D2T RA had less csDMARD use is not clear, but prior studies have supported early and aggressive use of csDMARD for best outcomes. The study did suggest that patients with D2T RA stayed on Janus kinase (JAK) inhibitor therapy the longest, and perhaps similar studies in future will help outline the best treatment strategy for patients with D2T RA and persistently high disease activity.

Finally, in a post hoc analysis of the ORAL Start trial of the JAK inhibitor tofacitinib vs methotrexate, Ciurea and colleagues looked at paired joint pathology scores (PJPS) — swollen and tender joint counts with left and right pooled — over the course of the 12-month study. Patients receiving tofacitinib had overall improved PJPS, though patients receiving methotrexate had more improvement in the foot. These findings, generally supporting those of the initial study, are unlikely to further change therapy.

Given the frequency of autoimmune conditions in women, the possible effects of estrogen and hormonal therapy exposure over the lifespan on the development of rheumatoid arthritis (RA) has long been of interest. Prior studies have identified a potential increase in RA risk in older women taking estrogen replacement. Hadizadeh and colleagues used the UK Biobank to identify cases of RA among over 236,000 women taking oral contraceptives and over 102,000 women taking hormone replacement therapy. Oral contraceptive use was associated with lower risk for RA (hazard ratio [HR] 0.89), whereas hormone replacement therapy was associated with higher risk for RA (HR 1.16) compared with women who had never used these therapies. Exogenous estrogen exposure may affect the development of RA, but the potential mechanisms (including the effect on systemic inflammation) remain unclear.

Among the multitude of studies on a treat-to-target (T2T) strategy in RA, a recent cluster randomized trial by Bessette and colleagues compared use of abatacept in 284 patients treated by 44 physicians. Patients assigned to both T2T and routine care had significant improvement in RA disease activity (as measured by the Clinical Disease Activity Index) with abatacept, with close to 40% in low disease activity at 12 months. Those treated with routine care experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with slightly higher odds of low disease activity and a shorter time to Simplified Disease Activity Index remission (14 vs 19 months). With T2T being largely accepted as a standard of care on the basis of prior studies, this study raises the question of why little difference was seen between the two groups — perhaps it was related to the use of abatacept. It is unlikely to further change the standard of care to reduce use of disease activity measures.

To better understand refractory or difficult-to-treat (D2T) RA, Jung and colleagues used the KOBIO (KOrean College of Rheumatology BIOlogics) registry to compare characteristics of patients with D2T RA vs those who respond more readily to therapy. Of the 2321 patients included in the study, about 12% (271) had D2T RA. Patients with D2T RA tended to be younger and have longer disease duration, as well as a negative rheumatoid factor (RF); less use of conventional synthetic disease-modifying antirheumatic drugs (csDMARD); and, as expected, higher disease activity measures. Given that about 80% of patients were seropositive for RF and the fact that patients with D2T RA tended to have higher inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), it is not likely that patients were misclassified with RA. The reason why patients with D2T RA had less csDMARD use is not clear, but prior studies have supported early and aggressive use of csDMARD for best outcomes. The study did suggest that patients with D2T RA stayed on Janus kinase (JAK) inhibitor therapy the longest, and perhaps similar studies in future will help outline the best treatment strategy for patients with D2T RA and persistently high disease activity.

Finally, in a post hoc analysis of the ORAL Start trial of the JAK inhibitor tofacitinib vs methotrexate, Ciurea and colleagues looked at paired joint pathology scores (PJPS) — swollen and tender joint counts with left and right pooled — over the course of the 12-month study. Patients receiving tofacitinib had overall improved PJPS, though patients receiving methotrexate had more improvement in the foot. These findings, generally supporting those of the initial study, are unlikely to further change therapy.

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

Anti-drug antibody (ADA) testing for biologics, particularly anti–tumor necrosis factor (TNF) agents, has been commercially available for several years, though its clinical use in rheumatoid arthritis (RA) is not known owing to lack of prospective data. Bitoun and colleagues analyzed data from the European ABI-RA registry to evaluate the association between ADA and the anti–TNF monoclonal antibodies (mAb) etanercept, tocilizumab, and rituximab, and clinical response (as measured by disease activity scores, inflammatory markers, and European Alliance of Associations for Rheumatology [EULAR] response rate). Higher rates of ADA positivity were seen in patients treated with rituximab (50%), anti-TNF mAb (38%), and tocilizumab (20%) compared with etanercept (6%). Patients who had a positive ADA test were less likely to have a EULAR response. In addition, patients treated with methotrexate were less likely to have persistent ADA. Though the study was not powered enough to detect differences between the drug classes, the evidence presented is compelling and suggests a role for measuring ADA in patients with RA who do not respond to treatment.

RA is well-known to be associated with cardiovascular disease, particularly atherosclerotic disease and heart failure, but its association with valvular heart disease and its progression has not been well-explored in the literature. Johnson and colleagues performed a cohort study of over 73,000 patients with RA in the Veterans Health Administration (VHA) system compared with 640,000 patients without RA to evaluate the incidence of aortic stenosis, need for intervention, and risk for death. Though the overall incidence rate was low (about 3%), patients with RA had a higher risk for aortic stenosis, with a hazard ratio of 1.48 compared with those without RA, as well as a higher risk for aortic valve replacement and aortic stenosis–related death. The risk for aortic stenosis was associated with hypertension, stroke, and other cardiovascular disease, as well as a body mass index > 30 kg/m², although not with a history of smoking or diabetes. Because the study was performed using data from the VHA — that is, from predominantly male patients — this finding may not be generalizable. In addition, the diagnosis of aortic stenosis is generally reliant on echocardiography and may be detected while searching for other conditions not evaluated here (such as pericarditis). As such, these findings would not support routine screening in patients with RA without other reasons for suspicion of valvular heart disease.

In particular, the increase in cardiovascular risk associated with glucocorticoid therapy in patients with RA has received increased scrutiny, along with other side effects of systemic glucocorticoids. In a recent retrospective study, So and colleagues examined the clinical data of over 12,000 patients with RA treated in public hospitals in Hong Kong with a mean of 9 years of follow-up. Consistent with prior studies, systemic glucocorticoid use (prednisolone equivalent > 5 mg daily) was associated with an increased risk for adverse cardiovascular events, whereas lower doses did not increase cardiovascular risk. Because the data on some disease activity measures and traditional cardiovascular risk factors (such as smoking or obesity) were not available in the database, the study supports, but does not expand on, prior evidence regarding cardiovascular risk.

Almayali and colleagues also looked at glucocorticoid therapy in RA in a follow-up study to the previously published pragmatic randomized double-blinded placebo-controlled GLORIA study, which evaluated the effects of 5 mg/d prednisolone added to standard care for 2 years in patients with active RA who were age 65 years or older. In the current study, 191 patients out of the initial 451 were followed for 3 months and prednisolone tapered off. Patients who tapered off prednisolone had, as expected, an increased risk for flare but no evidence of adrenal insufficiency. Although, again, this is not likely to change practice, it does suggest that glucocorticoid tapering is a reasonable goal in RA therapeutic trials.

Anti-drug antibody (ADA) testing for biologics, particularly anti–tumor necrosis factor (TNF) agents, has been commercially available for several years, though its clinical use in rheumatoid arthritis (RA) is not known owing to lack of prospective data. Bitoun and colleagues analyzed data from the European ABI-RA registry to evaluate the association between ADA and the anti–TNF monoclonal antibodies (mAb) etanercept, tocilizumab, and rituximab, and clinical response (as measured by disease activity scores, inflammatory markers, and European Alliance of Associations for Rheumatology [EULAR] response rate). Higher rates of ADA positivity were seen in patients treated with rituximab (50%), anti-TNF mAb (38%), and tocilizumab (20%) compared with etanercept (6%). Patients who had a positive ADA test were less likely to have a EULAR response. In addition, patients treated with methotrexate were less likely to have persistent ADA. Though the study was not powered enough to detect differences between the drug classes, the evidence presented is compelling and suggests a role for measuring ADA in patients with RA who do not respond to treatment.

RA is well-known to be associated with cardiovascular disease, particularly atherosclerotic disease and heart failure, but its association with valvular heart disease and its progression has not been well-explored in the literature. Johnson and colleagues performed a cohort study of over 73,000 patients with RA in the Veterans Health Administration (VHA) system compared with 640,000 patients without RA to evaluate the incidence of aortic stenosis, need for intervention, and risk for death. Though the overall incidence rate was low (about 3%), patients with RA had a higher risk for aortic stenosis, with a hazard ratio of 1.48 compared with those without RA, as well as a higher risk for aortic valve replacement and aortic stenosis–related death. The risk for aortic stenosis was associated with hypertension, stroke, and other cardiovascular disease, as well as a body mass index > 30 kg/m², although not with a history of smoking or diabetes. Because the study was performed using data from the VHA — that is, from predominantly male patients — this finding may not be generalizable. In addition, the diagnosis of aortic stenosis is generally reliant on echocardiography and may be detected while searching for other conditions not evaluated here (such as pericarditis). As such, these findings would not support routine screening in patients with RA without other reasons for suspicion of valvular heart disease.

In particular, the increase in cardiovascular risk associated with glucocorticoid therapy in patients with RA has received increased scrutiny, along with other side effects of systemic glucocorticoids. In a recent retrospective study, So and colleagues examined the clinical data of over 12,000 patients with RA treated in public hospitals in Hong Kong with a mean of 9 years of follow-up. Consistent with prior studies, systemic glucocorticoid use (prednisolone equivalent > 5 mg daily) was associated with an increased risk for adverse cardiovascular events, whereas lower doses did not increase cardiovascular risk. Because the data on some disease activity measures and traditional cardiovascular risk factors (such as smoking or obesity) were not available in the database, the study supports, but does not expand on, prior evidence regarding cardiovascular risk.

Almayali and colleagues also looked at glucocorticoid therapy in RA in a follow-up study to the previously published pragmatic randomized double-blinded placebo-controlled GLORIA study, which evaluated the effects of 5 mg/d prednisolone added to standard care for 2 years in patients with active RA who were age 65 years or older. In the current study, 191 patients out of the initial 451 were followed for 3 months and prednisolone tapered off. Patients who tapered off prednisolone had, as expected, an increased risk for flare but no evidence of adrenal insufficiency. Although, again, this is not likely to change practice, it does suggest that glucocorticoid tapering is a reasonable goal in RA therapeutic trials.

Anti-drug antibody (ADA) testing for biologics, particularly anti–tumor necrosis factor (TNF) agents, has been commercially available for several years, though its clinical use in rheumatoid arthritis (RA) is not known owing to lack of prospective data. Bitoun and colleagues analyzed data from the European ABI-RA registry to evaluate the association between ADA and the anti–TNF monoclonal antibodies (mAb) etanercept, tocilizumab, and rituximab, and clinical response (as measured by disease activity scores, inflammatory markers, and European Alliance of Associations for Rheumatology [EULAR] response rate). Higher rates of ADA positivity were seen in patients treated with rituximab (50%), anti-TNF mAb (38%), and tocilizumab (20%) compared with etanercept (6%). Patients who had a positive ADA test were less likely to have a EULAR response. In addition, patients treated with methotrexate were less likely to have persistent ADA. Though the study was not powered enough to detect differences between the drug classes, the evidence presented is compelling and suggests a role for measuring ADA in patients with RA who do not respond to treatment.

RA is well-known to be associated with cardiovascular disease, particularly atherosclerotic disease and heart failure, but its association with valvular heart disease and its progression has not been well-explored in the literature. Johnson and colleagues performed a cohort study of over 73,000 patients with RA in the Veterans Health Administration (VHA) system compared with 640,000 patients without RA to evaluate the incidence of aortic stenosis, need for intervention, and risk for death. Though the overall incidence rate was low (about 3%), patients with RA had a higher risk for aortic stenosis, with a hazard ratio of 1.48 compared with those without RA, as well as a higher risk for aortic valve replacement and aortic stenosis–related death. The risk for aortic stenosis was associated with hypertension, stroke, and other cardiovascular disease, as well as a body mass index > 30 kg/m², although not with a history of smoking or diabetes. Because the study was performed using data from the VHA — that is, from predominantly male patients — this finding may not be generalizable. In addition, the diagnosis of aortic stenosis is generally reliant on echocardiography and may be detected while searching for other conditions not evaluated here (such as pericarditis). As such, these findings would not support routine screening in patients with RA without other reasons for suspicion of valvular heart disease.

In particular, the increase in cardiovascular risk associated with glucocorticoid therapy in patients with RA has received increased scrutiny, along with other side effects of systemic glucocorticoids. In a recent retrospective study, So and colleagues examined the clinical data of over 12,000 patients with RA treated in public hospitals in Hong Kong with a mean of 9 years of follow-up. Consistent with prior studies, systemic glucocorticoid use (prednisolone equivalent > 5 mg daily) was associated with an increased risk for adverse cardiovascular events, whereas lower doses did not increase cardiovascular risk. Because the data on some disease activity measures and traditional cardiovascular risk factors (such as smoking or obesity) were not available in the database, the study supports, but does not expand on, prior evidence regarding cardiovascular risk.

Almayali and colleagues also looked at glucocorticoid therapy in RA in a follow-up study to the previously published pragmatic randomized double-blinded placebo-controlled GLORIA study, which evaluated the effects of 5 mg/d prednisolone added to standard care for 2 years in patients with active RA who were age 65 years or older. In the current study, 191 patients out of the initial 451 were followed for 3 months and prednisolone tapered off. Patients who tapered off prednisolone had, as expected, an increased risk for flare but no evidence of adrenal insufficiency. Although, again, this is not likely to change practice, it does suggest that glucocorticoid tapering is a reasonable goal in RA therapeutic trials.

With several new biologic (b) disease-modifying antirheumatic drugs (DMARD) and targeted synthetic (ts) DMARD now available for the treatment of rheumatoid arthritis (RA), information regarding their comparative effectiveness would be of interest. Relatively few head-to-head trials have been published, however. Though "real-world" studies have been published to provide some information about comparative effectiveness, Deakin and colleagues used a target trial emulation framework to apply clinical trial methods to real-world data. Using the Australian OPAL registry of bDMARD/tsDMARD-naive patients, they developed a randomized controlled trial protocol of tofacitinib vs adalimumab using an intention-to-treat analysis. Under this framework, there was small reduction of disease activity with tofacitinib vs adalimumab at 3 months and no difference at 9 months. While this framework is conceptually interesting, it may be more meaningful used in side-by-side comparison to a real-world analysis of the same data to evaluate pitfalls and biases in both; otherwise, its utility as a stand-alone analysis of observational data is not fully clear.

Østergaard and colleagues also performed a head-to-head study of several different therapies to address the question of optimal treatment strategies for patients with early RA. Patients with moderate to severe disease activity were randomly assigned to treatment with methotrexate combined with (1) oral glucocorticoid or sulfasalazine, hydroxychloroquine, and intra-articular steroid injections, (2) certolizumab, (3) abatacept, or (4) tocilizumab. Disease activity and radiographic changes were evaluated at 48 weeks. In this study of over 800 patients, treatment with abatacept or certolizumab was associated with improved Clinical Disease Activity Index (CDAI) remission rates compared with the active conventional therapy (group 1), but tocilizumab was not. The overall differences between bDMARD treatment groups were small and thus may not reflect significant differences in effectiveness. Instead, this study challenges the notion of initiating conventional synthetic DMARD (csDMARD) therapy in patients with early RA and stepping up to bDMARD, as initial bDMARD therapy may be of benefit in patients with more active early RA.

Alongside the question of the effectiveness of bMARD and tsDMARD in real-world settings, the appropriate role for long-term low-dose prednisone in the treatment of RA remains unknown. A recent study by Güler-Yüksel and colleagues examined the effects of 5 mg prednisolone daily in addition to standard therapy in patients over 65 years of age with active RA. Due to the potential complications of weight gain and glucose intolerance with long-term glucocorticoids, in addition to low-bone-density issues, their use has generally not been viewed favorably. In this multicenter trial, 449 patients were randomly assigned to receive prednisolone vs placebo in addition to their usual medications over 2 years. Notably, patients in the prednisolone group had an average of 0.9 kg weight gain compared with placebo with 0.4 kg weight loss over 2 years. By the end of 2 years, 29% of patients in the prednisolone group had a weight gain of > 2 kg compared with 18% of patients in the placebo group. Only 57 patients in all underwent body composition analysis, and, interestingly, those in the prednisolone group had small increases in lean body mass compared with fat mass, though these patients were not necessarily representative. The authors suggest, though the study does not prove, that low-dose prednisolone can be protective against sarcopenia, which is associated with older age and "rheumatoid cachexia." The study also did not examine the interaction of glucocorticoid use with diet and exercise. While it is reassuring that patients in this study did not experience major weight gain, it does not appear to be a generalizable finding at this point.

With several new biologic (b) disease-modifying antirheumatic drugs (DMARD) and targeted synthetic (ts) DMARD now available for the treatment of rheumatoid arthritis (RA), information regarding their comparative effectiveness would be of interest. Relatively few head-to-head trials have been published, however. Though "real-world" studies have been published to provide some information about comparative effectiveness, Deakin and colleagues used a target trial emulation framework to apply clinical trial methods to real-world data. Using the Australian OPAL registry of bDMARD/tsDMARD-naive patients, they developed a randomized controlled trial protocol of tofacitinib vs adalimumab using an intention-to-treat analysis. Under this framework, there was small reduction of disease activity with tofacitinib vs adalimumab at 3 months and no difference at 9 months. While this framework is conceptually interesting, it may be more meaningful used in side-by-side comparison to a real-world analysis of the same data to evaluate pitfalls and biases in both; otherwise, its utility as a stand-alone analysis of observational data is not fully clear.

Østergaard and colleagues also performed a head-to-head study of several different therapies to address the question of optimal treatment strategies for patients with early RA. Patients with moderate to severe disease activity were randomly assigned to treatment with methotrexate combined with (1) oral glucocorticoid or sulfasalazine, hydroxychloroquine, and intra-articular steroid injections, (2) certolizumab, (3) abatacept, or (4) tocilizumab. Disease activity and radiographic changes were evaluated at 48 weeks. In this study of over 800 patients, treatment with abatacept or certolizumab was associated with improved Clinical Disease Activity Index (CDAI) remission rates compared with the active conventional therapy (group 1), but tocilizumab was not. The overall differences between bDMARD treatment groups were small and thus may not reflect significant differences in effectiveness. Instead, this study challenges the notion of initiating conventional synthetic DMARD (csDMARD) therapy in patients with early RA and stepping up to bDMARD, as initial bDMARD therapy may be of benefit in patients with more active early RA.

Alongside the question of the effectiveness of bMARD and tsDMARD in real-world settings, the appropriate role for long-term low-dose prednisone in the treatment of RA remains unknown. A recent study by Güler-Yüksel and colleagues examined the effects of 5 mg prednisolone daily in addition to standard therapy in patients over 65 years of age with active RA. Due to the potential complications of weight gain and glucose intolerance with long-term glucocorticoids, in addition to low-bone-density issues, their use has generally not been viewed favorably. In this multicenter trial, 449 patients were randomly assigned to receive prednisolone vs placebo in addition to their usual medications over 2 years. Notably, patients in the prednisolone group had an average of 0.9 kg weight gain compared with placebo with 0.4 kg weight loss over 2 years. By the end of 2 years, 29% of patients in the prednisolone group had a weight gain of > 2 kg compared with 18% of patients in the placebo group. Only 57 patients in all underwent body composition analysis, and, interestingly, those in the prednisolone group had small increases in lean body mass compared with fat mass, though these patients were not necessarily representative. The authors suggest, though the study does not prove, that low-dose prednisolone can be protective against sarcopenia, which is associated with older age and "rheumatoid cachexia." The study also did not examine the interaction of glucocorticoid use with diet and exercise. While it is reassuring that patients in this study did not experience major weight gain, it does not appear to be a generalizable finding at this point.

With several new biologic (b) disease-modifying antirheumatic drugs (DMARD) and targeted synthetic (ts) DMARD now available for the treatment of rheumatoid arthritis (RA), information regarding their comparative effectiveness would be of interest. Relatively few head-to-head trials have been published, however. Though "real-world" studies have been published to provide some information about comparative effectiveness, Deakin and colleagues used a target trial emulation framework to apply clinical trial methods to real-world data. Using the Australian OPAL registry of bDMARD/tsDMARD-naive patients, they developed a randomized controlled trial protocol of tofacitinib vs adalimumab using an intention-to-treat analysis. Under this framework, there was small reduction of disease activity with tofacitinib vs adalimumab at 3 months and no difference at 9 months. While this framework is conceptually interesting, it may be more meaningful used in side-by-side comparison to a real-world analysis of the same data to evaluate pitfalls and biases in both; otherwise, its utility as a stand-alone analysis of observational data is not fully clear.

Østergaard and colleagues also performed a head-to-head study of several different therapies to address the question of optimal treatment strategies for patients with early RA. Patients with moderate to severe disease activity were randomly assigned to treatment with methotrexate combined with (1) oral glucocorticoid or sulfasalazine, hydroxychloroquine, and intra-articular steroid injections, (2) certolizumab, (3) abatacept, or (4) tocilizumab. Disease activity and radiographic changes were evaluated at 48 weeks. In this study of over 800 patients, treatment with abatacept or certolizumab was associated with improved Clinical Disease Activity Index (CDAI) remission rates compared with the active conventional therapy (group 1), but tocilizumab was not. The overall differences between bDMARD treatment groups were small and thus may not reflect significant differences in effectiveness. Instead, this study challenges the notion of initiating conventional synthetic DMARD (csDMARD) therapy in patients with early RA and stepping up to bDMARD, as initial bDMARD therapy may be of benefit in patients with more active early RA.

Alongside the question of the effectiveness of bMARD and tsDMARD in real-world settings, the appropriate role for long-term low-dose prednisone in the treatment of RA remains unknown. A recent study by Güler-Yüksel and colleagues examined the effects of 5 mg prednisolone daily in addition to standard therapy in patients over 65 years of age with active RA. Due to the potential complications of weight gain and glucose intolerance with long-term glucocorticoids, in addition to low-bone-density issues, their use has generally not been viewed favorably. In this multicenter trial, 449 patients were randomly assigned to receive prednisolone vs placebo in addition to their usual medications over 2 years. Notably, patients in the prednisolone group had an average of 0.9 kg weight gain compared with placebo with 0.4 kg weight loss over 2 years. By the end of 2 years, 29% of patients in the prednisolone group had a weight gain of > 2 kg compared with 18% of patients in the placebo group. Only 57 patients in all underwent body composition analysis, and, interestingly, those in the prednisolone group had small increases in lean body mass compared with fat mass, though these patients were not necessarily representative. The authors suggest, though the study does not prove, that low-dose prednisolone can be protective against sarcopenia, which is associated with older age and "rheumatoid cachexia." The study also did not examine the interaction of glucocorticoid use with diet and exercise. While it is reassuring that patients in this study did not experience major weight gain, it does not appear to be a generalizable finding at this point.

Despite multiple existing conventional synthetic disease-modifying antirheumatic drug (csDMARD) and biologic DMARD (bDMARD) options, many patients with rheumatoid arthritis (RA) do not respond adequately to treatment. In an exciting development, a recent phase 2 study by Tuttle and colleagues examined a novel treatment approach in RA: stimulation of the programmed cell death protein 1 (PD-1) inhibitor pathway. PD-1 is a checkpoint inhibitor receptor whose activation reflects T-cell activation and may play a role in synovitis and extra-articular inflammation. Blocking PD-1 in cancer therapy has been associated with an increase in inflammatory arthritis. In this 12-week study, RA disease activity was analyzed in patients randomly assigned to two different monthly intravenous doses of peresolimab or placebo. Of note, a large majority of participants were seropositive for rheumatoid factor (RF) or cyclic citrullinated peptide (CCP). Patients receiving the 700-mg dose of peresolimab had a better American College of Rheumatology (ACR) 20 response than did those receiving placebo (71% vs 42%), but not a better ACR50 or ACR70 response; the 300-mg dose was not better than placebo. Although reported adverse events were similar in all three groups, with a short timeframe it would be difficult to address concerns about cancer risk. Though this novel treatment is exciting, a larger and longer-term trial is necessary to address this concern as well as potentially tease out risk factors (including age or other immunosuppression) in this susceptible group.

Two other studies examined use of a much older csDMARD therapy, hydroxychloroquine (HCQ), in Brazilian patients with RA. Bredemeier and colleagues looked at the effects of HCQ on adverse events as well as the persistence of bDMARD/targeted synthetic DMARD (tsDMARD) therapy in over 1300 patients with RA. Using the BiobadaBrasil registry of patients starting their first bDMARD or Janus kinase (JAK) inhibitor, they looked at effects of combination therapy with HCQ during the treatment course of up to six bDMARD or JAK inhibitors. At baseline, patients prescribed antimalarial therapy had shorter RA duration and began treatment earlier, perhaps due to patient or physician preferences regarding starting "milder" antimalarial medication earlier or due to use of "triple therapy" with methotrexate and sulfasalazine. Of interest, patients receiving antimalarial therapy had a lower incidence of adverse events, especially serious infections, but no effect on cardiovascular events was seen despite HCQ's perceived beneficial effects on thrombotic risk and cholesterol profile. Patients receiving HCQ were also more likely to persist in their course of bDMARD or JAK inhibitor therapy, though the effect size seems relatively small. As the focus in this study was on adverse effects, the authors' analysis of the effects on antimalarials on the persistence of therapy was not detailed.

Lin and colleagues also looked at the effects of HCQ in patients with older-onset RA with respect to mortality risk. Using data from the electronic health records of a hospital in Taiwan, mortality-associated risk factors were evaluated in 980 patients with RA diagnosed at >60 years. Male sex, current smoking status, and cancer status were all associated with mortality, whereas HCQ use was associated with reduced mortality (hazard ratio 0.30). In contrast to the registry study mentioned above, patients receiving HCQ had a lower risk for cardiovascular events, hyperlipidemia, diabetes, and chronic kidney disease. Interaction with cancer was less clear due to lower number of patients. Of interest, use of cyclosporine, leflunomide, and a bDMARD was associated with higher mortality risk. The source and true relevance of the potential risk reduction in this study is not clear because of the lack of prospective data, but combined with the information above, this study suggests that the benefits of HCQ use should not be discounted in patients with RA.

Despite multiple existing conventional synthetic disease-modifying antirheumatic drug (csDMARD) and biologic DMARD (bDMARD) options, many patients with rheumatoid arthritis (RA) do not respond adequately to treatment. In an exciting development, a recent phase 2 study by Tuttle and colleagues examined a novel treatment approach in RA: stimulation of the programmed cell death protein 1 (PD-1) inhibitor pathway. PD-1 is a checkpoint inhibitor receptor whose activation reflects T-cell activation and may play a role in synovitis and extra-articular inflammation. Blocking PD-1 in cancer therapy has been associated with an increase in inflammatory arthritis. In this 12-week study, RA disease activity was analyzed in patients randomly assigned to two different monthly intravenous doses of peresolimab or placebo. Of note, a large majority of participants were seropositive for rheumatoid factor (RF) or cyclic citrullinated peptide (CCP). Patients receiving the 700-mg dose of peresolimab had a better American College of Rheumatology (ACR) 20 response than did those receiving placebo (71% vs 42%), but not a better ACR50 or ACR70 response; the 300-mg dose was not better than placebo. Although reported adverse events were similar in all three groups, with a short timeframe it would be difficult to address concerns about cancer risk. Though this novel treatment is exciting, a larger and longer-term trial is necessary to address this concern as well as potentially tease out risk factors (including age or other immunosuppression) in this susceptible group.

Two other studies examined use of a much older csDMARD therapy, hydroxychloroquine (HCQ), in Brazilian patients with RA. Bredemeier and colleagues looked at the effects of HCQ on adverse events as well as the persistence of bDMARD/targeted synthetic DMARD (tsDMARD) therapy in over 1300 patients with RA. Using the BiobadaBrasil registry of patients starting their first bDMARD or Janus kinase (JAK) inhibitor, they looked at effects of combination therapy with HCQ during the treatment course of up to six bDMARD or JAK inhibitors. At baseline, patients prescribed antimalarial therapy had shorter RA duration and began treatment earlier, perhaps due to patient or physician preferences regarding starting "milder" antimalarial medication earlier or due to use of "triple therapy" with methotrexate and sulfasalazine. Of interest, patients receiving antimalarial therapy had a lower incidence of adverse events, especially serious infections, but no effect on cardiovascular events was seen despite HCQ's perceived beneficial effects on thrombotic risk and cholesterol profile. Patients receiving HCQ were also more likely to persist in their course of bDMARD or JAK inhibitor therapy, though the effect size seems relatively small. As the focus in this study was on adverse effects, the authors' analysis of the effects on antimalarials on the persistence of therapy was not detailed.

Lin and colleagues also looked at the effects of HCQ in patients with older-onset RA with respect to mortality risk. Using data from the electronic health records of a hospital in Taiwan, mortality-associated risk factors were evaluated in 980 patients with RA diagnosed at >60 years. Male sex, current smoking status, and cancer status were all associated with mortality, whereas HCQ use was associated with reduced mortality (hazard ratio 0.30). In contrast to the registry study mentioned above, patients receiving HCQ had a lower risk for cardiovascular events, hyperlipidemia, diabetes, and chronic kidney disease. Interaction with cancer was less clear due to lower number of patients. Of interest, use of cyclosporine, leflunomide, and a bDMARD was associated with higher mortality risk. The source and true relevance of the potential risk reduction in this study is not clear because of the lack of prospective data, but combined with the information above, this study suggests that the benefits of HCQ use should not be discounted in patients with RA.

Despite multiple existing conventional synthetic disease-modifying antirheumatic drug (csDMARD) and biologic DMARD (bDMARD) options, many patients with rheumatoid arthritis (RA) do not respond adequately to treatment. In an exciting development, a recent phase 2 study by Tuttle and colleagues examined a novel treatment approach in RA: stimulation of the programmed cell death protein 1 (PD-1) inhibitor pathway. PD-1 is a checkpoint inhibitor receptor whose activation reflects T-cell activation and may play a role in synovitis and extra-articular inflammation. Blocking PD-1 in cancer therapy has been associated with an increase in inflammatory arthritis. In this 12-week study, RA disease activity was analyzed in patients randomly assigned to two different monthly intravenous doses of peresolimab or placebo. Of note, a large majority of participants were seropositive for rheumatoid factor (RF) or cyclic citrullinated peptide (CCP). Patients receiving the 700-mg dose of peresolimab had a better American College of Rheumatology (ACR) 20 response than did those receiving placebo (71% vs 42%), but not a better ACR50 or ACR70 response; the 300-mg dose was not better than placebo. Although reported adverse events were similar in all three groups, with a short timeframe it would be difficult to address concerns about cancer risk. Though this novel treatment is exciting, a larger and longer-term trial is necessary to address this concern as well as potentially tease out risk factors (including age or other immunosuppression) in this susceptible group.

Two other studies examined use of a much older csDMARD therapy, hydroxychloroquine (HCQ), in Brazilian patients with RA. Bredemeier and colleagues looked at the effects of HCQ on adverse events as well as the persistence of bDMARD/targeted synthetic DMARD (tsDMARD) therapy in over 1300 patients with RA. Using the BiobadaBrasil registry of patients starting their first bDMARD or Janus kinase (JAK) inhibitor, they looked at effects of combination therapy with HCQ during the treatment course of up to six bDMARD or JAK inhibitors. At baseline, patients prescribed antimalarial therapy had shorter RA duration and began treatment earlier, perhaps due to patient or physician preferences regarding starting "milder" antimalarial medication earlier or due to use of "triple therapy" with methotrexate and sulfasalazine. Of interest, patients receiving antimalarial therapy had a lower incidence of adverse events, especially serious infections, but no effect on cardiovascular events was seen despite HCQ's perceived beneficial effects on thrombotic risk and cholesterol profile. Patients receiving HCQ were also more likely to persist in their course of bDMARD or JAK inhibitor therapy, though the effect size seems relatively small. As the focus in this study was on adverse effects, the authors' analysis of the effects on antimalarials on the persistence of therapy was not detailed.

Lin and colleagues also looked at the effects of HCQ in patients with older-onset RA with respect to mortality risk. Using data from the electronic health records of a hospital in Taiwan, mortality-associated risk factors were evaluated in 980 patients with RA diagnosed at >60 years. Male sex, current smoking status, and cancer status were all associated with mortality, whereas HCQ use was associated with reduced mortality (hazard ratio 0.30). In contrast to the registry study mentioned above, patients receiving HCQ had a lower risk for cardiovascular events, hyperlipidemia, diabetes, and chronic kidney disease. Interaction with cancer was less clear due to lower number of patients. Of interest, use of cyclosporine, leflunomide, and a bDMARD was associated with higher mortality risk. The source and true relevance of the potential risk reduction in this study is not clear because of the lack of prospective data, but combined with the information above, this study suggests that the benefits of HCQ use should not be discounted in patients with RA.

Several environmental risk factors are associated with the development of rheumatoid arthritis (RA), with smoking having one of the strongest associations. Exposure to airborne toxins has also been associated with development of anti–cyclic citrullinated peptide antibodies. Beidelschies and colleagues performed a cross-sectional analysis using data from the National Health and Nutrition Examination Survey to examine a potential interaction between smoking and polycyclic aromatic hydrocarbons (PAH) affecting the development of RA. Stored blood and urine samples of survey respondents were examined, and levels of PAH as well as other toxicants were measured. Of nearly 22,000 participants, about 1400 of whom reported a diagnosis of RA, toxicants were measured in about 7000. Higher levels of PAH and phthalate metabolites were more strongly associated with development of RA. Because cigarettes are a source of PAH, the authors postulated that PAH mediated the impact of smoking on development of RA, a plausible explanation given that smoking was not associated with RA after adjustment for PAH levels. However, given the cross-sectional design, causality cannot be determined.

Janus kinase (JAK) inhibitors have been found in several surveillance studies to be associated with an increased risk for cancer and cardiovascular events. Westermann and colleagues performed an observational cohort study using Danish nationwide registries to evaluate cancer risk (other than nonmelanomatous skin cancer) in patients with RA treated with tofacitinib or baricitinib. Among 875 patients treated with JAK inhibitors vs 4247 patients treated with biologic disease-modifying antirheumatic drugs (bDMARD), cancer incidence rates were similar (14.4 vs 12.9 per 1000 patient-years, respectively). Interestingly, though cancer incidence rates increased in patients > 50 and those > 65 years of age, the effect was similar between patients treated with JAK inhibitors and bDMARD. The largest difference was seen in patients up to 1 year vs > 1 year of follow-up, with hazard ratios of 1.54 vs 1.07. These findings are somewhat reassuring in light of results from the ORAL Surveillance study, suggesting increased cancer and cardiovascular risk among older patients with RA. However, as with bDMARD, increased scrutiny may be warranted among patients > 65 years, especially in the first year of treatment.

Finally, regarding withdrawal of therapy, Curtis and colleagues performed a randomized controlled study of patients with RA on combination therapy with methotrexate and etanercept and evaluated factors associated with maintenance of remission. In this study, withdrawal of methotrexate and etanercept were compared: About 250 patients whose disease was in remission, on the basis of the Simplified Disease Activity Index, were randomized in a 2:2:1 ratio to receive methotrexate monotherapy, etanercept monotherapy, or combination therapy. Prior analyses of these data have shown that continuing etanercept monotherapy showed a benefit in maintaining remission compared with continuing methotrexate monotherapy. Several baseline characteristics, including higher patient global activity at baseline and rheumatoid factor seropositivity, were associated with a lower likelihood of maintaining remission or low disease activity. Interestingly, higher serum magnesium levels seemed to negatively affect maintenance of remission, though the mechanism for this finding is not clear. In general, however, this study did not add more information to prior work in terms of shedding light on which patients may be able to stop therapy.

Several environmental risk factors are associated with the development of rheumatoid arthritis (RA), with smoking having one of the strongest associations. Exposure to airborne toxins has also been associated with development of anti–cyclic citrullinated peptide antibodies. Beidelschies and colleagues performed a cross-sectional analysis using data from the National Health and Nutrition Examination Survey to examine a potential interaction between smoking and polycyclic aromatic hydrocarbons (PAH) affecting the development of RA. Stored blood and urine samples of survey respondents were examined, and levels of PAH as well as other toxicants were measured. Of nearly 22,000 participants, about 1400 of whom reported a diagnosis of RA, toxicants were measured in about 7000. Higher levels of PAH and phthalate metabolites were more strongly associated with development of RA. Because cigarettes are a source of PAH, the authors postulated that PAH mediated the impact of smoking on development of RA, a plausible explanation given that smoking was not associated with RA after adjustment for PAH levels. However, given the cross-sectional design, causality cannot be determined.

Janus kinase (JAK) inhibitors have been found in several surveillance studies to be associated with an increased risk for cancer and cardiovascular events. Westermann and colleagues performed an observational cohort study using Danish nationwide registries to evaluate cancer risk (other than nonmelanomatous skin cancer) in patients with RA treated with tofacitinib or baricitinib. Among 875 patients treated with JAK inhibitors vs 4247 patients treated with biologic disease-modifying antirheumatic drugs (bDMARD), cancer incidence rates were similar (14.4 vs 12.9 per 1000 patient-years, respectively). Interestingly, though cancer incidence rates increased in patients > 50 and those > 65 years of age, the effect was similar between patients treated with JAK inhibitors and bDMARD. The largest difference was seen in patients up to 1 year vs > 1 year of follow-up, with hazard ratios of 1.54 vs 1.07. These findings are somewhat reassuring in light of results from the ORAL Surveillance study, suggesting increased cancer and cardiovascular risk among older patients with RA. However, as with bDMARD, increased scrutiny may be warranted among patients > 65 years, especially in the first year of treatment.

Finally, regarding withdrawal of therapy, Curtis and colleagues performed a randomized controlled study of patients with RA on combination therapy with methotrexate and etanercept and evaluated factors associated with maintenance of remission. In this study, withdrawal of methotrexate and etanercept were compared: About 250 patients whose disease was in remission, on the basis of the Simplified Disease Activity Index, were randomized in a 2:2:1 ratio to receive methotrexate monotherapy, etanercept monotherapy, or combination therapy. Prior analyses of these data have shown that continuing etanercept monotherapy showed a benefit in maintaining remission compared with continuing methotrexate monotherapy. Several baseline characteristics, including higher patient global activity at baseline and rheumatoid factor seropositivity, were associated with a lower likelihood of maintaining remission or low disease activity. Interestingly, higher serum magnesium levels seemed to negatively affect maintenance of remission, though the mechanism for this finding is not clear. In general, however, this study did not add more information to prior work in terms of shedding light on which patients may be able to stop therapy.

Several environmental risk factors are associated with the development of rheumatoid arthritis (RA), with smoking having one of the strongest associations. Exposure to airborne toxins has also been associated with development of anti–cyclic citrullinated peptide antibodies. Beidelschies and colleagues performed a cross-sectional analysis using data from the National Health and Nutrition Examination Survey to examine a potential interaction between smoking and polycyclic aromatic hydrocarbons (PAH) affecting the development of RA. Stored blood and urine samples of survey respondents were examined, and levels of PAH as well as other toxicants were measured. Of nearly 22,000 participants, about 1400 of whom reported a diagnosis of RA, toxicants were measured in about 7000. Higher levels of PAH and phthalate metabolites were more strongly associated with development of RA. Because cigarettes are a source of PAH, the authors postulated that PAH mediated the impact of smoking on development of RA, a plausible explanation given that smoking was not associated with RA after adjustment for PAH levels. However, given the cross-sectional design, causality cannot be determined.

Janus kinase (JAK) inhibitors have been found in several surveillance studies to be associated with an increased risk for cancer and cardiovascular events. Westermann and colleagues performed an observational cohort study using Danish nationwide registries to evaluate cancer risk (other than nonmelanomatous skin cancer) in patients with RA treated with tofacitinib or baricitinib. Among 875 patients treated with JAK inhibitors vs 4247 patients treated with biologic disease-modifying antirheumatic drugs (bDMARD), cancer incidence rates were similar (14.4 vs 12.9 per 1000 patient-years, respectively). Interestingly, though cancer incidence rates increased in patients > 50 and those > 65 years of age, the effect was similar between patients treated with JAK inhibitors and bDMARD. The largest difference was seen in patients up to 1 year vs > 1 year of follow-up, with hazard ratios of 1.54 vs 1.07. These findings are somewhat reassuring in light of results from the ORAL Surveillance study, suggesting increased cancer and cardiovascular risk among older patients with RA. However, as with bDMARD, increased scrutiny may be warranted among patients > 65 years, especially in the first year of treatment.

Finally, regarding withdrawal of therapy, Curtis and colleagues performed a randomized controlled study of patients with RA on combination therapy with methotrexate and etanercept and evaluated factors associated with maintenance of remission. In this study, withdrawal of methotrexate and etanercept were compared: About 250 patients whose disease was in remission, on the basis of the Simplified Disease Activity Index, were randomized in a 2:2:1 ratio to receive methotrexate monotherapy, etanercept monotherapy, or combination therapy. Prior analyses of these data have shown that continuing etanercept monotherapy showed a benefit in maintaining remission compared with continuing methotrexate monotherapy. Several baseline characteristics, including higher patient global activity at baseline and rheumatoid factor seropositivity, were associated with a lower likelihood of maintaining remission or low disease activity. Interestingly, higher serum magnesium levels seemed to negatively affect maintenance of remission, though the mechanism for this finding is not clear. In general, however, this study did not add more information to prior work in terms of shedding light on which patients may be able to stop therapy.

Although rheumatoid arthritis (RA) is well understood to be associated with cigarette smoking as well as with a risk for interstitial lung disease (ILD), its association with airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and with allergic disorders such as atopic dermatitis and allergic rhinitis, is unknown. Kim and colleagues performed a cross-sectional study using information from the Korean National Health and Nutrition Examination Survey by 334 respondents with RA and over 13,000 respondents without RA and analyzed the association of RA with asthma and asthma-related comorbidities. The prevalence of asthma was higher in respondents with RA (7.5% vs 2.8%; P < .001), but the prevalence of other allergic disorders and COPD wassimilar between groups. This finding in a small group of respondents is not striking and its importance is unclear compared with other nonallergic pulmonary disorders. Inferring a mechanistic connection to T-helper (Th) 1- vs Th2 immunity would thus be premature.

Baker and colleagues examined the risk for RA-associated ILD in patients taking different therapies for RA, a topic of great interest due to the frequency of this complication as well as uncertainty regarding its association with medications, including anti-tumor necrosis factor (TNF) agents and methotrexate. Using a claims database, they performed a retrospective study of patients with RA without existing ILD who were treated with a biologic (b) or targeted synthetic disease-modifying antirheumatic drugs (DMARD; abatacept, adalimumab, rituximab, tocilizumab, and tofacitinib). In over 28,000 patients with RA, incidence ratios for ILD were > 1 for all bDMARD, while the incidence ratio for ILD with tofacitinib was 1.47. As the group of patients treated with tofacitinib was the smallest, the reliability of this result is uncertain and thus not strong enough to suggest a protective effect or preference for this medication in patients with known ILD. However, prospective studies looking at ILD in RA patients taking tofacitinib would be of interest.

Kristensen and colleagues also looked at risks associated with tofacitinib and anti-TNF agents, in particular cardiovascular disease, malignancy, and venous thromboembolism, using data from the open-label randomized ORAL Surveillance study, which looked at patients taking 5 mg or 10 mg tofacitinib twice daily, adalimumab, or etanercept. The 10 mg dose was reduced to 5 mg twice daily after it was found that rates of pulmonary embolism were higher in the group taking the higher dose. Age and smoking are also known to be risk factors for malignancy and cardiovascular disease in patients with RA, and these findings carried through in this analysis as well. Within the study, patients taking tofacitinib over age 65 who had ever smoked had a higher risk for cardiovascular events, myocardial infarction, malignancy, venous thromboembolism, and death compared with patients on anti-TNF therapy, while patients taking tofacitinib who were younger than 65 and had never smoked had a risk similar to those on anti-TNF therapy.The study confirms prior knowledge regarding the risks of tofacitinib in different patient populations, suggesting that caution should be used with this medication in older patients and those who smoke.

Although rheumatoid arthritis (RA) is well understood to be associated with cigarette smoking as well as with a risk for interstitial lung disease (ILD), its association with airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and with allergic disorders such as atopic dermatitis and allergic rhinitis, is unknown. Kim and colleagues performed a cross-sectional study using information from the Korean National Health and Nutrition Examination Survey by 334 respondents with RA and over 13,000 respondents without RA and analyzed the association of RA with asthma and asthma-related comorbidities. The prevalence of asthma was higher in respondents with RA (7.5% vs 2.8%; P < .001), but the prevalence of other allergic disorders and COPD wassimilar between groups. This finding in a small group of respondents is not striking and its importance is unclear compared with other nonallergic pulmonary disorders. Inferring a mechanistic connection to T-helper (Th) 1- vs Th2 immunity would thus be premature.

Baker and colleagues examined the risk for RA-associated ILD in patients taking different therapies for RA, a topic of great interest due to the frequency of this complication as well as uncertainty regarding its association with medications, including anti-tumor necrosis factor (TNF) agents and methotrexate. Using a claims database, they performed a retrospective study of patients with RA without existing ILD who were treated with a biologic (b) or targeted synthetic disease-modifying antirheumatic drugs (DMARD; abatacept, adalimumab, rituximab, tocilizumab, and tofacitinib). In over 28,000 patients with RA, incidence ratios for ILD were > 1 for all bDMARD, while the incidence ratio for ILD with tofacitinib was 1.47. As the group of patients treated with tofacitinib was the smallest, the reliability of this result is uncertain and thus not strong enough to suggest a protective effect or preference for this medication in patients with known ILD. However, prospective studies looking at ILD in RA patients taking tofacitinib would be of interest.

Kristensen and colleagues also looked at risks associated with tofacitinib and anti-TNF agents, in particular cardiovascular disease, malignancy, and venous thromboembolism, using data from the open-label randomized ORAL Surveillance study, which looked at patients taking 5 mg or 10 mg tofacitinib twice daily, adalimumab, or etanercept. The 10 mg dose was reduced to 5 mg twice daily after it was found that rates of pulmonary embolism were higher in the group taking the higher dose. Age and smoking are also known to be risk factors for malignancy and cardiovascular disease in patients with RA, and these findings carried through in this analysis as well. Within the study, patients taking tofacitinib over age 65 who had ever smoked had a higher risk for cardiovascular events, myocardial infarction, malignancy, venous thromboembolism, and death compared with patients on anti-TNF therapy, while patients taking tofacitinib who were younger than 65 and had never smoked had a risk similar to those on anti-TNF therapy.The study confirms prior knowledge regarding the risks of tofacitinib in different patient populations, suggesting that caution should be used with this medication in older patients and those who smoke.

Although rheumatoid arthritis (RA) is well understood to be associated with cigarette smoking as well as with a risk for interstitial lung disease (ILD), its association with airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and with allergic disorders such as atopic dermatitis and allergic rhinitis, is unknown. Kim and colleagues performed a cross-sectional study using information from the Korean National Health and Nutrition Examination Survey by 334 respondents with RA and over 13,000 respondents without RA and analyzed the association of RA with asthma and asthma-related comorbidities. The prevalence of asthma was higher in respondents with RA (7.5% vs 2.8%; P < .001), but the prevalence of other allergic disorders and COPD wassimilar between groups. This finding in a small group of respondents is not striking and its importance is unclear compared with other nonallergic pulmonary disorders. Inferring a mechanistic connection to T-helper (Th) 1- vs Th2 immunity would thus be premature.

Baker and colleagues examined the risk for RA-associated ILD in patients taking different therapies for RA, a topic of great interest due to the frequency of this complication as well as uncertainty regarding its association with medications, including anti-tumor necrosis factor (TNF) agents and methotrexate. Using a claims database, they performed a retrospective study of patients with RA without existing ILD who were treated with a biologic (b) or targeted synthetic disease-modifying antirheumatic drugs (DMARD; abatacept, adalimumab, rituximab, tocilizumab, and tofacitinib). In over 28,000 patients with RA, incidence ratios for ILD were > 1 for all bDMARD, while the incidence ratio for ILD with tofacitinib was 1.47. As the group of patients treated with tofacitinib was the smallest, the reliability of this result is uncertain and thus not strong enough to suggest a protective effect or preference for this medication in patients with known ILD. However, prospective studies looking at ILD in RA patients taking tofacitinib would be of interest.

Kristensen and colleagues also looked at risks associated with tofacitinib and anti-TNF agents, in particular cardiovascular disease, malignancy, and venous thromboembolism, using data from the open-label randomized ORAL Surveillance study, which looked at patients taking 5 mg or 10 mg tofacitinib twice daily, adalimumab, or etanercept. The 10 mg dose was reduced to 5 mg twice daily after it was found that rates of pulmonary embolism were higher in the group taking the higher dose. Age and smoking are also known to be risk factors for malignancy and cardiovascular disease in patients with RA, and these findings carried through in this analysis as well. Within the study, patients taking tofacitinib over age 65 who had ever smoked had a higher risk for cardiovascular events, myocardial infarction, malignancy, venous thromboembolism, and death compared with patients on anti-TNF therapy, while patients taking tofacitinib who were younger than 65 and had never smoked had a risk similar to those on anti-TNF therapy.The study confirms prior knowledge regarding the risks of tofacitinib in different patient populations, suggesting that caution should be used with this medication in older patients and those who smoke.

In evaluating the importance of early aggressive treatment of rheumatoid arthritis (RA), we often look at prognostic factors for severe disease, such as seropositivity, elevated inflammatory markers, and erosions. Eberhard and colleagues looked at the relationship between damage as seen on radiography (including erosions and joint space narrowing) and pain and disability in early RA using an inception cohort with <12 months of symptoms. Over 200 patients in Sweden were followed for 5 years with clinical, laboratory, and radiographic evaluations. Of interest, pain was associated with female sex, tender joint count, and inflammatory markers at various time points but not with radiographic damage. This may reflect that pain is related to current inflammation rather than past joint damage or that pain is related to other factors, such as central sensitization. Radiographic damage was, however, associated with disability and thus remains an important target and outcome measure for assessing treatment effectiveness.

Leon and colleagues also looked at early RA but instead, at the category of difficult-to-treat RA (D2T RA), meaning persistent RA symptoms after a trial of at least two biologic or targeted synthetic disease-modifying antirheumatic drugs. In order to gain better insight in preventing D2T RA, the authors examined its association with potentially modifiable risk factors early in the course of disease. Of the over 600 patients followed in this inception cohort, only about 6% were classified as having D2T RA. The study found that patients who had D2T RA tended to be younger, with a higher tender joint count, higher pain scores, and a higher initial level of disability. The Disease Activity Score (DAS28) itself was higher in patients with D2T RA, but the difference did not reach statistical significance. The small number of patients (35) in the D2T RA group may have affected the findings as well as their wider applicability. However, it is interesting to consider whether the associations may also reflect the impact of noninflammatory factors, as in the previous study, on the classification of D2T RA.

Park and colleagues evaluated the difference in clinical outcomes in postmenopausal patients with RA who underwent menopause at younger than 45 years or 45 years or older. Among over 2800 patients in Korea, those who underwent early menopause were more likely to be seronegative and have high disease activity and worse patient-reported outcome scores in fatigue, sleep, and health-related quality of life despite comparable treatments and prevalence of erosions. The authors suggest this may be related to lower cumulative estrogen exposure; whether this correlates to inflammatory cytokine signatures is not yet known. However, as with the prior studies, central sensitization and noninflammatory pain may also contribute and should be considered in interpreting response to therapy.

Finally, addressing the potential risk for cancer in patients with RA before or during treatment with immunosuppressive medications, Miyata and colleagues reported a study that screened nearly 2200 patients who underwent CT (from neck to pelvis) and compared them with those who underwent routine screening with physical exam plus radiography. The study found that CT screening enhanced cancer detection, with a large number of cancers detected at an earlier stage with CT screening compared with routine screening. The overall number of cancers detected was low (33), and thus routine screening with neck-to-pelvis CT for all patients with RA may not be a cost-effective practice. However, it bears further examination for potentially higher-risk populations or specific cancers.

In evaluating the importance of early aggressive treatment of rheumatoid arthritis (RA), we often look at prognostic factors for severe disease, such as seropositivity, elevated inflammatory markers, and erosions. Eberhard and colleagues looked at the relationship between damage as seen on radiography (including erosions and joint space narrowing) and pain and disability in early RA using an inception cohort with <12 months of symptoms. Over 200 patients in Sweden were followed for 5 years with clinical, laboratory, and radiographic evaluations. Of interest, pain was associated with female sex, tender joint count, and inflammatory markers at various time points but not with radiographic damage. This may reflect that pain is related to current inflammation rather than past joint damage or that pain is related to other factors, such as central sensitization. Radiographic damage was, however, associated with disability and thus remains an important target and outcome measure for assessing treatment effectiveness.

Leon and colleagues also looked at early RA but instead, at the category of difficult-to-treat RA (D2T RA), meaning persistent RA symptoms after a trial of at least two biologic or targeted synthetic disease-modifying antirheumatic drugs. In order to gain better insight in preventing D2T RA, the authors examined its association with potentially modifiable risk factors early in the course of disease. Of the over 600 patients followed in this inception cohort, only about 6% were classified as having D2T RA. The study found that patients who had D2T RA tended to be younger, with a higher tender joint count, higher pain scores, and a higher initial level of disability. The Disease Activity Score (DAS28) itself was higher in patients with D2T RA, but the difference did not reach statistical significance. The small number of patients (35) in the D2T RA group may have affected the findings as well as their wider applicability. However, it is interesting to consider whether the associations may also reflect the impact of noninflammatory factors, as in the previous study, on the classification of D2T RA.

Park and colleagues evaluated the difference in clinical outcomes in postmenopausal patients with RA who underwent menopause at younger than 45 years or 45 years or older. Among over 2800 patients in Korea, those who underwent early menopause were more likely to be seronegative and have high disease activity and worse patient-reported outcome scores in fatigue, sleep, and health-related quality of life despite comparable treatments and prevalence of erosions. The authors suggest this may be related to lower cumulative estrogen exposure; whether this correlates to inflammatory cytokine signatures is not yet known. However, as with the prior studies, central sensitization and noninflammatory pain may also contribute and should be considered in interpreting response to therapy.

Finally, addressing the potential risk for cancer in patients with RA before or during treatment with immunosuppressive medications, Miyata and colleagues reported a study that screened nearly 2200 patients who underwent CT (from neck to pelvis) and compared them with those who underwent routine screening with physical exam plus radiography. The study found that CT screening enhanced cancer detection, with a large number of cancers detected at an earlier stage with CT screening compared with routine screening. The overall number of cancers detected was low (33), and thus routine screening with neck-to-pelvis CT for all patients with RA may not be a cost-effective practice. However, it bears further examination for potentially higher-risk populations or specific cancers.

In evaluating the importance of early aggressive treatment of rheumatoid arthritis (RA), we often look at prognostic factors for severe disease, such as seropositivity, elevated inflammatory markers, and erosions. Eberhard and colleagues looked at the relationship between damage as seen on radiography (including erosions and joint space narrowing) and pain and disability in early RA using an inception cohort with <12 months of symptoms. Over 200 patients in Sweden were followed for 5 years with clinical, laboratory, and radiographic evaluations. Of interest, pain was associated with female sex, tender joint count, and inflammatory markers at various time points but not with radiographic damage. This may reflect that pain is related to current inflammation rather than past joint damage or that pain is related to other factors, such as central sensitization. Radiographic damage was, however, associated with disability and thus remains an important target and outcome measure for assessing treatment effectiveness.

Leon and colleagues also looked at early RA but instead, at the category of difficult-to-treat RA (D2T RA), meaning persistent RA symptoms after a trial of at least two biologic or targeted synthetic disease-modifying antirheumatic drugs. In order to gain better insight in preventing D2T RA, the authors examined its association with potentially modifiable risk factors early in the course of disease. Of the over 600 patients followed in this inception cohort, only about 6% were classified as having D2T RA. The study found that patients who had D2T RA tended to be younger, with a higher tender joint count, higher pain scores, and a higher initial level of disability. The Disease Activity Score (DAS28) itself was higher in patients with D2T RA, but the difference did not reach statistical significance. The small number of patients (35) in the D2T RA group may have affected the findings as well as their wider applicability. However, it is interesting to consider whether the associations may also reflect the impact of noninflammatory factors, as in the previous study, on the classification of D2T RA.

Park and colleagues evaluated the difference in clinical outcomes in postmenopausal patients with RA who underwent menopause at younger than 45 years or 45 years or older. Among over 2800 patients in Korea, those who underwent early menopause were more likely to be seronegative and have high disease activity and worse patient-reported outcome scores in fatigue, sleep, and health-related quality of life despite comparable treatments and prevalence of erosions. The authors suggest this may be related to lower cumulative estrogen exposure; whether this correlates to inflammatory cytokine signatures is not yet known. However, as with the prior studies, central sensitization and noninflammatory pain may also contribute and should be considered in interpreting response to therapy.

Finally, addressing the potential risk for cancer in patients with RA before or during treatment with immunosuppressive medications, Miyata and colleagues reported a study that screened nearly 2200 patients who underwent CT (from neck to pelvis) and compared them with those who underwent routine screening with physical exam plus radiography. The study found that CT screening enhanced cancer detection, with a large number of cancers detected at an earlier stage with CT screening compared with routine screening. The overall number of cancers detected was low (33), and thus routine screening with neck-to-pelvis CT for all patients with RA may not be a cost-effective practice. However, it bears further examination for potentially higher-risk populations or specific cancers.

Two recent studies examined interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Albrecht and colleagues examined the prevalence of ILD in German patients with RA using a nationwide claims database from 2007 to 2020. Using diagnosis codes for seropositive and seronegative RA (along with disease-modifying antirheumatic drug prescriptions) as well as ILD, they found the prevalence of ILD to be relatively stable from 1.6% to 2.2%, and that incidence was stable (reported as 0.13%-0.21% per year, rather than per patient-year) over the course of the study. There is likely some misclassification with the primary reliance on diagnosis codes (of the included patients with RA only 44% were seropositive). They also excluded drug-induced ILD by diagnosis code, which may not be sufficient. Overall, the prevalence of ILD seems on the low end of what might be expected and may reflect a need for earlier evaluation to detect subclinical ILD.

Kronzer and colleagues performed a case-control study of 84 patients with incident RA-ILD compared with 233 patients with RA without ILD to evaluate the risk associated with specific anticitrullinated protein antibodies (ACPA) for the development of ILD. Compared with the clinical risk factors of smoking, disease activity, obesity, and glucocorticoid use, six "fine-specificity" ACPA were better able to predict ILD risk, with immunoglobulin (Ig) A2 to citrullinated histone 4 associated with an odds ratio (OR) of 0.08, and the others (IgA2 to citrullinated histone 2A, IgA2 to native cyclic histone 2A, IgA2 to native histone 2A, IgG to cyclic citrullinated filaggrin, and IgG to native cyclic filaggrin) were associated with OR of 2.5-5.5 for ILD. In combination with clinical characteristics, the authors developed a risk score with 93% specificity for RA-ILD that should be validated in other populations.

Suh and colleagues examined the association of RA with another less well-studied organ complication, end-stage renal disease (ESRD), using a large national insurance database. Once again, the accuracy of diagnosis is not fully clear using International Classification of Diseases, Tenth Edition (ICD-10), codes for classification. Overall, people with RA had a higher risk for ESRD than did people without RA, regardless of sex or smoking status. Because no immediate mechanistic connection between RA and ESRD is evident, it is possible that part of the increased risk is due to medications used in RA treatment, such as nonsteroidal anti-inflammatory drugs, but this hypothesis remains to be tested.

Finally, a footnote to the success of the treat-to-target strategy (T2T) in RA comes in a study by Ramiro and colleagues of the RA-BIODAM cohort, which, along with other studies, has shown the success of T2T in achieving and maintaining long-term clinical remission in RA. The effect of T2T on radiographic progression, however, is less clear. In this study, over 500 patients were followed for 2 years and a comparison between the T2T strategy and radiographic damage was made. The T2T strategy consisted of intensification of treatment if the Disease Activity Score (DAS-44) did not achieve a goal of < 1.6. This was compared with the radiographic damage (based on the change in Sharp-van der Heijde score[SvdH]) over a 6-month period. Overall, the change in progression was not different among patients who were treated with a stricter adherence to T2T (ie, a higher proportion of T2T) compared with those who were not, suggesting that a looser application of T2T will not necessarily cause a worsening of radiographic progression. It is possible, given the intervals of assessment in this study, that a longer follow-up after T2T is necessary to detect progression, or, given that patients were not randomly assigned, patients who were more strictly treated with T2T were already at higher risk for radiographic progression. However, this study is also helpful in understanding how insights from controlled trials may play out in usual clinical practice.

Two recent studies examined interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Albrecht and colleagues examined the prevalence of ILD in German patients with RA using a nationwide claims database from 2007 to 2020. Using diagnosis codes for seropositive and seronegative RA (along with disease-modifying antirheumatic drug prescriptions) as well as ILD, they found the prevalence of ILD to be relatively stable from 1.6% to 2.2%, and that incidence was stable (reported as 0.13%-0.21% per year, rather than per patient-year) over the course of the study. There is likely some misclassification with the primary reliance on diagnosis codes (of the included patients with RA only 44% were seropositive). They also excluded drug-induced ILD by diagnosis code, which may not be sufficient. Overall, the prevalence of ILD seems on the low end of what might be expected and may reflect a need for earlier evaluation to detect subclinical ILD.

Kronzer and colleagues performed a case-control study of 84 patients with incident RA-ILD compared with 233 patients with RA without ILD to evaluate the risk associated with specific anticitrullinated protein antibodies (ACPA) for the development of ILD. Compared with the clinical risk factors of smoking, disease activity, obesity, and glucocorticoid use, six "fine-specificity" ACPA were better able to predict ILD risk, with immunoglobulin (Ig) A2 to citrullinated histone 4 associated with an odds ratio (OR) of 0.08, and the others (IgA2 to citrullinated histone 2A, IgA2 to native cyclic histone 2A, IgA2 to native histone 2A, IgG to cyclic citrullinated filaggrin, and IgG to native cyclic filaggrin) were associated with OR of 2.5-5.5 for ILD. In combination with clinical characteristics, the authors developed a risk score with 93% specificity for RA-ILD that should be validated in other populations.

Suh and colleagues examined the association of RA with another less well-studied organ complication, end-stage renal disease (ESRD), using a large national insurance database. Once again, the accuracy of diagnosis is not fully clear using International Classification of Diseases, Tenth Edition (ICD-10), codes for classification. Overall, people with RA had a higher risk for ESRD than did people without RA, regardless of sex or smoking status. Because no immediate mechanistic connection between RA and ESRD is evident, it is possible that part of the increased risk is due to medications used in RA treatment, such as nonsteroidal anti-inflammatory drugs, but this hypothesis remains to be tested.

Finally, a footnote to the success of the treat-to-target strategy (T2T) in RA comes in a study by Ramiro and colleagues of the RA-BIODAM cohort, which, along with other studies, has shown the success of T2T in achieving and maintaining long-term clinical remission in RA. The effect of T2T on radiographic progression, however, is less clear. In this study, over 500 patients were followed for 2 years and a comparison between the T2T strategy and radiographic damage was made. The T2T strategy consisted of intensification of treatment if the Disease Activity Score (DAS-44) did not achieve a goal of < 1.6. This was compared with the radiographic damage (based on the change in Sharp-van der Heijde score[SvdH]) over a 6-month period. Overall, the change in progression was not different among patients who were treated with a stricter adherence to T2T (ie, a higher proportion of T2T) compared with those who were not, suggesting that a looser application of T2T will not necessarily cause a worsening of radiographic progression. It is possible, given the intervals of assessment in this study, that a longer follow-up after T2T is necessary to detect progression, or, given that patients were not randomly assigned, patients who were more strictly treated with T2T were already at higher risk for radiographic progression. However, this study is also helpful in understanding how insights from controlled trials may play out in usual clinical practice.

Two recent studies examined interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Albrecht and colleagues examined the prevalence of ILD in German patients with RA using a nationwide claims database from 2007 to 2020. Using diagnosis codes for seropositive and seronegative RA (along with disease-modifying antirheumatic drug prescriptions) as well as ILD, they found the prevalence of ILD to be relatively stable from 1.6% to 2.2%, and that incidence was stable (reported as 0.13%-0.21% per year, rather than per patient-year) over the course of the study. There is likely some misclassification with the primary reliance on diagnosis codes (of the included patients with RA only 44% were seropositive). They also excluded drug-induced ILD by diagnosis code, which may not be sufficient. Overall, the prevalence of ILD seems on the low end of what might be expected and may reflect a need for earlier evaluation to detect subclinical ILD.

Kronzer and colleagues performed a case-control study of 84 patients with incident RA-ILD compared with 233 patients with RA without ILD to evaluate the risk associated with specific anticitrullinated protein antibodies (ACPA) for the development of ILD. Compared with the clinical risk factors of smoking, disease activity, obesity, and glucocorticoid use, six "fine-specificity" ACPA were better able to predict ILD risk, with immunoglobulin (Ig) A2 to citrullinated histone 4 associated with an odds ratio (OR) of 0.08, and the others (IgA2 to citrullinated histone 2A, IgA2 to native cyclic histone 2A, IgA2 to native histone 2A, IgG to cyclic citrullinated filaggrin, and IgG to native cyclic filaggrin) were associated with OR of 2.5-5.5 for ILD. In combination with clinical characteristics, the authors developed a risk score with 93% specificity for RA-ILD that should be validated in other populations.

Suh and colleagues examined the association of RA with another less well-studied organ complication, end-stage renal disease (ESRD), using a large national insurance database. Once again, the accuracy of diagnosis is not fully clear using International Classification of Diseases, Tenth Edition (ICD-10), codes for classification. Overall, people with RA had a higher risk for ESRD than did people without RA, regardless of sex or smoking status. Because no immediate mechanistic connection between RA and ESRD is evident, it is possible that part of the increased risk is due to medications used in RA treatment, such as nonsteroidal anti-inflammatory drugs, but this hypothesis remains to be tested.

Finally, a footnote to the success of the treat-to-target strategy (T2T) in RA comes in a study by Ramiro and colleagues of the RA-BIODAM cohort, which, along with other studies, has shown the success of T2T in achieving and maintaining long-term clinical remission in RA. The effect of T2T on radiographic progression, however, is less clear. In this study, over 500 patients were followed for 2 years and a comparison between the T2T strategy and radiographic damage was made. The T2T strategy consisted of intensification of treatment if the Disease Activity Score (DAS-44) did not achieve a goal of < 1.6. This was compared with the radiographic damage (based on the change in Sharp-van der Heijde score[SvdH]) over a 6-month period. Overall, the change in progression was not different among patients who were treated with a stricter adherence to T2T (ie, a higher proportion of T2T) compared with those who were not, suggesting that a looser application of T2T will not necessarily cause a worsening of radiographic progression. It is possible, given the intervals of assessment in this study, that a longer follow-up after T2T is necessary to detect progression, or, given that patients were not randomly assigned, patients who were more strictly treated with T2T were already at higher risk for radiographic progression. However, this study is also helpful in understanding how insights from controlled trials may play out in usual clinical practice.