Arundathi Jayatilleke, MD

Several recent studies have assessed the use of glucocorticoids, a frequent companion to disease-modifying antirheumatic drug (DMARD) and biologic therapy. Many patients are treated with glucocorticoids early in their disease course as a bridging therapy to long-term treatment, and others receive glucocorticoid therapy chronically or intermittently for flares. Van Ouwerkerk and colleagues performed a combined analysis of seven clinical trials, identified in a systematic literature review, that included a glucocorticoid taper protocol for the treatment of newly diagnosed rheumatoid arthritis (RA), undifferentiated arthritis, or "high-risk profile for persistent arthritis." These studies encompassed intravenous, intramuscular, and oral glucocorticoid regimens, and the continued use of glucocorticoids after bridging. These regimens, including cumulative doses, were examined and found to result in a low probability of ongoing use, especially in patients with lower initial doses and shorter bridging schedules. However, though reassuring as to the early use of glucocorticoids in clinical practice, this finding can be affected by patient characteristics not examined in detail in the aggregated results, including whether the patients were classified as having RA, undifferentiated arthritis, or a "high-risk profile."

Adami and colleagues also looked at tapering of glucocorticoids in patients with RA (though not necessarily early RA) in order to determine risk for flare associated with different tapering schedules. They examined the characteristics of patients with RA experiencing a flare (defined as an increase in Disease Activity Score 28 for Rheumatoid Arthritis with C-reactive protein [DAS28-CRP] > 1.2) and their glucocorticoid therapy in the preceding 6 months and found that tapering to a prednisone equivalent ≤ 2.5 mg daily was associated with a higher risk for flare but that doses > 2.5 mg daily were not. Though this finding is perhaps expected, it does not provide further insight into a strategy to minimize the associated adverse effects of glucocorticoid therapy.

Adding further weight to this point is a study performed in Denmark by Dieperink and colleagues examining risk for Staphylococcus aureus bacteremia (SAB) using a nation-wide registry of over 30,000 patients with RA. They found 180 cases of SAB and examined the patient characteristics. Patients who were currently using or previously used a biologic DMARD had an increased risk for SAB as well as those with moderate to high RA disease activity. Study participants who were currently using a prednisone-equivalent of ≤ 7.5 mg daily had an adjusted odds ratio (aOR) of 2.2 and those using > 7.5 mg daily had an aOR of 9.5 for SAB. This concerning finding suggests that even a relatively "low" dose of prednisone use is not benign for patients with RA, and these studies bring to light the need to research optimal strategies for disease control and balancing immunosuppression with the risk for infection and other adverse events.

Heckert and colleagues looked at another aspect of RA disease control, namely, local progression in a single affected joint. Their prior work has suggested that patients with RA may be prone to recurrent inflammation in a single joint despite systemic treatment, a finding that aligns with common clinical observations. This study evaluates radiographic progression in susceptible joints via post hoc analysis using data from the BeSt study including tender and swollen joints, hand and foot radiographs, and disease activity scores. Despite systemic treatment to a target low disease activity or remission state (as per the BeSt protocol), the study found an association between recurrent joint inflammation and radiographic progression (ie, erosions). However, because they only looked at hand and foot joints, the strength of this association in other joints is unknown, as is the use of local treatment, such as steroid injection to minimize inflammation, though both questions may be difficult to evaluate in a small prospective study.

Several recent studies have assessed the use of glucocorticoids, a frequent companion to disease-modifying antirheumatic drug (DMARD) and biologic therapy. Many patients are treated with glucocorticoids early in their disease course as a bridging therapy to long-term treatment, and others receive glucocorticoid therapy chronically or intermittently for flares. Van Ouwerkerk and colleagues performed a combined analysis of seven clinical trials, identified in a systematic literature review, that included a glucocorticoid taper protocol for the treatment of newly diagnosed rheumatoid arthritis (RA), undifferentiated arthritis, or "high-risk profile for persistent arthritis." These studies encompassed intravenous, intramuscular, and oral glucocorticoid regimens, and the continued use of glucocorticoids after bridging. These regimens, including cumulative doses, were examined and found to result in a low probability of ongoing use, especially in patients with lower initial doses and shorter bridging schedules. However, though reassuring as to the early use of glucocorticoids in clinical practice, this finding can be affected by patient characteristics not examined in detail in the aggregated results, including whether the patients were classified as having RA, undifferentiated arthritis, or a "high-risk profile."

Adami and colleagues also looked at tapering of glucocorticoids in patients with RA (though not necessarily early RA) in order to determine risk for flare associated with different tapering schedules. They examined the characteristics of patients with RA experiencing a flare (defined as an increase in Disease Activity Score 28 for Rheumatoid Arthritis with C-reactive protein [DAS28-CRP] > 1.2) and their glucocorticoid therapy in the preceding 6 months and found that tapering to a prednisone equivalent ≤ 2.5 mg daily was associated with a higher risk for flare but that doses > 2.5 mg daily were not. Though this finding is perhaps expected, it does not provide further insight into a strategy to minimize the associated adverse effects of glucocorticoid therapy.

Adding further weight to this point is a study performed in Denmark by Dieperink and colleagues examining risk for Staphylococcus aureus bacteremia (SAB) using a nation-wide registry of over 30,000 patients with RA. They found 180 cases of SAB and examined the patient characteristics. Patients who were currently using or previously used a biologic DMARD had an increased risk for SAB as well as those with moderate to high RA disease activity. Study participants who were currently using a prednisone-equivalent of ≤ 7.5 mg daily had an adjusted odds ratio (aOR) of 2.2 and those using > 7.5 mg daily had an aOR of 9.5 for SAB. This concerning finding suggests that even a relatively "low" dose of prednisone use is not benign for patients with RA, and these studies bring to light the need to research optimal strategies for disease control and balancing immunosuppression with the risk for infection and other adverse events.

Heckert and colleagues looked at another aspect of RA disease control, namely, local progression in a single affected joint. Their prior work has suggested that patients with RA may be prone to recurrent inflammation in a single joint despite systemic treatment, a finding that aligns with common clinical observations. This study evaluates radiographic progression in susceptible joints via post hoc analysis using data from the BeSt study including tender and swollen joints, hand and foot radiographs, and disease activity scores. Despite systemic treatment to a target low disease activity or remission state (as per the BeSt protocol), the study found an association between recurrent joint inflammation and radiographic progression (ie, erosions). However, because they only looked at hand and foot joints, the strength of this association in other joints is unknown, as is the use of local treatment, such as steroid injection to minimize inflammation, though both questions may be difficult to evaluate in a small prospective study.

Several recent studies have assessed the use of glucocorticoids, a frequent companion to disease-modifying antirheumatic drug (DMARD) and biologic therapy. Many patients are treated with glucocorticoids early in their disease course as a bridging therapy to long-term treatment, and others receive glucocorticoid therapy chronically or intermittently for flares. Van Ouwerkerk and colleagues performed a combined analysis of seven clinical trials, identified in a systematic literature review, that included a glucocorticoid taper protocol for the treatment of newly diagnosed rheumatoid arthritis (RA), undifferentiated arthritis, or "high-risk profile for persistent arthritis." These studies encompassed intravenous, intramuscular, and oral glucocorticoid regimens, and the continued use of glucocorticoids after bridging. These regimens, including cumulative doses, were examined and found to result in a low probability of ongoing use, especially in patients with lower initial doses and shorter bridging schedules. However, though reassuring as to the early use of glucocorticoids in clinical practice, this finding can be affected by patient characteristics not examined in detail in the aggregated results, including whether the patients were classified as having RA, undifferentiated arthritis, or a "high-risk profile."

Adami and colleagues also looked at tapering of glucocorticoids in patients with RA (though not necessarily early RA) in order to determine risk for flare associated with different tapering schedules. They examined the characteristics of patients with RA experiencing a flare (defined as an increase in Disease Activity Score 28 for Rheumatoid Arthritis with C-reactive protein [DAS28-CRP] > 1.2) and their glucocorticoid therapy in the preceding 6 months and found that tapering to a prednisone equivalent ≤ 2.5 mg daily was associated with a higher risk for flare but that doses > 2.5 mg daily were not. Though this finding is perhaps expected, it does not provide further insight into a strategy to minimize the associated adverse effects of glucocorticoid therapy.

Adding further weight to this point is a study performed in Denmark by Dieperink and colleagues examining risk for Staphylococcus aureus bacteremia (SAB) using a nation-wide registry of over 30,000 patients with RA. They found 180 cases of SAB and examined the patient characteristics. Patients who were currently using or previously used a biologic DMARD had an increased risk for SAB as well as those with moderate to high RA disease activity. Study participants who were currently using a prednisone-equivalent of ≤ 7.5 mg daily had an adjusted odds ratio (aOR) of 2.2 and those using > 7.5 mg daily had an aOR of 9.5 for SAB. This concerning finding suggests that even a relatively "low" dose of prednisone use is not benign for patients with RA, and these studies bring to light the need to research optimal strategies for disease control and balancing immunosuppression with the risk for infection and other adverse events.

Heckert and colleagues looked at another aspect of RA disease control, namely, local progression in a single affected joint. Their prior work has suggested that patients with RA may be prone to recurrent inflammation in a single joint despite systemic treatment, a finding that aligns with common clinical observations. This study evaluates radiographic progression in susceptible joints via post hoc analysis using data from the BeSt study including tender and swollen joints, hand and foot radiographs, and disease activity scores. Despite systemic treatment to a target low disease activity or remission state (as per the BeSt protocol), the study found an association between recurrent joint inflammation and radiographic progression (ie, erosions). However, because they only looked at hand and foot joints, the strength of this association in other joints is unknown, as is the use of local treatment, such as steroid injection to minimize inflammation, though both questions may be difficult to evaluate in a small prospective study.

Though rheumatoid arthritis (RA)–associated interstitial lung disease (RA-ILD) is a feared complication that can significantly affect morbidity and mortality, the role of methotrexate in treatment and its possible contribution to ILD is yet unknown. Kim and colleagues performed a retrospective analysis of a series of 170 patients with RA-ILD to try to identify risk factors and protective factors for mortality and decline of lung function. Previously known risk factors included older age, smoking, and seropositivity for cyclic citrullinated peptide (CCP). In this series, patients who had exposure to methotrexate after a diagnosis of RA-ILD were found to have less progression of decline in lung function and decreased mortality compared with those who did not, which is a finding that warrants further examination. On the other hand, there was a suggestion that sulfasalazine use is associated with increased mortality, though this finding was not borne out in multivariate analysis.

A different group of authors also examined the association with conventional disease-modifying antirheumatic drugs (DMARD) with ILD progression in a prospective analysis of 143 patients in the multicenter Korean RA-ILD cohort. Patients were classified regarding exposure to methotrexate, leflunomide, or tacrolimus as well as biologic DMARD and glucocorticoid exposure, with a primary outcome of ILD progression based on pulmonary function tests or mortality. The study did not detect any difference in time to ILD progression with methotrexate exposure, though it is not clear that the study would be able to detect a protective effect as was possible in the prior study. However, patients who were exposed to leflunomide had a shorter time to ILD progression than did those who were not, though this did not persist in multivariate analysis, and tacrolimus exposure had a statistically insignificant impact on ILD progression. Because the study is small, other associations which could affect use of leflunomide in these patients were not examined, though prior studies have suggested an association with leflunomide in ILD progression in patients with existing RA-ILD.

Li and colleagues addressed the characteristics and prognosis of late-onset RA (LORA) in people 60 years or older compared with younger-onset RA (YORA) in a prospective cohort study using a Canadian RA registry. Patients in the registry were enrolled early in the course of their illness and clinical characteristics as well as time to Disease Activity Score (DAS28) remission were analyzed. Of note, YORA and LORA patients had similar times to remission but were on less aggressive medication regimens, such as conventional DMARD without biologic DMARD or Janus kinase (JAK) inhibitors. In this registry, a smaller percentage of LORA patients compared with YORA patients were seropositive, which, given the enrollment of patients early in their disease course, may affect the use of biologic DMARD and JAK inhibitors.

Finally, the issue of noninflammatory pain contributing to disease activity and quality of life in RA has received increased scrutiny recently. Choy and colleagues studied disproportionate articular pain (DP) and its response to sarilumab, adalimumab, or placebo in a post hoc analysis of data from prior randomized clinical trials. DP was defined as a tender joint count that exceeded swollen joint count by seven and was present in about 20% of patients in the three randomized clinical trials examined. In these studies, DP was reduced in patients treated with sarilumab compared with placebo or adalimumab. Although this finding is exciting in raising the possibility of an immunologic explanation for DP via interleukin 6 (IL-6), the results should be considered carefully in the context of this post hoc analysis, especially before considering sarilumab or other IL-6 inhibitors as viable treatment options for DP in RA.

Though rheumatoid arthritis (RA)–associated interstitial lung disease (RA-ILD) is a feared complication that can significantly affect morbidity and mortality, the role of methotrexate in treatment and its possible contribution to ILD is yet unknown. Kim and colleagues performed a retrospective analysis of a series of 170 patients with RA-ILD to try to identify risk factors and protective factors for mortality and decline of lung function. Previously known risk factors included older age, smoking, and seropositivity for cyclic citrullinated peptide (CCP). In this series, patients who had exposure to methotrexate after a diagnosis of RA-ILD were found to have less progression of decline in lung function and decreased mortality compared with those who did not, which is a finding that warrants further examination. On the other hand, there was a suggestion that sulfasalazine use is associated with increased mortality, though this finding was not borne out in multivariate analysis.

A different group of authors also examined the association with conventional disease-modifying antirheumatic drugs (DMARD) with ILD progression in a prospective analysis of 143 patients in the multicenter Korean RA-ILD cohort. Patients were classified regarding exposure to methotrexate, leflunomide, or tacrolimus as well as biologic DMARD and glucocorticoid exposure, with a primary outcome of ILD progression based on pulmonary function tests or mortality. The study did not detect any difference in time to ILD progression with methotrexate exposure, though it is not clear that the study would be able to detect a protective effect as was possible in the prior study. However, patients who were exposed to leflunomide had a shorter time to ILD progression than did those who were not, though this did not persist in multivariate analysis, and tacrolimus exposure had a statistically insignificant impact on ILD progression. Because the study is small, other associations which could affect use of leflunomide in these patients were not examined, though prior studies have suggested an association with leflunomide in ILD progression in patients with existing RA-ILD.

Li and colleagues addressed the characteristics and prognosis of late-onset RA (LORA) in people 60 years or older compared with younger-onset RA (YORA) in a prospective cohort study using a Canadian RA registry. Patients in the registry were enrolled early in the course of their illness and clinical characteristics as well as time to Disease Activity Score (DAS28) remission were analyzed. Of note, YORA and LORA patients had similar times to remission but were on less aggressive medication regimens, such as conventional DMARD without biologic DMARD or Janus kinase (JAK) inhibitors. In this registry, a smaller percentage of LORA patients compared with YORA patients were seropositive, which, given the enrollment of patients early in their disease course, may affect the use of biologic DMARD and JAK inhibitors.

Finally, the issue of noninflammatory pain contributing to disease activity and quality of life in RA has received increased scrutiny recently. Choy and colleagues studied disproportionate articular pain (DP) and its response to sarilumab, adalimumab, or placebo in a post hoc analysis of data from prior randomized clinical trials. DP was defined as a tender joint count that exceeded swollen joint count by seven and was present in about 20% of patients in the three randomized clinical trials examined. In these studies, DP was reduced in patients treated with sarilumab compared with placebo or adalimumab. Although this finding is exciting in raising the possibility of an immunologic explanation for DP via interleukin 6 (IL-6), the results should be considered carefully in the context of this post hoc analysis, especially before considering sarilumab or other IL-6 inhibitors as viable treatment options for DP in RA.

Though rheumatoid arthritis (RA)–associated interstitial lung disease (RA-ILD) is a feared complication that can significantly affect morbidity and mortality, the role of methotrexate in treatment and its possible contribution to ILD is yet unknown. Kim and colleagues performed a retrospective analysis of a series of 170 patients with RA-ILD to try to identify risk factors and protective factors for mortality and decline of lung function. Previously known risk factors included older age, smoking, and seropositivity for cyclic citrullinated peptide (CCP). In this series, patients who had exposure to methotrexate after a diagnosis of RA-ILD were found to have less progression of decline in lung function and decreased mortality compared with those who did not, which is a finding that warrants further examination. On the other hand, there was a suggestion that sulfasalazine use is associated with increased mortality, though this finding was not borne out in multivariate analysis.

A different group of authors also examined the association with conventional disease-modifying antirheumatic drugs (DMARD) with ILD progression in a prospective analysis of 143 patients in the multicenter Korean RA-ILD cohort. Patients were classified regarding exposure to methotrexate, leflunomide, or tacrolimus as well as biologic DMARD and glucocorticoid exposure, with a primary outcome of ILD progression based on pulmonary function tests or mortality. The study did not detect any difference in time to ILD progression with methotrexate exposure, though it is not clear that the study would be able to detect a protective effect as was possible in the prior study. However, patients who were exposed to leflunomide had a shorter time to ILD progression than did those who were not, though this did not persist in multivariate analysis, and tacrolimus exposure had a statistically insignificant impact on ILD progression. Because the study is small, other associations which could affect use of leflunomide in these patients were not examined, though prior studies have suggested an association with leflunomide in ILD progression in patients with existing RA-ILD.

Li and colleagues addressed the characteristics and prognosis of late-onset RA (LORA) in people 60 years or older compared with younger-onset RA (YORA) in a prospective cohort study using a Canadian RA registry. Patients in the registry were enrolled early in the course of their illness and clinical characteristics as well as time to Disease Activity Score (DAS28) remission were analyzed. Of note, YORA and LORA patients had similar times to remission but were on less aggressive medication regimens, such as conventional DMARD without biologic DMARD or Janus kinase (JAK) inhibitors. In this registry, a smaller percentage of LORA patients compared with YORA patients were seropositive, which, given the enrollment of patients early in their disease course, may affect the use of biologic DMARD and JAK inhibitors.

Finally, the issue of noninflammatory pain contributing to disease activity and quality of life in RA has received increased scrutiny recently. Choy and colleagues studied disproportionate articular pain (DP) and its response to sarilumab, adalimumab, or placebo in a post hoc analysis of data from prior randomized clinical trials. DP was defined as a tender joint count that exceeded swollen joint count by seven and was present in about 20% of patients in the three randomized clinical trials examined. In these studies, DP was reduced in patients treated with sarilumab compared with placebo or adalimumab. Although this finding is exciting in raising the possibility of an immunologic explanation for DP via interleukin 6 (IL-6), the results should be considered carefully in the context of this post hoc analysis, especially before considering sarilumab or other IL-6 inhibitors as viable treatment options for DP in RA.

Several studies have addressed the efficacy of COVID vaccines in patients with autoimmune and rheumatic diseases owing to the concern for possible reduced vaccine immunogenicity in patients who are immunocompromised or taking immunosuppressive medications. With the availability of additional booster doses for the COVID vaccines, the effect of immunosuppressive medications on the humoral response to mRNA vaccines has been of increased interest in terms of counseling patients on how to manage their medications and vaccine timing. Prior studies have suggested that holding methotrexate after COVID vaccine administration improves antibody response to the COVID vaccine. Stahl and colleagues performed a retrospective study to look at vaccine response to a third (booster) dose in patients with rheumatoid arthritis (RA) over 65 years of age (vs those under 65 years of age) and found that patients over 65 receiving methotrexate had lower levels of neutralizing antibodies than did those receiving other treatments for RA, whereas no differences were seen with different treatments among patients under 65. Although COVID vaccine guidance continues to evolve, this finding raises the possibility of a need to tailor guidance in older patients with RA. However, the finding is far from conclusive given the small number of patients in the study.

In addition to COVID vaccine efficacy, the possibility of vaccine-related adverse effects has been a topic of concern in the rheumatology community, especially regarding the potential for a flare of autoimmune diseases. Anxiety regarding adverse effects may also exacerbate COVID vaccine hesitancy among some people. Naveen and colleagues performed an online international cross-sectional survey study regarding rheumatic diseases and 7-day adverse events. Over 9000 people completed the survey, about half of whom had autoimmune diseases (including nonrheumatic autoimmune diseases). Roughly three quarters of patients with RA reported adverse effects, with differences seen in frequencies of events between the different vaccine manufacturers. However, the majority of these adverse effects were minor (such as fatigue, headache, and body ache), without substantial differences between those with inactive and those with active RA.

The treat-to-target strategy is well-accepted in treatment of RA and pursuit of improved long-term disease outcomes. Hartman and colleagues evaluated the effect of using a treat-to-target strategy starting with the combination therapy with RA-light (COBRA-light) protocol (with initial methotrexate and tapering prednisolone) in early RA. Patients who were deemed at high risk for worsening RA (n = 150) received COBRA-light, whereas those in the low-risk category (n = 40) received methotrexate monotherapy. At 13 weeks, nonresponders were randomized to intensification or continuation of their regimens, with a primary endpoint of European Alliance of Associations for Rheumatology (EULAR) response and secondary endpoint of Disease Activity Score (DAS44). After 13 weeks, 73% of patients in the high-risk category achieved the targets of EULAR good response and DAS44 < 1.6, whereas after 26 weeks, 80% of patients who received intensified therapy and 44% of those who continued their regimens reached the target, though these numbers were small. Overall, the strategy appears to be successful in treatment of early RA in patients at high risk for disease progression, but it does lead to increased use of higher chronic glucocorticoid doses. In addition, the small numbers of patients in the low-risk category, as well as their less aggressive treatment, does not allow for a nuanced analysis of the best initial treatment in this group of patients.

Finally, a cohort study by Takanashi and colleagues evaluated the rates of seropositivity for rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) in patients diagnosed with RA and its association with demographic categories. Seropositivity was associated with smoking and family history of RA, as expected. Among the 1685 patients, 83% of whom were women, older age at RA diagnosis was associated with seronegativity for RF and CCP in women but not in men. The decline in seropositivity with age among women cannot be further evaluated with the limited information in this small study and may have to do with other factors, including erosive or inflammatory osteoarthritis.

Several studies have addressed the efficacy of COVID vaccines in patients with autoimmune and rheumatic diseases owing to the concern for possible reduced vaccine immunogenicity in patients who are immunocompromised or taking immunosuppressive medications. With the availability of additional booster doses for the COVID vaccines, the effect of immunosuppressive medications on the humoral response to mRNA vaccines has been of increased interest in terms of counseling patients on how to manage their medications and vaccine timing. Prior studies have suggested that holding methotrexate after COVID vaccine administration improves antibody response to the COVID vaccine. Stahl and colleagues performed a retrospective study to look at vaccine response to a third (booster) dose in patients with rheumatoid arthritis (RA) over 65 years of age (vs those under 65 years of age) and found that patients over 65 receiving methotrexate had lower levels of neutralizing antibodies than did those receiving other treatments for RA, whereas no differences were seen with different treatments among patients under 65. Although COVID vaccine guidance continues to evolve, this finding raises the possibility of a need to tailor guidance in older patients with RA. However, the finding is far from conclusive given the small number of patients in the study.

In addition to COVID vaccine efficacy, the possibility of vaccine-related adverse effects has been a topic of concern in the rheumatology community, especially regarding the potential for a flare of autoimmune diseases. Anxiety regarding adverse effects may also exacerbate COVID vaccine hesitancy among some people. Naveen and colleagues performed an online international cross-sectional survey study regarding rheumatic diseases and 7-day adverse events. Over 9000 people completed the survey, about half of whom had autoimmune diseases (including nonrheumatic autoimmune diseases). Roughly three quarters of patients with RA reported adverse effects, with differences seen in frequencies of events between the different vaccine manufacturers. However, the majority of these adverse effects were minor (such as fatigue, headache, and body ache), without substantial differences between those with inactive and those with active RA.

The treat-to-target strategy is well-accepted in treatment of RA and pursuit of improved long-term disease outcomes. Hartman and colleagues evaluated the effect of using a treat-to-target strategy starting with the combination therapy with RA-light (COBRA-light) protocol (with initial methotrexate and tapering prednisolone) in early RA. Patients who were deemed at high risk for worsening RA (n = 150) received COBRA-light, whereas those in the low-risk category (n = 40) received methotrexate monotherapy. At 13 weeks, nonresponders were randomized to intensification or continuation of their regimens, with a primary endpoint of European Alliance of Associations for Rheumatology (EULAR) response and secondary endpoint of Disease Activity Score (DAS44). After 13 weeks, 73% of patients in the high-risk category achieved the targets of EULAR good response and DAS44 < 1.6, whereas after 26 weeks, 80% of patients who received intensified therapy and 44% of those who continued their regimens reached the target, though these numbers were small. Overall, the strategy appears to be successful in treatment of early RA in patients at high risk for disease progression, but it does lead to increased use of higher chronic glucocorticoid doses. In addition, the small numbers of patients in the low-risk category, as well as their less aggressive treatment, does not allow for a nuanced analysis of the best initial treatment in this group of patients.

Finally, a cohort study by Takanashi and colleagues evaluated the rates of seropositivity for rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) in patients diagnosed with RA and its association with demographic categories. Seropositivity was associated with smoking and family history of RA, as expected. Among the 1685 patients, 83% of whom were women, older age at RA diagnosis was associated with seronegativity for RF and CCP in women but not in men. The decline in seropositivity with age among women cannot be further evaluated with the limited information in this small study and may have to do with other factors, including erosive or inflammatory osteoarthritis.

Several studies have addressed the efficacy of COVID vaccines in patients with autoimmune and rheumatic diseases owing to the concern for possible reduced vaccine immunogenicity in patients who are immunocompromised or taking immunosuppressive medications. With the availability of additional booster doses for the COVID vaccines, the effect of immunosuppressive medications on the humoral response to mRNA vaccines has been of increased interest in terms of counseling patients on how to manage their medications and vaccine timing. Prior studies have suggested that holding methotrexate after COVID vaccine administration improves antibody response to the COVID vaccine. Stahl and colleagues performed a retrospective study to look at vaccine response to a third (booster) dose in patients with rheumatoid arthritis (RA) over 65 years of age (vs those under 65 years of age) and found that patients over 65 receiving methotrexate had lower levels of neutralizing antibodies than did those receiving other treatments for RA, whereas no differences were seen with different treatments among patients under 65. Although COVID vaccine guidance continues to evolve, this finding raises the possibility of a need to tailor guidance in older patients with RA. However, the finding is far from conclusive given the small number of patients in the study.

In addition to COVID vaccine efficacy, the possibility of vaccine-related adverse effects has been a topic of concern in the rheumatology community, especially regarding the potential for a flare of autoimmune diseases. Anxiety regarding adverse effects may also exacerbate COVID vaccine hesitancy among some people. Naveen and colleagues performed an online international cross-sectional survey study regarding rheumatic diseases and 7-day adverse events. Over 9000 people completed the survey, about half of whom had autoimmune diseases (including nonrheumatic autoimmune diseases). Roughly three quarters of patients with RA reported adverse effects, with differences seen in frequencies of events between the different vaccine manufacturers. However, the majority of these adverse effects were minor (such as fatigue, headache, and body ache), without substantial differences between those with inactive and those with active RA.

The treat-to-target strategy is well-accepted in treatment of RA and pursuit of improved long-term disease outcomes. Hartman and colleagues evaluated the effect of using a treat-to-target strategy starting with the combination therapy with RA-light (COBRA-light) protocol (with initial methotrexate and tapering prednisolone) in early RA. Patients who were deemed at high risk for worsening RA (n = 150) received COBRA-light, whereas those in the low-risk category (n = 40) received methotrexate monotherapy. At 13 weeks, nonresponders were randomized to intensification or continuation of their regimens, with a primary endpoint of European Alliance of Associations for Rheumatology (EULAR) response and secondary endpoint of Disease Activity Score (DAS44). After 13 weeks, 73% of patients in the high-risk category achieved the targets of EULAR good response and DAS44 < 1.6, whereas after 26 weeks, 80% of patients who received intensified therapy and 44% of those who continued their regimens reached the target, though these numbers were small. Overall, the strategy appears to be successful in treatment of early RA in patients at high risk for disease progression, but it does lead to increased use of higher chronic glucocorticoid doses. In addition, the small numbers of patients in the low-risk category, as well as their less aggressive treatment, does not allow for a nuanced analysis of the best initial treatment in this group of patients.

Finally, a cohort study by Takanashi and colleagues evaluated the rates of seropositivity for rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) in patients diagnosed with RA and its association with demographic categories. Seropositivity was associated with smoking and family history of RA, as expected. Among the 1685 patients, 83% of whom were women, older age at RA diagnosis was associated with seronegativity for RF and CCP in women but not in men. The decline in seropositivity with age among women cannot be further evaluated with the limited information in this small study and may have to do with other factors, including erosive or inflammatory osteoarthritis.

Multiple studies have emphasized the potential for severe COVID-19 outcomes in patients with rheumatic disease, including patients with rheumatoid arthritis (RA). Because these studies often group together patients with different diseases, medications, and manifestations, differences in outcomes between patients with these conditions may be difficult to tease out.

Figueroa-Parra and colleagues performed a retrospective cohort study comparing people with RA who developed COVID-19 to those who did not have RA to examine the effect of RA characteristics, such as interstitial lung disease (ILD), serostatus, and bone erosions, on COVID-19 outcomes. Patients with RA, particularly those with seropositive RA, bone erosions, and RA-associated ILD, had approximately twofold (or higher) risk for severe COVID-19 outcomes, such as mortality or mechanical ventilation, than did those without RA. However, there was no difference in outcomes seen between patients with RA who were seropositive compared with those who were seronegative, with or without bone erosions, or with or without ILD. The mechanism by which RA phenotypes and their treatment affect this risk remains unclear.

Li and colleagues also looked at COVID-19 outcomes in patients with RA according to vaccination status using a UK primary care database. Among unvaccinated patients, the risk for SARS-CoV-2 infection and hospitalization or mortality because of COVID-19 were modestly higher in people with RA. Among vaccinated patients, there was no increased risk for breakthrough infection, COVID-19 hospitalization, or mortality observed in patients with RA over 3 or 6 months of follow-up, with a slight increase over 9 months of follow-up. Overall, both studies support prior research suggesting a higher risk for more severe COVID-19 in patients with RA, as well as potential mitigation with vaccination.

Predictors of RA course and severity are of great interest in determining the optimal therapy to reduce joint damage and prevent RA progression while also minimizing the adverse effects of treatment. Early disease course has been shown to be important in several studies. Giollo and colleagues compared patients with "difficult-to-treat RA," ie, RA that is resistant to multiple biologic disease-modifying antirheumatic drugs (bDMARD) or targeted synthetic DMARD (tsDMARD), with those without in an inception cohort study and found that early difficult management as well as delay of methotrexate initiation was associated with persistent inflammatory symptoms. This finding does not show a causative relationship between methotrexate and protection from the development of refractory RA but does lend support for early aggressive treatment in patients with a high inflammatory burden.

Conversely, Parisi and colleagues performed a subanalysis of the STARTER study of patients with RA in clinical remission to evaluate the impact of different therapies. The STARTER study had shown an association between ultrasound detection of tenosynovitis and RA flares. Of the more than 250 patients completing the study, ultrasound evidence of tenosynovitis was better controlled in patients on combination bDMARD and conventional synthetic DMARD (csDMARD) therapy than in those on csDMARDs monotherapy, with a trend toward reduction in flares in patients on combination therapy. Given the relatively small effect, it is not clear that combination therapy is associated with deeper remission, but, as suggested in prior studies, ultrasound evidence of tenosynovitis may be worthwhile considering prior to tapering therapy.

Multiple studies have emphasized the potential for severe COVID-19 outcomes in patients with rheumatic disease, including patients with rheumatoid arthritis (RA). Because these studies often group together patients with different diseases, medications, and manifestations, differences in outcomes between patients with these conditions may be difficult to tease out.

Figueroa-Parra and colleagues performed a retrospective cohort study comparing people with RA who developed COVID-19 to those who did not have RA to examine the effect of RA characteristics, such as interstitial lung disease (ILD), serostatus, and bone erosions, on COVID-19 outcomes. Patients with RA, particularly those with seropositive RA, bone erosions, and RA-associated ILD, had approximately twofold (or higher) risk for severe COVID-19 outcomes, such as mortality or mechanical ventilation, than did those without RA. However, there was no difference in outcomes seen between patients with RA who were seropositive compared with those who were seronegative, with or without bone erosions, or with or without ILD. The mechanism by which RA phenotypes and their treatment affect this risk remains unclear.

Li and colleagues also looked at COVID-19 outcomes in patients with RA according to vaccination status using a UK primary care database. Among unvaccinated patients, the risk for SARS-CoV-2 infection and hospitalization or mortality because of COVID-19 were modestly higher in people with RA. Among vaccinated patients, there was no increased risk for breakthrough infection, COVID-19 hospitalization, or mortality observed in patients with RA over 3 or 6 months of follow-up, with a slight increase over 9 months of follow-up. Overall, both studies support prior research suggesting a higher risk for more severe COVID-19 in patients with RA, as well as potential mitigation with vaccination.

Predictors of RA course and severity are of great interest in determining the optimal therapy to reduce joint damage and prevent RA progression while also minimizing the adverse effects of treatment. Early disease course has been shown to be important in several studies. Giollo and colleagues compared patients with "difficult-to-treat RA," ie, RA that is resistant to multiple biologic disease-modifying antirheumatic drugs (bDMARD) or targeted synthetic DMARD (tsDMARD), with those without in an inception cohort study and found that early difficult management as well as delay of methotrexate initiation was associated with persistent inflammatory symptoms. This finding does not show a causative relationship between methotrexate and protection from the development of refractory RA but does lend support for early aggressive treatment in patients with a high inflammatory burden.

Conversely, Parisi and colleagues performed a subanalysis of the STARTER study of patients with RA in clinical remission to evaluate the impact of different therapies. The STARTER study had shown an association between ultrasound detection of tenosynovitis and RA flares. Of the more than 250 patients completing the study, ultrasound evidence of tenosynovitis was better controlled in patients on combination bDMARD and conventional synthetic DMARD (csDMARD) therapy than in those on csDMARDs monotherapy, with a trend toward reduction in flares in patients on combination therapy. Given the relatively small effect, it is not clear that combination therapy is associated with deeper remission, but, as suggested in prior studies, ultrasound evidence of tenosynovitis may be worthwhile considering prior to tapering therapy.

Multiple studies have emphasized the potential for severe COVID-19 outcomes in patients with rheumatic disease, including patients with rheumatoid arthritis (RA). Because these studies often group together patients with different diseases, medications, and manifestations, differences in outcomes between patients with these conditions may be difficult to tease out.

Figueroa-Parra and colleagues performed a retrospective cohort study comparing people with RA who developed COVID-19 to those who did not have RA to examine the effect of RA characteristics, such as interstitial lung disease (ILD), serostatus, and bone erosions, on COVID-19 outcomes. Patients with RA, particularly those with seropositive RA, bone erosions, and RA-associated ILD, had approximately twofold (or higher) risk for severe COVID-19 outcomes, such as mortality or mechanical ventilation, than did those without RA. However, there was no difference in outcomes seen between patients with RA who were seropositive compared with those who were seronegative, with or without bone erosions, or with or without ILD. The mechanism by which RA phenotypes and their treatment affect this risk remains unclear.

Li and colleagues also looked at COVID-19 outcomes in patients with RA according to vaccination status using a UK primary care database. Among unvaccinated patients, the risk for SARS-CoV-2 infection and hospitalization or mortality because of COVID-19 were modestly higher in people with RA. Among vaccinated patients, there was no increased risk for breakthrough infection, COVID-19 hospitalization, or mortality observed in patients with RA over 3 or 6 months of follow-up, with a slight increase over 9 months of follow-up. Overall, both studies support prior research suggesting a higher risk for more severe COVID-19 in patients with RA, as well as potential mitigation with vaccination.

Predictors of RA course and severity are of great interest in determining the optimal therapy to reduce joint damage and prevent RA progression while also minimizing the adverse effects of treatment. Early disease course has been shown to be important in several studies. Giollo and colleagues compared patients with "difficult-to-treat RA," ie, RA that is resistant to multiple biologic disease-modifying antirheumatic drugs (bDMARD) or targeted synthetic DMARD (tsDMARD), with those without in an inception cohort study and found that early difficult management as well as delay of methotrexate initiation was associated with persistent inflammatory symptoms. This finding does not show a causative relationship between methotrexate and protection from the development of refractory RA but does lend support for early aggressive treatment in patients with a high inflammatory burden.

Conversely, Parisi and colleagues performed a subanalysis of the STARTER study of patients with RA in clinical remission to evaluate the impact of different therapies. The STARTER study had shown an association between ultrasound detection of tenosynovitis and RA flares. Of the more than 250 patients completing the study, ultrasound evidence of tenosynovitis was better controlled in patients on combination bDMARD and conventional synthetic DMARD (csDMARD) therapy than in those on csDMARDs monotherapy, with a trend toward reduction in flares in patients on combination therapy. Given the relatively small effect, it is not clear that combination therapy is associated with deeper remission, but, as suggested in prior studies, ultrasound evidence of tenosynovitis may be worthwhile considering prior to tapering therapy.

Interleukin (IL)–6 is known to be of great importance in the pathogenesis of rheumatoid arthritis (RA) owing to its role in the inflammatory response. Current IL-6-directed therapies in RA, namely sarilumab and tocilizumab, target the receptor. In a double-blind randomized controlled trial with both placebo and active comparators, Smolen and colleagues evaluated the efficacy of olokizumab, which directly binds and inhibits the activity of IL-6, in combination with methotrexate, in the treatment of people with RA. Patients were treated with methotrexate alone or in combination with adalimumab or olokizumab, and clinical outcomes were evaluated after 12 weeks, a relatively short time frame. Olokizumab was noninferior to adalimumab in terms of the proportion of patients achieving an American College of Rheumatology 20 response, with similar rates of serious adverse events, the most common of which was infection. Though this study included patients from across the globe, the percentage of Black and Asian patients was relatively low and thus may affect the generalizability of this study to a US population; the numbers of patients in each group was also relatively small. These results certainly warrant larger-scale and longer studies to evaluate olokizumab's efficacy.

For those patients with RA who achieve sustained disease remission, the question of medication tapering has been raised as a possible strategy for minimizing risks for therapy. Using insurance database information, Birkner and colleagues performed a prospective cohort study of over 400 patients in Germany. Using shared decision-making between patients and their rheumatologists, two groups of patients were followed: 237 people who elected to remain on therapy and 200 who decided to taper medication. Of note, similar proportions of patients in both groups were taking conventional and biologic disease-modifying antirheumatic drug (DMARD) monotherapy, but more patients in the tapering group were taking a combination therapy with both. Flares and loss of remission were more common in the continuation group, a difference that did not persist after adjusting for patient risk characteristics. Overall, results from this "real-world" study were consistent with prior studies and support the possibility of tapering with flare in a subset of patients. Although the authors address the potential for selection bias in terms of patients "assigned" to each group, this can also be viewed as part of the shared decision-making in determining the appropriateness of tapering therapy in individual patients.

Because people receiving rituximab have experienced more severe COVID-19, studies aimed at enhancing the protection of these patients are of current interest. Of note, in a follow-up to a prior observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab, they looked at responses to the third (booster) dose of the COVID-19 vaccine. Only about 20% of patients treated with rituximab developed a humoral response to a third vaccine dose, as defined by immunoglobulins (Ig; total, IgG, and IgM) against SARS-CoV-2. Patients treated with 200 mg rituximab had a higher response rate than did those treated with 500 mg or 1000 mg, though this difference was not statistically significant. The study lacked a control arm of people being treated with other DMARD and also did not measure B-cell counts, COVID-19, or outcomes. Reassuringly, those patients who did have a positive humoral response to the first two vaccine doses tended to maintain a humoral response to the third, regardless of rituximab dose or timing.

Interleukin (IL)–6 is known to be of great importance in the pathogenesis of rheumatoid arthritis (RA) owing to its role in the inflammatory response. Current IL-6-directed therapies in RA, namely sarilumab and tocilizumab, target the receptor. In a double-blind randomized controlled trial with both placebo and active comparators, Smolen and colleagues evaluated the efficacy of olokizumab, which directly binds and inhibits the activity of IL-6, in combination with methotrexate, in the treatment of people with RA. Patients were treated with methotrexate alone or in combination with adalimumab or olokizumab, and clinical outcomes were evaluated after 12 weeks, a relatively short time frame. Olokizumab was noninferior to adalimumab in terms of the proportion of patients achieving an American College of Rheumatology 20 response, with similar rates of serious adverse events, the most common of which was infection. Though this study included patients from across the globe, the percentage of Black and Asian patients was relatively low and thus may affect the generalizability of this study to a US population; the numbers of patients in each group was also relatively small. These results certainly warrant larger-scale and longer studies to evaluate olokizumab's efficacy.

For those patients with RA who achieve sustained disease remission, the question of medication tapering has been raised as a possible strategy for minimizing risks for therapy. Using insurance database information, Birkner and colleagues performed a prospective cohort study of over 400 patients in Germany. Using shared decision-making between patients and their rheumatologists, two groups of patients were followed: 237 people who elected to remain on therapy and 200 who decided to taper medication. Of note, similar proportions of patients in both groups were taking conventional and biologic disease-modifying antirheumatic drug (DMARD) monotherapy, but more patients in the tapering group were taking a combination therapy with both. Flares and loss of remission were more common in the continuation group, a difference that did not persist after adjusting for patient risk characteristics. Overall, results from this "real-world" study were consistent with prior studies and support the possibility of tapering with flare in a subset of patients. Although the authors address the potential for selection bias in terms of patients "assigned" to each group, this can also be viewed as part of the shared decision-making in determining the appropriateness of tapering therapy in individual patients.

Because people receiving rituximab have experienced more severe COVID-19, studies aimed at enhancing the protection of these patients are of current interest. Of note, in a follow-up to a prior observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab, they looked at responses to the third (booster) dose of the COVID-19 vaccine. Only about 20% of patients treated with rituximab developed a humoral response to a third vaccine dose, as defined by immunoglobulins (Ig; total, IgG, and IgM) against SARS-CoV-2. Patients treated with 200 mg rituximab had a higher response rate than did those treated with 500 mg or 1000 mg, though this difference was not statistically significant. The study lacked a control arm of people being treated with other DMARD and also did not measure B-cell counts, COVID-19, or outcomes. Reassuringly, those patients who did have a positive humoral response to the first two vaccine doses tended to maintain a humoral response to the third, regardless of rituximab dose or timing.

Interleukin (IL)–6 is known to be of great importance in the pathogenesis of rheumatoid arthritis (RA) owing to its role in the inflammatory response. Current IL-6-directed therapies in RA, namely sarilumab and tocilizumab, target the receptor. In a double-blind randomized controlled trial with both placebo and active comparators, Smolen and colleagues evaluated the efficacy of olokizumab, which directly binds and inhibits the activity of IL-6, in combination with methotrexate, in the treatment of people with RA. Patients were treated with methotrexate alone or in combination with adalimumab or olokizumab, and clinical outcomes were evaluated after 12 weeks, a relatively short time frame. Olokizumab was noninferior to adalimumab in terms of the proportion of patients achieving an American College of Rheumatology 20 response, with similar rates of serious adverse events, the most common of which was infection. Though this study included patients from across the globe, the percentage of Black and Asian patients was relatively low and thus may affect the generalizability of this study to a US population; the numbers of patients in each group was also relatively small. These results certainly warrant larger-scale and longer studies to evaluate olokizumab's efficacy.

For those patients with RA who achieve sustained disease remission, the question of medication tapering has been raised as a possible strategy for minimizing risks for therapy. Using insurance database information, Birkner and colleagues performed a prospective cohort study of over 400 patients in Germany. Using shared decision-making between patients and their rheumatologists, two groups of patients were followed: 237 people who elected to remain on therapy and 200 who decided to taper medication. Of note, similar proportions of patients in both groups were taking conventional and biologic disease-modifying antirheumatic drug (DMARD) monotherapy, but more patients in the tapering group were taking a combination therapy with both. Flares and loss of remission were more common in the continuation group, a difference that did not persist after adjusting for patient risk characteristics. Overall, results from this "real-world" study were consistent with prior studies and support the possibility of tapering with flare in a subset of patients. Although the authors address the potential for selection bias in terms of patients "assigned" to each group, this can also be viewed as part of the shared decision-making in determining the appropriateness of tapering therapy in individual patients.

Because people receiving rituximab have experienced more severe COVID-19, studies aimed at enhancing the protection of these patients are of current interest. Of note, in a follow-up to a prior observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab, they looked at responses to the third (booster) dose of the COVID-19 vaccine. Only about 20% of patients treated with rituximab developed a humoral response to a third vaccine dose, as defined by immunoglobulins (Ig; total, IgG, and IgM) against SARS-CoV-2. Patients treated with 200 mg rituximab had a higher response rate than did those treated with 500 mg or 1000 mg, though this difference was not statistically significant. The study lacked a control arm of people being treated with other DMARD and also did not measure B-cell counts, COVID-19, or outcomes. Reassuringly, those patients who did have a positive humoral response to the first two vaccine doses tended to maintain a humoral response to the third, regardless of rituximab dose or timing.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

Interstitial lung disease (ILD) is a serious and not infrequent complication of rheumatoid arthritis (RA). Despite the use of several immunosuppressive medications for ILD as well as others for RA, the most effective treatment for both is yet unclear. Prior cross-sectional, retrospective, and open-label registry studies have suggested that abatacept can be used in patients with RA-ILD, with stability or improvement in pulmonary parameters in a majority of patients. Mena-Vazquez and colleagues present the results of a prospective, observational cohort study with 57 patients from multiple centers in Spain. Similar to previously published results, this study found stability or improvement in pulmonary function tests in 70% of patients as well as improvement in RA disease activity. A relatively high proportion of patients (25 in 57) experienced infections. The study lends further weight to the proposal that abatacept is a reasonable choice in patients with RA-ILD for treatment of both joint and pulmonary inflammation, given the lack of randomized controlled trials.

Lauper and colleagues published the results of a large cohort study of more than 30,000 treatment courses in patients with RA, looking at the efficacy of different biologics and a Janus kinase (JAK) inhibitor. Discontinuation of therapy was used as the primary efficacy outcome, and one secondary outcome was low disease activity based on Clinical Disease Activity Index (CDAI) at 12 months. Over 17,000 courses were anti–tumor necrosis factor (TNF) therapy, with about 7000 JAK-inhibitor therapy courses and the remainder an interleukin 6 (IL-6) inhibitor or abatacept therapy; individual data was only available from 13 to 17 registries (depending on the parameter of interest). Overall, IL-6 inhibitors and JAK inhibitors were less frequently stopped for ineffectiveness compared with anti-TNF agents, but were more frequently stopped owing to adverse events. Drug retention rates also varied between different countries, suggesting that prescription pattern differences may affect the primary outcome. In terms of CDAI, response rates at 1 year were similar between anti-TNF agents, JAK inhibitors, and IL-6 inhibitors and was slightly lower for abatacept. This real-world study does support similar efficacy between these classes of medications, though further conclusions are somewhat hampered by the lack of individual data.

A study in Japan by Mori and colleagues looked at biologic disease-modifying antirheumatic drugs (bDMARD) (TNF inhibitors and an IL-6 inhibitor) and tofacitinib discontinuation in a cohort of 97 patients with RA . Patients were required to initially be in a high or moderate disease activity state prior to treatment, then in remission or a low disease activity state with treatment for more than 48 weeks. Mean follow-up was 2.1 years and disease flare occurred in about 75% of patients at about 1.6 years after medication discontinuation. Though bDMARD- or targeted synthetic DMARD (tsDMARD)–free remission was not "durable" for most patients, the majority of those patients who experienced flares improved with resumption of their previous medication. Though it is reassuring that most study patients were able to discontinue their bDMARD or tsDMARD medication for a period of time, the fact that most experienced flares within 2 years suggests that discontinuation of these medications in patients with high disease activity is not a viable long-term approach.

Krekeler and colleagues performed a retrospective analysis of about 500 patients seen in a single rheumatology clinic to evaluate possible misdiagnosis of RA. The diagnosis of calcium pyrophosphate deposition disease (CPPD), as well as the presence of radiographic chondrocalcinosis, were more frequently found among patients diagnosed with seronegative RA vs those diagnosed with seropositive RA, particularly RA in the wrists. The CPPD diagnosis was made by rheumatologists on the basis of the presence of radiographic chondrocalcinosis along with typical joint swelling and signs of inflammation. Because chondrocalcinosis was part of the CPPD diagnosis, it is unsurprising that both followed similar patterns. Whether patients with CPPD were actually misdiagnosed as having seronegative RA is unclear from this retrospective study; as the authors note, chondrocalcinosis itself has been found to be associated with older age and osteoarthritis in prior studies, particularly in the knee. However, the study confirms that alternative diagnoses in seronegative RA should be considered.

Interstitial lung disease (ILD) is a serious and not infrequent complication of rheumatoid arthritis (RA). Despite the use of several immunosuppressive medications for ILD as well as others for RA, the most effective treatment for both is yet unclear. Prior cross-sectional, retrospective, and open-label registry studies have suggested that abatacept can be used in patients with RA-ILD, with stability or improvement in pulmonary parameters in a majority of patients. Mena-Vazquez and colleagues present the results of a prospective, observational cohort study with 57 patients from multiple centers in Spain. Similar to previously published results, this study found stability or improvement in pulmonary function tests in 70% of patients as well as improvement in RA disease activity. A relatively high proportion of patients (25 in 57) experienced infections. The study lends further weight to the proposal that abatacept is a reasonable choice in patients with RA-ILD for treatment of both joint and pulmonary inflammation, given the lack of randomized controlled trials.

Lauper and colleagues published the results of a large cohort study of more than 30,000 treatment courses in patients with RA, looking at the efficacy of different biologics and a Janus kinase (JAK) inhibitor. Discontinuation of therapy was used as the primary efficacy outcome, and one secondary outcome was low disease activity based on Clinical Disease Activity Index (CDAI) at 12 months. Over 17,000 courses were anti–tumor necrosis factor (TNF) therapy, with about 7000 JAK-inhibitor therapy courses and the remainder an interleukin 6 (IL-6) inhibitor or abatacept therapy; individual data was only available from 13 to 17 registries (depending on the parameter of interest). Overall, IL-6 inhibitors and JAK inhibitors were less frequently stopped for ineffectiveness compared with anti-TNF agents, but were more frequently stopped owing to adverse events. Drug retention rates also varied between different countries, suggesting that prescription pattern differences may affect the primary outcome. In terms of CDAI, response rates at 1 year were similar between anti-TNF agents, JAK inhibitors, and IL-6 inhibitors and was slightly lower for abatacept. This real-world study does support similar efficacy between these classes of medications, though further conclusions are somewhat hampered by the lack of individual data.

A study in Japan by Mori and colleagues looked at biologic disease-modifying antirheumatic drugs (bDMARD) (TNF inhibitors and an IL-6 inhibitor) and tofacitinib discontinuation in a cohort of 97 patients with RA . Patients were required to initially be in a high or moderate disease activity state prior to treatment, then in remission or a low disease activity state with treatment for more than 48 weeks. Mean follow-up was 2.1 years and disease flare occurred in about 75% of patients at about 1.6 years after medication discontinuation. Though bDMARD- or targeted synthetic DMARD (tsDMARD)–free remission was not "durable" for most patients, the majority of those patients who experienced flares improved with resumption of their previous medication. Though it is reassuring that most study patients were able to discontinue their bDMARD or tsDMARD medication for a period of time, the fact that most experienced flares within 2 years suggests that discontinuation of these medications in patients with high disease activity is not a viable long-term approach.

Krekeler and colleagues performed a retrospective analysis of about 500 patients seen in a single rheumatology clinic to evaluate possible misdiagnosis of RA. The diagnosis of calcium pyrophosphate deposition disease (CPPD), as well as the presence of radiographic chondrocalcinosis, were more frequently found among patients diagnosed with seronegative RA vs those diagnosed with seropositive RA, particularly RA in the wrists. The CPPD diagnosis was made by rheumatologists on the basis of the presence of radiographic chondrocalcinosis along with typical joint swelling and signs of inflammation. Because chondrocalcinosis was part of the CPPD diagnosis, it is unsurprising that both followed similar patterns. Whether patients with CPPD were actually misdiagnosed as having seronegative RA is unclear from this retrospective study; as the authors note, chondrocalcinosis itself has been found to be associated with older age and osteoarthritis in prior studies, particularly in the knee. However, the study confirms that alternative diagnoses in seronegative RA should be considered.

Interstitial lung disease (ILD) is a serious and not infrequent complication of rheumatoid arthritis (RA). Despite the use of several immunosuppressive medications for ILD as well as others for RA, the most effective treatment for both is yet unclear. Prior cross-sectional, retrospective, and open-label registry studies have suggested that abatacept can be used in patients with RA-ILD, with stability or improvement in pulmonary parameters in a majority of patients. Mena-Vazquez and colleagues present the results of a prospective, observational cohort study with 57 patients from multiple centers in Spain. Similar to previously published results, this study found stability or improvement in pulmonary function tests in 70% of patients as well as improvement in RA disease activity. A relatively high proportion of patients (25 in 57) experienced infections. The study lends further weight to the proposal that abatacept is a reasonable choice in patients with RA-ILD for treatment of both joint and pulmonary inflammation, given the lack of randomized controlled trials.

Lauper and colleagues published the results of a large cohort study of more than 30,000 treatment courses in patients with RA, looking at the efficacy of different biologics and a Janus kinase (JAK) inhibitor. Discontinuation of therapy was used as the primary efficacy outcome, and one secondary outcome was low disease activity based on Clinical Disease Activity Index (CDAI) at 12 months. Over 17,000 courses were anti–tumor necrosis factor (TNF) therapy, with about 7000 JAK-inhibitor therapy courses and the remainder an interleukin 6 (IL-6) inhibitor or abatacept therapy; individual data was only available from 13 to 17 registries (depending on the parameter of interest). Overall, IL-6 inhibitors and JAK inhibitors were less frequently stopped for ineffectiveness compared with anti-TNF agents, but were more frequently stopped owing to adverse events. Drug retention rates also varied between different countries, suggesting that prescription pattern differences may affect the primary outcome. In terms of CDAI, response rates at 1 year were similar between anti-TNF agents, JAK inhibitors, and IL-6 inhibitors and was slightly lower for abatacept. This real-world study does support similar efficacy between these classes of medications, though further conclusions are somewhat hampered by the lack of individual data.

A study in Japan by Mori and colleagues looked at biologic disease-modifying antirheumatic drugs (bDMARD) (TNF inhibitors and an IL-6 inhibitor) and tofacitinib discontinuation in a cohort of 97 patients with RA . Patients were required to initially be in a high or moderate disease activity state prior to treatment, then in remission or a low disease activity state with treatment for more than 48 weeks. Mean follow-up was 2.1 years and disease flare occurred in about 75% of patients at about 1.6 years after medication discontinuation. Though bDMARD- or targeted synthetic DMARD (tsDMARD)–free remission was not "durable" for most patients, the majority of those patients who experienced flares improved with resumption of their previous medication. Though it is reassuring that most study patients were able to discontinue their bDMARD or tsDMARD medication for a period of time, the fact that most experienced flares within 2 years suggests that discontinuation of these medications in patients with high disease activity is not a viable long-term approach.

Krekeler and colleagues performed a retrospective analysis of about 500 patients seen in a single rheumatology clinic to evaluate possible misdiagnosis of RA. The diagnosis of calcium pyrophosphate deposition disease (CPPD), as well as the presence of radiographic chondrocalcinosis, were more frequently found among patients diagnosed with seronegative RA vs those diagnosed with seropositive RA, particularly RA in the wrists. The CPPD diagnosis was made by rheumatologists on the basis of the presence of radiographic chondrocalcinosis along with typical joint swelling and signs of inflammation. Because chondrocalcinosis was part of the CPPD diagnosis, it is unsurprising that both followed similar patterns. Whether patients with CPPD were actually misdiagnosed as having seronegative RA is unclear from this retrospective study; as the authors note, chondrocalcinosis itself has been found to be associated with older age and osteoarthritis in prior studies, particularly in the knee. However, the study confirms that alternative diagnoses in seronegative RA should be considered.

In keeping with other studies suggesting that lower-than-standard doses of rituximab (for example, two 500 mg doses every 6 months) are effective in the treatment of rheumatoid arthritis (RA), Bertsias and colleagues evaluated the efficacy of low-dose rituximab (1 g every 6 months) in a cohort of patients with RA. Of 361 patients in the initial registry, 81 achieved sustained low disease activity or remission on standard rituximab regimens and were transitioned to the low-dose regimen; their outcomes were compared with the 280 patients in the registry who received a standard-dose regimen. Only 7.5% experienced flares of RA (compared with 5.9% in the standard-dose group), and patients in the low-dose group had fewer serious adverse events, infections, and hospitalizations. Tapering biologic disease-modifying antirheumatic drugs (DMARD) may thus be a reasonable strategy for some patients with RA, with an eye to their prior results with the medication.

The prospect of achieving sustained DMARD-free remission (SDFR) in people with RA has seemed increasingly feasible in recent studies, although it seems to be affected by anti-citrullinated protein/peptide antibody (ACPA) positivity. That is, people who are ACPA-negative are more likely to reach this target. Verstappen and colleagues examined MRI patterns of joint inflammation in the Leiden Early Arthritis Clinic cohort, as well as another cohort of patients with RA, but only included patients with an RA duration > 1 year to reduce the likelihood of misclassification. Interestingly, ACPA-positive patients who achieved SDFR tended to have lower baseline evidence of joint inflammation (including erosions, synovitis, and osteitis), which was persistent throughout follow-up, whereas ACPA-negative patients who achieved SDFR had similar joint inflammation at baseline to those who did not, but had a better initial response to DMARD therapy. Further study of the potential impact of treatment based on ACPA status would be helpful.

Recent results from the ORAL Surveillance postmarketing safety analysis suggest that tofacitinib is associated with an increased risk for cancer in patients with RA patients who are aged >50 years, compared with anti–tumor necrosis factor (TNF) agents. Khosrow-Khavar and colleagues used insurance claims data to further investigate the risk for cancer with tofacitinib vs anti-TNF agents. They created two cohorts of patients who were new users of anti-TNF agents or tofacitinib: One was a "real-world" cohort including all patients with RA, whereas the other applied the inclusion and exclusion criteria from the ORAL Surveillance trial, including age >50 years, one cardiovascular risk factor, and use of methotrexate. Results from the real-world cohort, including over 10,000 patients who had used tofacitinib, did not show any increase in cancer risk, whereas the trial-simulating conditions did yield higher numbers of cancers in the group exposed to tofacitinib. Though reassuring, these results are limited by the short follow-up duration, and longer-term follow-up studies are necessary for further evaluation.

In another interesting note with respect to medication morbidity and risk, Xu and colleagues performed a meta-analysis looking at the association of methotrexate use and mortality in patients with RA. Only 15 studies were included in the final analysis, though they did encompass a large total number of patients. Overall, methotrexate use in these studies was associated with lower rates of overall mortality as well as mortality due to cardiovascular and interstitial lung disease. However, conclusions as to the direct impact of methotrexate were limited by the heterogeneity of study designs, doses of methotrexate, and additional therapy as well as comparators.

In keeping with other studies suggesting that lower-than-standard doses of rituximab (for example, two 500 mg doses every 6 months) are effective in the treatment of rheumatoid arthritis (RA), Bertsias and colleagues evaluated the efficacy of low-dose rituximab (1 g every 6 months) in a cohort of patients with RA. Of 361 patients in the initial registry, 81 achieved sustained low disease activity or remission on standard rituximab regimens and were transitioned to the low-dose regimen; their outcomes were compared with the 280 patients in the registry who received a standard-dose regimen. Only 7.5% experienced flares of RA (compared with 5.9% in the standard-dose group), and patients in the low-dose group had fewer serious adverse events, infections, and hospitalizations. Tapering biologic disease-modifying antirheumatic drugs (DMARD) may thus be a reasonable strategy for some patients with RA, with an eye to their prior results with the medication.

The prospect of achieving sustained DMARD-free remission (SDFR) in people with RA has seemed increasingly feasible in recent studies, although it seems to be affected by anti-citrullinated protein/peptide antibody (ACPA) positivity. That is, people who are ACPA-negative are more likely to reach this target. Verstappen and colleagues examined MRI patterns of joint inflammation in the Leiden Early Arthritis Clinic cohort, as well as another cohort of patients with RA, but only included patients with an RA duration > 1 year to reduce the likelihood of misclassification. Interestingly, ACPA-positive patients who achieved SDFR tended to have lower baseline evidence of joint inflammation (including erosions, synovitis, and osteitis), which was persistent throughout follow-up, whereas ACPA-negative patients who achieved SDFR had similar joint inflammation at baseline to those who did not, but had a better initial response to DMARD therapy. Further study of the potential impact of treatment based on ACPA status would be helpful.

Recent results from the ORAL Surveillance postmarketing safety analysis suggest that tofacitinib is associated with an increased risk for cancer in patients with RA patients who are aged >50 years, compared with anti–tumor necrosis factor (TNF) agents. Khosrow-Khavar and colleagues used insurance claims data to further investigate the risk for cancer with tofacitinib vs anti-TNF agents. They created two cohorts of patients who were new users of anti-TNF agents or tofacitinib: One was a "real-world" cohort including all patients with RA, whereas the other applied the inclusion and exclusion criteria from the ORAL Surveillance trial, including age >50 years, one cardiovascular risk factor, and use of methotrexate. Results from the real-world cohort, including over 10,000 patients who had used tofacitinib, did not show any increase in cancer risk, whereas the trial-simulating conditions did yield higher numbers of cancers in the group exposed to tofacitinib. Though reassuring, these results are limited by the short follow-up duration, and longer-term follow-up studies are necessary for further evaluation.

In another interesting note with respect to medication morbidity and risk, Xu and colleagues performed a meta-analysis looking at the association of methotrexate use and mortality in patients with RA. Only 15 studies were included in the final analysis, though they did encompass a large total number of patients. Overall, methotrexate use in these studies was associated with lower rates of overall mortality as well as mortality due to cardiovascular and interstitial lung disease. However, conclusions as to the direct impact of methotrexate were limited by the heterogeneity of study designs, doses of methotrexate, and additional therapy as well as comparators.

In keeping with other studies suggesting that lower-than-standard doses of rituximab (for example, two 500 mg doses every 6 months) are effective in the treatment of rheumatoid arthritis (RA), Bertsias and colleagues evaluated the efficacy of low-dose rituximab (1 g every 6 months) in a cohort of patients with RA. Of 361 patients in the initial registry, 81 achieved sustained low disease activity or remission on standard rituximab regimens and were transitioned to the low-dose regimen; their outcomes were compared with the 280 patients in the registry who received a standard-dose regimen. Only 7.5% experienced flares of RA (compared with 5.9% in the standard-dose group), and patients in the low-dose group had fewer serious adverse events, infections, and hospitalizations. Tapering biologic disease-modifying antirheumatic drugs (DMARD) may thus be a reasonable strategy for some patients with RA, with an eye to their prior results with the medication.

The prospect of achieving sustained DMARD-free remission (SDFR) in people with RA has seemed increasingly feasible in recent studies, although it seems to be affected by anti-citrullinated protein/peptide antibody (ACPA) positivity. That is, people who are ACPA-negative are more likely to reach this target. Verstappen and colleagues examined MRI patterns of joint inflammation in the Leiden Early Arthritis Clinic cohort, as well as another cohort of patients with RA, but only included patients with an RA duration > 1 year to reduce the likelihood of misclassification. Interestingly, ACPA-positive patients who achieved SDFR tended to have lower baseline evidence of joint inflammation (including erosions, synovitis, and osteitis), which was persistent throughout follow-up, whereas ACPA-negative patients who achieved SDFR had similar joint inflammation at baseline to those who did not, but had a better initial response to DMARD therapy. Further study of the potential impact of treatment based on ACPA status would be helpful.

Recent results from the ORAL Surveillance postmarketing safety analysis suggest that tofacitinib is associated with an increased risk for cancer in patients with RA patients who are aged >50 years, compared with anti–tumor necrosis factor (TNF) agents. Khosrow-Khavar and colleagues used insurance claims data to further investigate the risk for cancer with tofacitinib vs anti-TNF agents. They created two cohorts of patients who were new users of anti-TNF agents or tofacitinib: One was a "real-world" cohort including all patients with RA, whereas the other applied the inclusion and exclusion criteria from the ORAL Surveillance trial, including age >50 years, one cardiovascular risk factor, and use of methotrexate. Results from the real-world cohort, including over 10,000 patients who had used tofacitinib, did not show any increase in cancer risk, whereas the trial-simulating conditions did yield higher numbers of cancers in the group exposed to tofacitinib. Though reassuring, these results are limited by the short follow-up duration, and longer-term follow-up studies are necessary for further evaluation.

In another interesting note with respect to medication morbidity and risk, Xu and colleagues performed a meta-analysis looking at the association of methotrexate use and mortality in patients with RA. Only 15 studies were included in the final analysis, though they did encompass a large total number of patients. Overall, methotrexate use in these studies was associated with lower rates of overall mortality as well as mortality due to cardiovascular and interstitial lung disease. However, conclusions as to the direct impact of methotrexate were limited by the heterogeneity of study designs, doses of methotrexate, and additional therapy as well as comparators.

Predicting severe disease is of great importance in rheumatoid arthritis (RA), ideally to establish which poor prognostic factors allow for early aggressive and targeted treatment for a subset of patients. In a post hoc analysis of the AGREE study by Durez and colleagues, 509 treatment-naive patients randomized to either methotrexate or methotrexate with abatacept were evaluated for predictors of joint damage and disease activity. Baseline swelling in the knee, temporomandibular joint (TMJ), elbow, and wrist was correlated with severe disease activity as well as tender and swollen joint counts, whereas baseline swelling at the second metacarpophalangeal joint was correlated with erosive disease. Overall, remission rates were better in patients with baseline wrist, TMJ, elbow, and knee swelling treated with combination therapy vs methotrexate alone, suggestive of a better response to more aggressive therapy. Further studies of patients with RA with poor prognostic factors would be helpful.

Laboratory biomarkers can also serve as prognostic indicators for patients with RA. Based in part on the association of obesity and lower rates of remission in people with RA, Baker and colleagues investigated the possible association of adipocytokines and disease activity in a cohort study of over 1200 patients with Disease Activity Score for Rheumatoid Arthritis (DAS28) > 3.2 enrolled in the Veterans Affairs RA registry. Of these, about 800 achieved low disease activity while the remainder did not. Interestingly, obesity was not a baseline characteristic associated with disease activity, though chronic obstructive pulmonary disease, heart failure, and mood disorders were. Baseline adipocytokine levels on average did not differ between the two groups, though higher baseline adiponectin and leptin levels (based on quartile) were associated with a lower likelihood of achieving low disease activity. Interestingly, this change did not increase progressively with higher quartile. Because these are baseline levels and were not tracked prospectively with medication use, it is difficult to assess the importance of this finding. The association may not reflect a causative relationship but may be affected by medications or disease duration. However, it appears worthwhile investigating in therapy-naive patients as well as those being observed with treatment.

Finally, with respect to novel therapeutic regimens, Fleischmann and colleagues report the results of a multicenter randomized clinical trial of a Bruton tyrosine kinase inhibitor, elsubrutinib, alone or in combination with the Janus kinase (JAK) inhibitor upadicitinib in the treatment of 242 patients with RA. At the end of 12 weeks, DAS28 with C-reactive protein scores were not measurably lower in patients treated with elsubrutinib at different doses. In addition, patients receiving the combination therapy of 15 mg upadicitinib with the highest dose of elsubrutinib (60 mg) did not have greater DAS28 improvement than patients treated with upadicitinib alone, suggesting a lack of synergistic effect. Short-term safety data does not suggest significant differences. Though this combination is also being investigated in systemic lupus erythematosus, it is not clear that the combination of two targeted synthetic disease-modifying antirheumatic drugs is feasible in RA, nor that long-term safety concerns would make it advisable.

Predicting severe disease is of great importance in rheumatoid arthritis (RA), ideally to establish which poor prognostic factors allow for early aggressive and targeted treatment for a subset of patients. In a post hoc analysis of the AGREE study by Durez and colleagues, 509 treatment-naive patients randomized to either methotrexate or methotrexate with abatacept were evaluated for predictors of joint damage and disease activity. Baseline swelling in the knee, temporomandibular joint (TMJ), elbow, and wrist was correlated with severe disease activity as well as tender and swollen joint counts, whereas baseline swelling at the second metacarpophalangeal joint was correlated with erosive disease. Overall, remission rates were better in patients with baseline wrist, TMJ, elbow, and knee swelling treated with combination therapy vs methotrexate alone, suggestive of a better response to more aggressive therapy. Further studies of patients with RA with poor prognostic factors would be helpful.

Laboratory biomarkers can also serve as prognostic indicators for patients with RA. Based in part on the association of obesity and lower rates of remission in people with RA, Baker and colleagues investigated the possible association of adipocytokines and disease activity in a cohort study of over 1200 patients with Disease Activity Score for Rheumatoid Arthritis (DAS28) > 3.2 enrolled in the Veterans Affairs RA registry. Of these, about 800 achieved low disease activity while the remainder did not. Interestingly, obesity was not a baseline characteristic associated with disease activity, though chronic obstructive pulmonary disease, heart failure, and mood disorders were. Baseline adipocytokine levels on average did not differ between the two groups, though higher baseline adiponectin and leptin levels (based on quartile) were associated with a lower likelihood of achieving low disease activity. Interestingly, this change did not increase progressively with higher quartile. Because these are baseline levels and were not tracked prospectively with medication use, it is difficult to assess the importance of this finding. The association may not reflect a causative relationship but may be affected by medications or disease duration. However, it appears worthwhile investigating in therapy-naive patients as well as those being observed with treatment.

Finally, with respect to novel therapeutic regimens, Fleischmann and colleagues report the results of a multicenter randomized clinical trial of a Bruton tyrosine kinase inhibitor, elsubrutinib, alone or in combination with the Janus kinase (JAK) inhibitor upadicitinib in the treatment of 242 patients with RA. At the end of 12 weeks, DAS28 with C-reactive protein scores were not measurably lower in patients treated with elsubrutinib at different doses. In addition, patients receiving the combination therapy of 15 mg upadicitinib with the highest dose of elsubrutinib (60 mg) did not have greater DAS28 improvement than patients treated with upadicitinib alone, suggesting a lack of synergistic effect. Short-term safety data does not suggest significant differences. Though this combination is also being investigated in systemic lupus erythematosus, it is not clear that the combination of two targeted synthetic disease-modifying antirheumatic drugs is feasible in RA, nor that long-term safety concerns would make it advisable.

Predicting severe disease is of great importance in rheumatoid arthritis (RA), ideally to establish which poor prognostic factors allow for early aggressive and targeted treatment for a subset of patients. In a post hoc analysis of the AGREE study by Durez and colleagues, 509 treatment-naive patients randomized to either methotrexate or methotrexate with abatacept were evaluated for predictors of joint damage and disease activity. Baseline swelling in the knee, temporomandibular joint (TMJ), elbow, and wrist was correlated with severe disease activity as well as tender and swollen joint counts, whereas baseline swelling at the second metacarpophalangeal joint was correlated with erosive disease. Overall, remission rates were better in patients with baseline wrist, TMJ, elbow, and knee swelling treated with combination therapy vs methotrexate alone, suggestive of a better response to more aggressive therapy. Further studies of patients with RA with poor prognostic factors would be helpful.

Laboratory biomarkers can also serve as prognostic indicators for patients with RA. Based in part on the association of obesity and lower rates of remission in people with RA, Baker and colleagues investigated the possible association of adipocytokines and disease activity in a cohort study of over 1200 patients with Disease Activity Score for Rheumatoid Arthritis (DAS28) > 3.2 enrolled in the Veterans Affairs RA registry. Of these, about 800 achieved low disease activity while the remainder did not. Interestingly, obesity was not a baseline characteristic associated with disease activity, though chronic obstructive pulmonary disease, heart failure, and mood disorders were. Baseline adipocytokine levels on average did not differ between the two groups, though higher baseline adiponectin and leptin levels (based on quartile) were associated with a lower likelihood of achieving low disease activity. Interestingly, this change did not increase progressively with higher quartile. Because these are baseline levels and were not tracked prospectively with medication use, it is difficult to assess the importance of this finding. The association may not reflect a causative relationship but may be affected by medications or disease duration. However, it appears worthwhile investigating in therapy-naive patients as well as those being observed with treatment.

Finally, with respect to novel therapeutic regimens, Fleischmann and colleagues report the results of a multicenter randomized clinical trial of a Bruton tyrosine kinase inhibitor, elsubrutinib, alone or in combination with the Janus kinase (JAK) inhibitor upadicitinib in the treatment of 242 patients with RA. At the end of 12 weeks, DAS28 with C-reactive protein scores were not measurably lower in patients treated with elsubrutinib at different doses. In addition, patients receiving the combination therapy of 15 mg upadicitinib with the highest dose of elsubrutinib (60 mg) did not have greater DAS28 improvement than patients treated with upadicitinib alone, suggesting a lack of synergistic effect. Short-term safety data does not suggest significant differences. Though this combination is also being investigated in systemic lupus erythematosus, it is not clear that the combination of two targeted synthetic disease-modifying antirheumatic drugs is feasible in RA, nor that long-term safety concerns would make it advisable.

Despite the improved outcomes in rheumatoid arthritis (RA) observed in clinical trials from early use of biologic disease-modifying antirheumatic drugs (bDMARD) in a treat-to-target strategy, real-world use may be limited by stopping medications for various reasons. Burkard and colleagues used the Swiss RA registry to examine potential reasons for discontinuation of bDMARD and targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) among over 2500 adults with RA who stopped these medications from 1999 through 2018. In this cohort study, patients were followed from date of discontinuation of their medication until restarting a bDMARD or tsDMARD. The most common reasons for discontinuation were nonresponse and adverse events; of these patients, over 80% restarted a bDMARD or tsDMARD. Only 8% of patients stopped due to remission; of these, nearly half restarted. The authors found a higher proportion of fibromyalgia among patients who stopped due to nonresponse and adverse events vs due to remission. Oddly, though 40%-50% of patients stopped for "unknown reasons" between 2002 and 2006, this proportion dropped to close to 0 after 2010; during the first time period, the proportions stopping medication due to adverse events and nonresponse were also low, suggesting possible misattribution of the reason for treatment cessation. As such, drawing further conclusions on association of different patient characteristics with reasons for treatment cessation is difficult.

The gap between control of inflammatory joint pain in RA and overall patient outcomes has come up frequently in recent studies. Gwinnutt and colleagues looked at patients participating in three European RA registries, comprising over 2500 patients followed over 8-10 years, and classified them as having high or low inflammation on the basis of Disease Activity Score (DAS28) and analyzed Health Assessment Questionnaire (HAQ) score trajectories as low vs high as a measure of disability. Overall, patients in the three registries had different trajectory patterns, though it appears clear, in keeping with other studies, that a subset of patients remain with high HAQ scores despite decreases in DAS28 scores. Older age; being a woman; and more pain, fatigue, and depressive symptoms were associated with higher HAQ trajectory in both the high and low inflammation pairs, suggesting that this phenomenon is not quite "excess disability" solely in patients with low inflammation.

An additional factor that increases morbidity as well as mortality in RA is frailty, which is associated with age as well as with RA (including people < 65 years old). Hanlon and colleagues examined the change in the "frailty phenotype" over time and its association with adverse clinical outcomes in people with early RA in the Scottish Early Rheumatoid Arthritis (SERA) and UK Biobank cohorts. Frailty was defined by different measures in the two cohorts, including elements of the HAQ disability index for SERA and self-reported fatigue, depression, and poor health for UK Biobank. The computed frailty index was higher in people with higher DAS28 scores and increased with age. Of note, frailty index values were higher prior to treatment initiation and improved somewhat with lower disease activity over time, though those with higher baseline frailty index values tended to have poorer physical function and disease activity over time. Understanding frailty in RA may allow us to better predict and prevent functional limitation, disease progression, and mortality in people with RA.

Of current interest is an observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab. Of patients who had previously been treated with 200, 500, or 1000 mg of rituximab prior to COVID-19 vaccination, those who received 200 mg  rituximab as well as those who had longer intervals between rituximab dose and vaccination had a better response to vaccination as defined by immunoglobulins (total, IgG, and IgM) against SARS-CoV-2. Although this study lacked a control arm of people being treated with other disease-modifying antirheumatic drugs and did not evaluate COVID-19 infections or outcomes, its findings do suggest that dosage and timing of rituximab in people with RA should be studied further in regard to vaccine response and infection risk.

Despite the improved outcomes in rheumatoid arthritis (RA) observed in clinical trials from early use of biologic disease-modifying antirheumatic drugs (bDMARD) in a treat-to-target strategy, real-world use may be limited by stopping medications for various reasons. Burkard and colleagues used the Swiss RA registry to examine potential reasons for discontinuation of bDMARD and targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) among over 2500 adults with RA who stopped these medications from 1999 through 2018. In this cohort study, patients were followed from date of discontinuation of their medication until restarting a bDMARD or tsDMARD. The most common reasons for discontinuation were nonresponse and adverse events; of these patients, over 80% restarted a bDMARD or tsDMARD. Only 8% of patients stopped due to remission; of these, nearly half restarted. The authors found a higher proportion of fibromyalgia among patients who stopped due to nonresponse and adverse events vs due to remission. Oddly, though 40%-50% of patients stopped for "unknown reasons" between 2002 and 2006, this proportion dropped to close to 0 after 2010; during the first time period, the proportions stopping medication due to adverse events and nonresponse were also low, suggesting possible misattribution of the reason for treatment cessation. As such, drawing further conclusions on association of different patient characteristics with reasons for treatment cessation is difficult.

The gap between control of inflammatory joint pain in RA and overall patient outcomes has come up frequently in recent studies. Gwinnutt and colleagues looked at patients participating in three European RA registries, comprising over 2500 patients followed over 8-10 years, and classified them as having high or low inflammation on the basis of Disease Activity Score (DAS28) and analyzed Health Assessment Questionnaire (HAQ) score trajectories as low vs high as a measure of disability. Overall, patients in the three registries had different trajectory patterns, though it appears clear, in keeping with other studies, that a subset of patients remain with high HAQ scores despite decreases in DAS28 scores. Older age; being a woman; and more pain, fatigue, and depressive symptoms were associated with higher HAQ trajectory in both the high and low inflammation pairs, suggesting that this phenomenon is not quite "excess disability" solely in patients with low inflammation.

An additional factor that increases morbidity as well as mortality in RA is frailty, which is associated with age as well as with RA (including people < 65 years old). Hanlon and colleagues examined the change in the "frailty phenotype" over time and its association with adverse clinical outcomes in people with early RA in the Scottish Early Rheumatoid Arthritis (SERA) and UK Biobank cohorts. Frailty was defined by different measures in the two cohorts, including elements of the HAQ disability index for SERA and self-reported fatigue, depression, and poor health for UK Biobank. The computed frailty index was higher in people with higher DAS28 scores and increased with age. Of note, frailty index values were higher prior to treatment initiation and improved somewhat with lower disease activity over time, though those with higher baseline frailty index values tended to have poorer physical function and disease activity over time. Understanding frailty in RA may allow us to better predict and prevent functional limitation, disease progression, and mortality in people with RA.

Of current interest is an observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab. Of patients who had previously been treated with 200, 500, or 1000 mg of rituximab prior to COVID-19 vaccination, those who received 200 mg  rituximab as well as those who had longer intervals between rituximab dose and vaccination had a better response to vaccination as defined by immunoglobulins (total, IgG, and IgM) against SARS-CoV-2. Although this study lacked a control arm of people being treated with other disease-modifying antirheumatic drugs and did not evaluate COVID-19 infections or outcomes, its findings do suggest that dosage and timing of rituximab in people with RA should be studied further in regard to vaccine response and infection risk.

Despite the improved outcomes in rheumatoid arthritis (RA) observed in clinical trials from early use of biologic disease-modifying antirheumatic drugs (bDMARD) in a treat-to-target strategy, real-world use may be limited by stopping medications for various reasons. Burkard and colleagues used the Swiss RA registry to examine potential reasons for discontinuation of bDMARD and targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) among over 2500 adults with RA who stopped these medications from 1999 through 2018. In this cohort study, patients were followed from date of discontinuation of their medication until restarting a bDMARD or tsDMARD. The most common reasons for discontinuation were nonresponse and adverse events; of these patients, over 80% restarted a bDMARD or tsDMARD. Only 8% of patients stopped due to remission; of these, nearly half restarted. The authors found a higher proportion of fibromyalgia among patients who stopped due to nonresponse and adverse events vs due to remission. Oddly, though 40%-50% of patients stopped for "unknown reasons" between 2002 and 2006, this proportion dropped to close to 0 after 2010; during the first time period, the proportions stopping medication due to adverse events and nonresponse were also low, suggesting possible misattribution of the reason for treatment cessation. As such, drawing further conclusions on association of different patient characteristics with reasons for treatment cessation is difficult.

The gap between control of inflammatory joint pain in RA and overall patient outcomes has come up frequently in recent studies. Gwinnutt and colleagues looked at patients participating in three European RA registries, comprising over 2500 patients followed over 8-10 years, and classified them as having high or low inflammation on the basis of Disease Activity Score (DAS28) and analyzed Health Assessment Questionnaire (HAQ) score trajectories as low vs high as a measure of disability. Overall, patients in the three registries had different trajectory patterns, though it appears clear, in keeping with other studies, that a subset of patients remain with high HAQ scores despite decreases in DAS28 scores. Older age; being a woman; and more pain, fatigue, and depressive symptoms were associated with higher HAQ trajectory in both the high and low inflammation pairs, suggesting that this phenomenon is not quite "excess disability" solely in patients with low inflammation.

An additional factor that increases morbidity as well as mortality in RA is frailty, which is associated with age as well as with RA (including people < 65 years old). Hanlon and colleagues examined the change in the "frailty phenotype" over time and its association with adverse clinical outcomes in people with early RA in the Scottish Early Rheumatoid Arthritis (SERA) and UK Biobank cohorts. Frailty was defined by different measures in the two cohorts, including elements of the HAQ disability index for SERA and self-reported fatigue, depression, and poor health for UK Biobank. The computed frailty index was higher in people with higher DAS28 scores and increased with age. Of note, frailty index values were higher prior to treatment initiation and improved somewhat with lower disease activity over time, though those with higher baseline frailty index values tended to have poorer physical function and disease activity over time. Understanding frailty in RA may allow us to better predict and prevent functional limitation, disease progression, and mortality in people with RA.

Of current interest is an observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab. Of patients who had previously been treated with 200, 500, or 1000 mg of rituximab prior to COVID-19 vaccination, those who received 200 mg  rituximab as well as those who had longer intervals between rituximab dose and vaccination had a better response to vaccination as defined by immunoglobulins (total, IgG, and IgM) against SARS-CoV-2. Although this study lacked a control arm of people being treated with other disease-modifying antirheumatic drugs and did not evaluate COVID-19 infections or outcomes, its findings do suggest that dosage and timing of rituximab in people with RA should be studied further in regard to vaccine response and infection risk.