Arundathi Jayatilleke, MD

Vaccination strategies for people with rheumatic diseases have received significant scrutiny in regard to COVID-19 vaccines. People with rheumatoid arthritis (RA) are at higher risk for adverse outcomes related to COVID-19 but also may have reduced immunogenicity to COVID-19 vaccines; thus, temporary withdrawal of medications has been suggested. Renner Araujo and colleagues report the results of a single-center randomized study from Brazil looking at the immune response to two doses of the Sinovac-CoronaVac vaccine in 129 patients with RA. They found that those who stopped methotrexate for 2 weeks after both doses had a higher rate of seroconversion, based on immunoglobulin (Ig) G positivity (78% vs. 54%), than those who remained on methotrexate. Antibody titers were also higher in the "methotrexate-hold" group. Flare rates were higher, based on the Clinical Disease Activity Index (CDAI) — though not on the Disease Activity Scale-28 (DAS-28) — in patients who withdrew from methotrexate. This information is interesting with respect to the use of future inactivated virus vaccines, though its applicability to mRNA vaccines, other than predicting the possibility of flare, is less clear. However, the results could be useful in informed discussions and decision-making regarding withdrawing immunosuppressive drugs.

Some people with rheumatic diseases have been concerned about flares of disease activity related to COVID-19 vaccination. Tedeschi and colleagues conducted a prospective observational study of 71 patients with RA who were previously inoculated against COVID-19 with two mRNA vaccine doses or one adenovirus vector vaccine dose. Using the patient-reported Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), they measured disease activity weekly from study enrollment through 4 weeks after an additional dose. They did not find any change in mean RADAI-5 score between pre- and post additional dose, nor was disease activity different in patients who stopped disease-modifying antirheumatic drugs (DMARD) compared with those who did not. The study also examined flow cytometry of lymphocyte populations among a subset of these patients (n = 27) and found no significant differences in T peripheral helper cells, T follicular helper cells, age-associated B cells, and plasmablasts among patients before and after the additional vaccine dose. Though the flow cytometry data are difficult to generalize, given the presumed heterogeneity and small number of patients, the lack of change in RA disease activity after the additional vaccine dose is reassuring.

Achievement of remission in patients with RA is also an area of continued interest, especially because of the difficulty of reaching this target under real-world conditions. Larid and colleagues report the prognostic factors of remission and characteristics of 215 patients with RA over 7 years of follow-up at an academic hospital in France. Notably, 33% of patients were in remission at 1 year, of whom 76% remained in remission at 7 years. However, 48% of patients who were not in remission at 1 year achieved remission at 7 years; 58% of study participants were in remission in total at 7 years of follow-up. Those in remission were more frequently being prescribed both conventional synthetic DMARD (csDMARD) and biologic DMARD (bDMARD), while those not in remission at 7 years were receiving corticosteroids at higher doses. Owing to the lack of more precise treatment information, as well as the large number of patients who did not complete the 7-year follow-up visit, drawing conclusions is difficult. While we cannot say, based on these results, that use of certain medication regimens or strategies is more likely to lead to remission, the data at least lend support to the possibility of achieving remission in the long term.

Finally, Ahmad and colleagues performed a post-hoc analysis of the phase 3b AVERT trial of abatacept vs. methotrexate; 172 patients in remission were evaluated at 6 and 12 months after withdrawal of abatacept + methotrexate, abatacept monotherapy, or methotrexate monotherapy. Similar proportions of patients in all three treatment groups experienced a flare (about 58% at 6 months and 66% at 12 months). Patients with higher Health Assessment Questionnaire Disability Index (HAQ-DI) scores and evidence of erosions on MRI at withdrawal were more likely to experience a flare, consistent with prior studies. This highlights potential predictors of withdrawal from therapy. Given the lack of significant difference between the treatment groups, however, it does raise the question of why combination therapy with abatacept and methotrexate is more likely to lead to patients achieving remission in studies without as big an effect on drug-free remission after withdrawal. A more stringent definition of remission rather than DAS-28 C-reactive protein may be desirable.

Vaccination strategies for people with rheumatic diseases have received significant scrutiny in regard to COVID-19 vaccines. People with rheumatoid arthritis (RA) are at higher risk for adverse outcomes related to COVID-19 but also may have reduced immunogenicity to COVID-19 vaccines; thus, temporary withdrawal of medications has been suggested. Renner Araujo and colleagues report the results of a single-center randomized study from Brazil looking at the immune response to two doses of the Sinovac-CoronaVac vaccine in 129 patients with RA. They found that those who stopped methotrexate for 2 weeks after both doses had a higher rate of seroconversion, based on immunoglobulin (Ig) G positivity (78% vs. 54%), than those who remained on methotrexate. Antibody titers were also higher in the "methotrexate-hold" group. Flare rates were higher, based on the Clinical Disease Activity Index (CDAI) — though not on the Disease Activity Scale-28 (DAS-28) — in patients who withdrew from methotrexate. This information is interesting with respect to the use of future inactivated virus vaccines, though its applicability to mRNA vaccines, other than predicting the possibility of flare, is less clear. However, the results could be useful in informed discussions and decision-making regarding withdrawing immunosuppressive drugs.

Some people with rheumatic diseases have been concerned about flares of disease activity related to COVID-19 vaccination. Tedeschi and colleagues conducted a prospective observational study of 71 patients with RA who were previously inoculated against COVID-19 with two mRNA vaccine doses or one adenovirus vector vaccine dose. Using the patient-reported Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), they measured disease activity weekly from study enrollment through 4 weeks after an additional dose. They did not find any change in mean RADAI-5 score between pre- and post additional dose, nor was disease activity different in patients who stopped disease-modifying antirheumatic drugs (DMARD) compared with those who did not. The study also examined flow cytometry of lymphocyte populations among a subset of these patients (n = 27) and found no significant differences in T peripheral helper cells, T follicular helper cells, age-associated B cells, and plasmablasts among patients before and after the additional vaccine dose. Though the flow cytometry data are difficult to generalize, given the presumed heterogeneity and small number of patients, the lack of change in RA disease activity after the additional vaccine dose is reassuring.

Achievement of remission in patients with RA is also an area of continued interest, especially because of the difficulty of reaching this target under real-world conditions. Larid and colleagues report the prognostic factors of remission and characteristics of 215 patients with RA over 7 years of follow-up at an academic hospital in France. Notably, 33% of patients were in remission at 1 year, of whom 76% remained in remission at 7 years. However, 48% of patients who were not in remission at 1 year achieved remission at 7 years; 58% of study participants were in remission in total at 7 years of follow-up. Those in remission were more frequently being prescribed both conventional synthetic DMARD (csDMARD) and biologic DMARD (bDMARD), while those not in remission at 7 years were receiving corticosteroids at higher doses. Owing to the lack of more precise treatment information, as well as the large number of patients who did not complete the 7-year follow-up visit, drawing conclusions is difficult. While we cannot say, based on these results, that use of certain medication regimens or strategies is more likely to lead to remission, the data at least lend support to the possibility of achieving remission in the long term.

Finally, Ahmad and colleagues performed a post-hoc analysis of the phase 3b AVERT trial of abatacept vs. methotrexate; 172 patients in remission were evaluated at 6 and 12 months after withdrawal of abatacept + methotrexate, abatacept monotherapy, or methotrexate monotherapy. Similar proportions of patients in all three treatment groups experienced a flare (about 58% at 6 months and 66% at 12 months). Patients with higher Health Assessment Questionnaire Disability Index (HAQ-DI) scores and evidence of erosions on MRI at withdrawal were more likely to experience a flare, consistent with prior studies. This highlights potential predictors of withdrawal from therapy. Given the lack of significant difference between the treatment groups, however, it does raise the question of why combination therapy with abatacept and methotrexate is more likely to lead to patients achieving remission in studies without as big an effect on drug-free remission after withdrawal. A more stringent definition of remission rather than DAS-28 C-reactive protein may be desirable.

Vaccination strategies for people with rheumatic diseases have received significant scrutiny in regard to COVID-19 vaccines. People with rheumatoid arthritis (RA) are at higher risk for adverse outcomes related to COVID-19 but also may have reduced immunogenicity to COVID-19 vaccines; thus, temporary withdrawal of medications has been suggested. Renner Araujo and colleagues report the results of a single-center randomized study from Brazil looking at the immune response to two doses of the Sinovac-CoronaVac vaccine in 129 patients with RA. They found that those who stopped methotrexate for 2 weeks after both doses had a higher rate of seroconversion, based on immunoglobulin (Ig) G positivity (78% vs. 54%), than those who remained on methotrexate. Antibody titers were also higher in the "methotrexate-hold" group. Flare rates were higher, based on the Clinical Disease Activity Index (CDAI) — though not on the Disease Activity Scale-28 (DAS-28) — in patients who withdrew from methotrexate. This information is interesting with respect to the use of future inactivated virus vaccines, though its applicability to mRNA vaccines, other than predicting the possibility of flare, is less clear. However, the results could be useful in informed discussions and decision-making regarding withdrawing immunosuppressive drugs.

Some people with rheumatic diseases have been concerned about flares of disease activity related to COVID-19 vaccination. Tedeschi and colleagues conducted a prospective observational study of 71 patients with RA who were previously inoculated against COVID-19 with two mRNA vaccine doses or one adenovirus vector vaccine dose. Using the patient-reported Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), they measured disease activity weekly from study enrollment through 4 weeks after an additional dose. They did not find any change in mean RADAI-5 score between pre- and post additional dose, nor was disease activity different in patients who stopped disease-modifying antirheumatic drugs (DMARD) compared with those who did not. The study also examined flow cytometry of lymphocyte populations among a subset of these patients (n = 27) and found no significant differences in T peripheral helper cells, T follicular helper cells, age-associated B cells, and plasmablasts among patients before and after the additional vaccine dose. Though the flow cytometry data are difficult to generalize, given the presumed heterogeneity and small number of patients, the lack of change in RA disease activity after the additional vaccine dose is reassuring.

Achievement of remission in patients with RA is also an area of continued interest, especially because of the difficulty of reaching this target under real-world conditions. Larid and colleagues report the prognostic factors of remission and characteristics of 215 patients with RA over 7 years of follow-up at an academic hospital in France. Notably, 33% of patients were in remission at 1 year, of whom 76% remained in remission at 7 years. However, 48% of patients who were not in remission at 1 year achieved remission at 7 years; 58% of study participants were in remission in total at 7 years of follow-up. Those in remission were more frequently being prescribed both conventional synthetic DMARD (csDMARD) and biologic DMARD (bDMARD), while those not in remission at 7 years were receiving corticosteroids at higher doses. Owing to the lack of more precise treatment information, as well as the large number of patients who did not complete the 7-year follow-up visit, drawing conclusions is difficult. While we cannot say, based on these results, that use of certain medication regimens or strategies is more likely to lead to remission, the data at least lend support to the possibility of achieving remission in the long term.

Finally, Ahmad and colleagues performed a post-hoc analysis of the phase 3b AVERT trial of abatacept vs. methotrexate; 172 patients in remission were evaluated at 6 and 12 months after withdrawal of abatacept + methotrexate, abatacept monotherapy, or methotrexate monotherapy. Similar proportions of patients in all three treatment groups experienced a flare (about 58% at 6 months and 66% at 12 months). Patients with higher Health Assessment Questionnaire Disability Index (HAQ-DI) scores and evidence of erosions on MRI at withdrawal were more likely to experience a flare, consistent with prior studies. This highlights potential predictors of withdrawal from therapy. Given the lack of significant difference between the treatment groups, however, it does raise the question of why combination therapy with abatacept and methotrexate is more likely to lead to patients achieving remission in studies without as big an effect on drug-free remission after withdrawal. A more stringent definition of remission rather than DAS-28 C-reactive protein may be desirable.

The recent ORAL Surveillance trial has raised concerns about the safety of tofacitinib (and potentially other JAK inhibitors) in the treatment of rheumatoid arthritis.¹ JAK inhibitors are known to increase cholesterol levels; however, this was not previously known to increase cardiovascular risk. The ORAL Surveillance trial was an open-label randomized non-inferiority trial comparing 5mg or 10 mg tofacitinib twice daily with tumor necrosis factor (TNF) inhibitor use. Both adverse cardiac events and cancer were increased in the tofacitinib groups (with hazard ratios of 1.33 and 1.48, respectively). The study did not include a control group and so the impact of RA itself on cardiac events and cancer is not known. However, the apparent risk was greatest in patients over the age of 65, suggesting caution should be used in treating older patients with RA with JAK inhibitors. Interestingly, the STAR-RA study, an observational cohort study, looked at claims data from several sources to try to replicate trial results as well as provide real-world evidence on the topic of cardiovascular risk associated with tofacitinib use.² The authors were able to replicate the inclusion/exclusion criteria from the ORAL Surveillance trial and found that the results were similar. However, on “relaxing” inclusion and exclusion criteria, ie, the “real-world evidence” cohort, there was no difference in incidence of cardiovascular outcomes between tofacitinib and TNF-inhibitor groups. Specifically, patients in the real-world cohort who had no cardiovascular risk factors or prior events were not found to have an increased cardiovascular risk with tofacitinib use, a reassuring finding supporting careful attention to cardiovascular risk in patients with RA when evaluating treatment options.

One consideration in the use of rituximab for treatment of RA is the possibility of changing or lowering subsequent or maintenance doses. Past studies have suggested that halving the dose of rituximab to a single 1000 mg infusion was tolerated by RA patients. The REDO trial, published in 2019, looked at even lower doses: 500 mg and 200 mg. The study did not establish non-inferiority of lower doses at 6 months in a per-protocol analysis, only in intention-to-treat. An extension study of REDO presented at the ACR Convergence in 2021 looked at a subset of those patients for up to 4 years and did find non-inferiority in terms of disease activity. Wientjes et al³ present further analysis of the REDO trial with 140 RA patients at 6 months, looking at the association of rituximab dosage with B cell counts as well as the predictive value of different patient characteristics in terms of response to lower dosages. Interestingly, serum drug levels and B cell counts at 3 and 6 months did not predict response to rituximab, nor did patient characteristics, such as age, smoking, disease, duration, or seropositivity for RF and CCP. Though the authors suggest that this implies even lower doses may be effective, it is not clear, and a similar analysis of the extension trial would be of interest. 

Use of methotrexate as a first-line DMARD for RA is cost-effective but often limited by patient fears or intolerance due to adverse events (AE). This observational cohort study by Sherbini et al⁴ evaluates not only the prevalence of AE, but also baseline factors that may predict the development of AE. Over 1,000 patients with early RA initiating methotrexate were included in analysis. More than 75% reported at least one AE in 12 months, with gastrointestinal AE, such as nausea, being most prevalent (42%); 18% developed elevated liver enzyme tests (defined as a single reading above the upper limit of normal). Few strong predictors of AE were identified, though women were overall more likely than men to report AE. Reassuringly, combination conventional synthetic DMARD therapy did not generally lead to more reported AE. Given the few predictive findings from this study, analysis of a comparator group or comparison of AE at different starting and maintenance doses of methotrexate would be of interest.

References

1.  Ytterberg SR et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386:316-326 (Jan 27).
2. Khosrow-Khavar F et al. Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study. Ann Rheum Dis. 2022 (Jan 13).
3. Wientjes MHM et al. Drug levels, anti-drug antibodies and B-cell counts were not predictive of response in rheumatoid arthritis patients on (ultra-)low-dose rituximab. Rheumatology (Oxford). 2022 (Jan 12).
4. Sherbini AA et al. Rates and predictors of methotrexate-related adverse events in patients with early rheumatoid arthritis: results from a nationwide UK study. Rheumatology (Oxford). 2022 (Jan 25).

The recent ORAL Surveillance trial has raised concerns about the safety of tofacitinib (and potentially other JAK inhibitors) in the treatment of rheumatoid arthritis.¹ JAK inhibitors are known to increase cholesterol levels; however, this was not previously known to increase cardiovascular risk. The ORAL Surveillance trial was an open-label randomized non-inferiority trial comparing 5mg or 10 mg tofacitinib twice daily with tumor necrosis factor (TNF) inhibitor use. Both adverse cardiac events and cancer were increased in the tofacitinib groups (with hazard ratios of 1.33 and 1.48, respectively). The study did not include a control group and so the impact of RA itself on cardiac events and cancer is not known. However, the apparent risk was greatest in patients over the age of 65, suggesting caution should be used in treating older patients with RA with JAK inhibitors. Interestingly, the STAR-RA study, an observational cohort study, looked at claims data from several sources to try to replicate trial results as well as provide real-world evidence on the topic of cardiovascular risk associated with tofacitinib use.² The authors were able to replicate the inclusion/exclusion criteria from the ORAL Surveillance trial and found that the results were similar. However, on “relaxing” inclusion and exclusion criteria, ie, the “real-world evidence” cohort, there was no difference in incidence of cardiovascular outcomes between tofacitinib and TNF-inhibitor groups. Specifically, patients in the real-world cohort who had no cardiovascular risk factors or prior events were not found to have an increased cardiovascular risk with tofacitinib use, a reassuring finding supporting careful attention to cardiovascular risk in patients with RA when evaluating treatment options.

One consideration in the use of rituximab for treatment of RA is the possibility of changing or lowering subsequent or maintenance doses. Past studies have suggested that halving the dose of rituximab to a single 1000 mg infusion was tolerated by RA patients. The REDO trial, published in 2019, looked at even lower doses: 500 mg and 200 mg. The study did not establish non-inferiority of lower doses at 6 months in a per-protocol analysis, only in intention-to-treat. An extension study of REDO presented at the ACR Convergence in 2021 looked at a subset of those patients for up to 4 years and did find non-inferiority in terms of disease activity. Wientjes et al³ present further analysis of the REDO trial with 140 RA patients at 6 months, looking at the association of rituximab dosage with B cell counts as well as the predictive value of different patient characteristics in terms of response to lower dosages. Interestingly, serum drug levels and B cell counts at 3 and 6 months did not predict response to rituximab, nor did patient characteristics, such as age, smoking, disease, duration, or seropositivity for RF and CCP. Though the authors suggest that this implies even lower doses may be effective, it is not clear, and a similar analysis of the extension trial would be of interest. 

Use of methotrexate as a first-line DMARD for RA is cost-effective but often limited by patient fears or intolerance due to adverse events (AE). This observational cohort study by Sherbini et al⁴ evaluates not only the prevalence of AE, but also baseline factors that may predict the development of AE. Over 1,000 patients with early RA initiating methotrexate were included in analysis. More than 75% reported at least one AE in 12 months, with gastrointestinal AE, such as nausea, being most prevalent (42%); 18% developed elevated liver enzyme tests (defined as a single reading above the upper limit of normal). Few strong predictors of AE were identified, though women were overall more likely than men to report AE. Reassuringly, combination conventional synthetic DMARD therapy did not generally lead to more reported AE. Given the few predictive findings from this study, analysis of a comparator group or comparison of AE at different starting and maintenance doses of methotrexate would be of interest.

References

1.  Ytterberg SR et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386:316-326 (Jan 27).
2. Khosrow-Khavar F et al. Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study. Ann Rheum Dis. 2022 (Jan 13).
3. Wientjes MHM et al. Drug levels, anti-drug antibodies and B-cell counts were not predictive of response in rheumatoid arthritis patients on (ultra-)low-dose rituximab. Rheumatology (Oxford). 2022 (Jan 12).
4. Sherbini AA et al. Rates and predictors of methotrexate-related adverse events in patients with early rheumatoid arthritis: results from a nationwide UK study. Rheumatology (Oxford). 2022 (Jan 25).

The recent ORAL Surveillance trial has raised concerns about the safety of tofacitinib (and potentially other JAK inhibitors) in the treatment of rheumatoid arthritis.¹ JAK inhibitors are known to increase cholesterol levels; however, this was not previously known to increase cardiovascular risk. The ORAL Surveillance trial was an open-label randomized non-inferiority trial comparing 5mg or 10 mg tofacitinib twice daily with tumor necrosis factor (TNF) inhibitor use. Both adverse cardiac events and cancer were increased in the tofacitinib groups (with hazard ratios of 1.33 and 1.48, respectively). The study did not include a control group and so the impact of RA itself on cardiac events and cancer is not known. However, the apparent risk was greatest in patients over the age of 65, suggesting caution should be used in treating older patients with RA with JAK inhibitors. Interestingly, the STAR-RA study, an observational cohort study, looked at claims data from several sources to try to replicate trial results as well as provide real-world evidence on the topic of cardiovascular risk associated with tofacitinib use.² The authors were able to replicate the inclusion/exclusion criteria from the ORAL Surveillance trial and found that the results were similar. However, on “relaxing” inclusion and exclusion criteria, ie, the “real-world evidence” cohort, there was no difference in incidence of cardiovascular outcomes between tofacitinib and TNF-inhibitor groups. Specifically, patients in the real-world cohort who had no cardiovascular risk factors or prior events were not found to have an increased cardiovascular risk with tofacitinib use, a reassuring finding supporting careful attention to cardiovascular risk in patients with RA when evaluating treatment options.

One consideration in the use of rituximab for treatment of RA is the possibility of changing or lowering subsequent or maintenance doses. Past studies have suggested that halving the dose of rituximab to a single 1000 mg infusion was tolerated by RA patients. The REDO trial, published in 2019, looked at even lower doses: 500 mg and 200 mg. The study did not establish non-inferiority of lower doses at 6 months in a per-protocol analysis, only in intention-to-treat. An extension study of REDO presented at the ACR Convergence in 2021 looked at a subset of those patients for up to 4 years and did find non-inferiority in terms of disease activity. Wientjes et al³ present further analysis of the REDO trial with 140 RA patients at 6 months, looking at the association of rituximab dosage with B cell counts as well as the predictive value of different patient characteristics in terms of response to lower dosages. Interestingly, serum drug levels and B cell counts at 3 and 6 months did not predict response to rituximab, nor did patient characteristics, such as age, smoking, disease, duration, or seropositivity for RF and CCP. Though the authors suggest that this implies even lower doses may be effective, it is not clear, and a similar analysis of the extension trial would be of interest. 

Use of methotrexate as a first-line DMARD for RA is cost-effective but often limited by patient fears or intolerance due to adverse events (AE). This observational cohort study by Sherbini et al⁴ evaluates not only the prevalence of AE, but also baseline factors that may predict the development of AE. Over 1,000 patients with early RA initiating methotrexate were included in analysis. More than 75% reported at least one AE in 12 months, with gastrointestinal AE, such as nausea, being most prevalent (42%); 18% developed elevated liver enzyme tests (defined as a single reading above the upper limit of normal). Few strong predictors of AE were identified, though women were overall more likely than men to report AE. Reassuringly, combination conventional synthetic DMARD therapy did not generally lead to more reported AE. Given the few predictive findings from this study, analysis of a comparator group or comparison of AE at different starting and maintenance doses of methotrexate would be of interest.

References

1.  Ytterberg SR et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386:316-326 (Jan 27).
2. Khosrow-Khavar F et al. Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study. Ann Rheum Dis. 2022 (Jan 13).
3. Wientjes MHM et al. Drug levels, anti-drug antibodies and B-cell counts were not predictive of response in rheumatoid arthritis patients on (ultra-)low-dose rituximab. Rheumatology (Oxford). 2022 (Jan 12).
4. Sherbini AA et al. Rates and predictors of methotrexate-related adverse events in patients with early rheumatoid arthritis: results from a nationwide UK study. Rheumatology (Oxford). 2022 (Jan 25).

Several recent RA studies have addressed aspects of systemic illness other than joint pain and inflammation, including sleep, fatigue, psychosocial burden, and well-being. A cohort study by Lyne et al¹ evaluated sleep duration and quality in 3,265 patients in the Swedish EIRA registry from 1-12 years after RA diagnosis. About 40% had problems in at least one sleep domain and the frequency of sleep problems increased somewhat with disease duration, but the strongest correlations with poor sleep were pain and functional impairment, suggesting that the overall activity of the RA was most important. Further research on improving sleep quality with improved control of disease activity would be helpful in supporting this hypothesis.

A systematic review by Shamail et al² examined mental health outcomes in patients with RA taking Janus kinase (JAK) inhibitors, limiting the review to studies reporting SF-36 mental health outcomes. The resulting 19 studies encompassed over 14,000 patients and did demonstrate clinically meaningful changes in SF-36 scores compared to baseline in patients treated with JAK inhibitors. When compared to changes with placebo or disease-modifying antirheumatic drug (DMARD) treatment, JAK inhibitors appeared to have a benefit, though few studies showed a clinically meaningful difference. Given that other studies have shown improvement in mental health outcomes with other classes of RA treatments, it is not clear that this is an effect of the JAK inhibitor class rather than related to overall improvement in quality of life.

Fatigue is a prevalent concern among patients with RA and may significantly impact quality of life; its origins in RA are not well-understood but thought to be related to inflammation. A UK study of an inception cohort by Ifeseman et al³ examines fatigue in early RA; about 75% of participants reported a decreased vitality score compared to the mean in the UK general population. Of the approximately 729 study participants in the longitudinal analysis, trajectory modeling was used to identify two groups of people: one with an “average” vitality score and another with a score that was significantly reduced compared to average. This group had worse disease activity scores, Health Assessment Questionnaire (HAQ) scores, and pain, though as with the other studies mentioned above, it is not clear if fatigue is a feature of worse control of RA or related to ongoing central sensitization or “non-inflammatory” mechanisms.

Doumen et al⁴ analyzed interaction between psychosocial variables and disease activity in an early RA cohort and found that better baseline short form-36 (SF-36) scores as well as other measures of psychosocial burden and coping were associated with sustained Disease Activity Score 28 for Rheumatoid Arthritis with C-Reactive Protein (DAS-28-CRP) remission, while negative illness perception was associated with lower probability of sustained remission. Of the 287 patients who achieved DAS-28-CRP remission at week 16, the 231 patients who had a low psychosocial burden were more likely to remain in remission. Causality and direction are not established in this small study, so while evaluating psychosocial needs is relevant, as with the other studies mentioned above, caution must be used in attributing lack of improvement in disease activity to psychosocial burden or mood disorders.

References

1. Lyne L et al. Sleep problems in rheumatoid arthritis over 12 years from diagnosis: results from the Swedish EIRA study. RMD Open. 2022;8:e001800 (Jan 5).
2. Shamail GMH et al. Association between janus kinase inhibitors therapy and mental health outcome in rheumatoid arthritis: A systematic review and meta-analysis. Rheumatol Ther. 2021 (Dec 13).
3. Ifesemen OS et al. Fatigue in early rheumatoid arthritis: data from the Early Rheumatoid Arthritis Network. Rheumatology (Oxford). 2021;keab861 (Dec 27).
4. Doumen M et al. Psychosocial burden predicts sustained remission in early rheumatoid arthritis: unraveling the complex interplay of wellbeing and disease activity. Arthritis Care Res (Hoboken). 2021 (Dec 20).

Several recent RA studies have addressed aspects of systemic illness other than joint pain and inflammation, including sleep, fatigue, psychosocial burden, and well-being. A cohort study by Lyne et al¹ evaluated sleep duration and quality in 3,265 patients in the Swedish EIRA registry from 1-12 years after RA diagnosis. About 40% had problems in at least one sleep domain and the frequency of sleep problems increased somewhat with disease duration, but the strongest correlations with poor sleep were pain and functional impairment, suggesting that the overall activity of the RA was most important. Further research on improving sleep quality with improved control of disease activity would be helpful in supporting this hypothesis.

A systematic review by Shamail et al² examined mental health outcomes in patients with RA taking Janus kinase (JAK) inhibitors, limiting the review to studies reporting SF-36 mental health outcomes. The resulting 19 studies encompassed over 14,000 patients and did demonstrate clinically meaningful changes in SF-36 scores compared to baseline in patients treated with JAK inhibitors. When compared to changes with placebo or disease-modifying antirheumatic drug (DMARD) treatment, JAK inhibitors appeared to have a benefit, though few studies showed a clinically meaningful difference. Given that other studies have shown improvement in mental health outcomes with other classes of RA treatments, it is not clear that this is an effect of the JAK inhibitor class rather than related to overall improvement in quality of life.

Fatigue is a prevalent concern among patients with RA and may significantly impact quality of life; its origins in RA are not well-understood but thought to be related to inflammation. A UK study of an inception cohort by Ifeseman et al³ examines fatigue in early RA; about 75% of participants reported a decreased vitality score compared to the mean in the UK general population. Of the approximately 729 study participants in the longitudinal analysis, trajectory modeling was used to identify two groups of people: one with an “average” vitality score and another with a score that was significantly reduced compared to average. This group had worse disease activity scores, Health Assessment Questionnaire (HAQ) scores, and pain, though as with the other studies mentioned above, it is not clear if fatigue is a feature of worse control of RA or related to ongoing central sensitization or “non-inflammatory” mechanisms.

Doumen et al⁴ analyzed interaction between psychosocial variables and disease activity in an early RA cohort and found that better baseline short form-36 (SF-36) scores as well as other measures of psychosocial burden and coping were associated with sustained Disease Activity Score 28 for Rheumatoid Arthritis with C-Reactive Protein (DAS-28-CRP) remission, while negative illness perception was associated with lower probability of sustained remission. Of the 287 patients who achieved DAS-28-CRP remission at week 16, the 231 patients who had a low psychosocial burden were more likely to remain in remission. Causality and direction are not established in this small study, so while evaluating psychosocial needs is relevant, as with the other studies mentioned above, caution must be used in attributing lack of improvement in disease activity to psychosocial burden or mood disorders.

References

1. Lyne L et al. Sleep problems in rheumatoid arthritis over 12 years from diagnosis: results from the Swedish EIRA study. RMD Open. 2022;8:e001800 (Jan 5).
2. Shamail GMH et al. Association between janus kinase inhibitors therapy and mental health outcome in rheumatoid arthritis: A systematic review and meta-analysis. Rheumatol Ther. 2021 (Dec 13).
3. Ifesemen OS et al. Fatigue in early rheumatoid arthritis: data from the Early Rheumatoid Arthritis Network. Rheumatology (Oxford). 2021;keab861 (Dec 27).
4. Doumen M et al. Psychosocial burden predicts sustained remission in early rheumatoid arthritis: unraveling the complex interplay of wellbeing and disease activity. Arthritis Care Res (Hoboken). 2021 (Dec 20).

Several recent RA studies have addressed aspects of systemic illness other than joint pain and inflammation, including sleep, fatigue, psychosocial burden, and well-being. A cohort study by Lyne et al¹ evaluated sleep duration and quality in 3,265 patients in the Swedish EIRA registry from 1-12 years after RA diagnosis. About 40% had problems in at least one sleep domain and the frequency of sleep problems increased somewhat with disease duration, but the strongest correlations with poor sleep were pain and functional impairment, suggesting that the overall activity of the RA was most important. Further research on improving sleep quality with improved control of disease activity would be helpful in supporting this hypothesis.

A systematic review by Shamail et al² examined mental health outcomes in patients with RA taking Janus kinase (JAK) inhibitors, limiting the review to studies reporting SF-36 mental health outcomes. The resulting 19 studies encompassed over 14,000 patients and did demonstrate clinically meaningful changes in SF-36 scores compared to baseline in patients treated with JAK inhibitors. When compared to changes with placebo or disease-modifying antirheumatic drug (DMARD) treatment, JAK inhibitors appeared to have a benefit, though few studies showed a clinically meaningful difference. Given that other studies have shown improvement in mental health outcomes with other classes of RA treatments, it is not clear that this is an effect of the JAK inhibitor class rather than related to overall improvement in quality of life.

Fatigue is a prevalent concern among patients with RA and may significantly impact quality of life; its origins in RA are not well-understood but thought to be related to inflammation. A UK study of an inception cohort by Ifeseman et al³ examines fatigue in early RA; about 75% of participants reported a decreased vitality score compared to the mean in the UK general population. Of the approximately 729 study participants in the longitudinal analysis, trajectory modeling was used to identify two groups of people: one with an “average” vitality score and another with a score that was significantly reduced compared to average. This group had worse disease activity scores, Health Assessment Questionnaire (HAQ) scores, and pain, though as with the other studies mentioned above, it is not clear if fatigue is a feature of worse control of RA or related to ongoing central sensitization or “non-inflammatory” mechanisms.

Doumen et al⁴ analyzed interaction between psychosocial variables and disease activity in an early RA cohort and found that better baseline short form-36 (SF-36) scores as well as other measures of psychosocial burden and coping were associated with sustained Disease Activity Score 28 for Rheumatoid Arthritis with C-Reactive Protein (DAS-28-CRP) remission, while negative illness perception was associated with lower probability of sustained remission. Of the 287 patients who achieved DAS-28-CRP remission at week 16, the 231 patients who had a low psychosocial burden were more likely to remain in remission. Causality and direction are not established in this small study, so while evaluating psychosocial needs is relevant, as with the other studies mentioned above, caution must be used in attributing lack of improvement in disease activity to psychosocial burden or mood disorders.

References

1. Lyne L et al. Sleep problems in rheumatoid arthritis over 12 years from diagnosis: results from the Swedish EIRA study. RMD Open. 2022;8:e001800 (Jan 5).
2. Shamail GMH et al. Association between janus kinase inhibitors therapy and mental health outcome in rheumatoid arthritis: A systematic review and meta-analysis. Rheumatol Ther. 2021 (Dec 13).
3. Ifesemen OS et al. Fatigue in early rheumatoid arthritis: data from the Early Rheumatoid Arthritis Network. Rheumatology (Oxford). 2021;keab861 (Dec 27).
4. Doumen M et al. Psychosocial burden predicts sustained remission in early rheumatoid arthritis: unraveling the complex interplay of wellbeing and disease activity. Arthritis Care Res (Hoboken). 2021 (Dec 20).

Along with long-standing concerns about immunodeficiency and use of immunosuppressive medication in people with rheumatoid arthritis (RA) are juxtaposed concerns about their additional risk of COVID-19 during the pandemic. Several studies have reported a high risk of severe COVID-19 outcomes in people with rheumatic disease, though few have compared this risk to the general population. This cohort study by Wang et al.¹ examines the risk of COVID-19 in people with RA compared to people with OA and the general population based on an electronic medical record database in the UK. The rate of COVID-19 was higher among people with RA than the general population, with a hazard ratio of 1.42 for confirmed COVID-19 cases, while the rate among people with OA was not increased. This finding confirms suspicions, though, due to the study design, it does not lend additional insight into nuances given the lack of information about RA treatment and activity as in prior studies.

Also of concern in the midst of the pandemic is the effect of RA and its treatment on response to vaccines against SARS-CoV-2. The rapid development of mRNA vaccines has been a boon, but research on vaccine response in people with rheumatic disease has suggested that certain medications can impact antibody formation. Iancovici et al.² examined antibody and B cell responses after vaccination in people with RA being treated with Janus kinase (JAK)-inhibitors or tumor necrosis factor (TNF)-inhibitors and in healthy volunteers. Though the study is flawed as responses were not assessed at the same timepoint after vaccination in all subjects and limited due to the heterogeneity of treatment and small numbers of subjects, antibody production and other assays were decreased in RA subjects, suggesting reduced humoral immunity. Whether a pause in JAK inhibitor treatment, as recommended by the American College of Rheumatology, makes an appreciable difference in these assessments of vaccine response is as yet unknown. Further, given the limited data, it is unclear whether having RA on its own, rather than the treatments involved, was the causative factor. Research is already underway on SARS-CoV-2 vaccine response in people with RA and other rheumatic diseases, but studies such as these also imply a relative immunodeficiency due to the diseases and their treatment that could extend to other vaccines or infections.

In addition to impacts on SARS-CoV-2 vaccine response, treatment with JAK inhibitors is known to increase risk of herpes zoster (HZ). A post hoc analysis of pooled data from 21 RA and 3 psoriatic arthritis (PsA) tofacitinib trials by Winthrop et al.³ evaluated the number and severity of HZ infections. Interestingly, HZ infections occurred more frequently in participants in the RA clinical trials, with about 11% having an infection compared to 5% in the PsA studies, once again highlighting a potential immunodeficiency particular to people with RA. Most patients had mild to moderate infections, but a small proportion of patients (<5%) had severe infections. Given the possibility of a reduced vaccine response, though unknown, after HZ vaccination in people with RA, consideration should be given not only to vaccination prior to initiation of JAK inhibitor therapy, but to assessment of vaccine efficacy and the ideal dosing schedules in these patients.

References

1. Wang Y et al. Increased risk of COVID-19 in patients with rheumatoid arthritis: a general population-based cohort study. Arthritis Care Res (Hoboken) 2021(Dec 7). 
2. Iancovici L et al. Rheumatoid arthritis patients treated with Janus kinase inhibitors show reduced humoral immune responses following BNT162b2 vaccination. Rheumatology (Oxford). 2021:keab879 (Nov 25).
3. Winthrop KL et al. Clinical management of herpes zoster in patients with rheumatoid arthritis or psoriatic arthritis receiving tofacitinib treatment. Rheumatol Ther. 2021 (Dec 6).

Along with long-standing concerns about immunodeficiency and use of immunosuppressive medication in people with rheumatoid arthritis (RA) are juxtaposed concerns about their additional risk of COVID-19 during the pandemic. Several studies have reported a high risk of severe COVID-19 outcomes in people with rheumatic disease, though few have compared this risk to the general population. This cohort study by Wang et al.¹ examines the risk of COVID-19 in people with RA compared to people with OA and the general population based on an electronic medical record database in the UK. The rate of COVID-19 was higher among people with RA than the general population, with a hazard ratio of 1.42 for confirmed COVID-19 cases, while the rate among people with OA was not increased. This finding confirms suspicions, though, due to the study design, it does not lend additional insight into nuances given the lack of information about RA treatment and activity as in prior studies.

Also of concern in the midst of the pandemic is the effect of RA and its treatment on response to vaccines against SARS-CoV-2. The rapid development of mRNA vaccines has been a boon, but research on vaccine response in people with rheumatic disease has suggested that certain medications can impact antibody formation. Iancovici et al.² examined antibody and B cell responses after vaccination in people with RA being treated with Janus kinase (JAK)-inhibitors or tumor necrosis factor (TNF)-inhibitors and in healthy volunteers. Though the study is flawed as responses were not assessed at the same timepoint after vaccination in all subjects and limited due to the heterogeneity of treatment and small numbers of subjects, antibody production and other assays were decreased in RA subjects, suggesting reduced humoral immunity. Whether a pause in JAK inhibitor treatment, as recommended by the American College of Rheumatology, makes an appreciable difference in these assessments of vaccine response is as yet unknown. Further, given the limited data, it is unclear whether having RA on its own, rather than the treatments involved, was the causative factor. Research is already underway on SARS-CoV-2 vaccine response in people with RA and other rheumatic diseases, but studies such as these also imply a relative immunodeficiency due to the diseases and their treatment that could extend to other vaccines or infections.

In addition to impacts on SARS-CoV-2 vaccine response, treatment with JAK inhibitors is known to increase risk of herpes zoster (HZ). A post hoc analysis of pooled data from 21 RA and 3 psoriatic arthritis (PsA) tofacitinib trials by Winthrop et al.³ evaluated the number and severity of HZ infections. Interestingly, HZ infections occurred more frequently in participants in the RA clinical trials, with about 11% having an infection compared to 5% in the PsA studies, once again highlighting a potential immunodeficiency particular to people with RA. Most patients had mild to moderate infections, but a small proportion of patients (<5%) had severe infections. Given the possibility of a reduced vaccine response, though unknown, after HZ vaccination in people with RA, consideration should be given not only to vaccination prior to initiation of JAK inhibitor therapy, but to assessment of vaccine efficacy and the ideal dosing schedules in these patients.

References

1. Wang Y et al. Increased risk of COVID-19 in patients with rheumatoid arthritis: a general population-based cohort study. Arthritis Care Res (Hoboken) 2021(Dec 7). 
2. Iancovici L et al. Rheumatoid arthritis patients treated with Janus kinase inhibitors show reduced humoral immune responses following BNT162b2 vaccination. Rheumatology (Oxford). 2021:keab879 (Nov 25).
3. Winthrop KL et al. Clinical management of herpes zoster in patients with rheumatoid arthritis or psoriatic arthritis receiving tofacitinib treatment. Rheumatol Ther. 2021 (Dec 6).

Along with long-standing concerns about immunodeficiency and use of immunosuppressive medication in people with rheumatoid arthritis (RA) are juxtaposed concerns about their additional risk of COVID-19 during the pandemic. Several studies have reported a high risk of severe COVID-19 outcomes in people with rheumatic disease, though few have compared this risk to the general population. This cohort study by Wang et al.¹ examines the risk of COVID-19 in people with RA compared to people with OA and the general population based on an electronic medical record database in the UK. The rate of COVID-19 was higher among people with RA than the general population, with a hazard ratio of 1.42 for confirmed COVID-19 cases, while the rate among people with OA was not increased. This finding confirms suspicions, though, due to the study design, it does not lend additional insight into nuances given the lack of information about RA treatment and activity as in prior studies.

Also of concern in the midst of the pandemic is the effect of RA and its treatment on response to vaccines against SARS-CoV-2. The rapid development of mRNA vaccines has been a boon, but research on vaccine response in people with rheumatic disease has suggested that certain medications can impact antibody formation. Iancovici et al.² examined antibody and B cell responses after vaccination in people with RA being treated with Janus kinase (JAK)-inhibitors or tumor necrosis factor (TNF)-inhibitors and in healthy volunteers. Though the study is flawed as responses were not assessed at the same timepoint after vaccination in all subjects and limited due to the heterogeneity of treatment and small numbers of subjects, antibody production and other assays were decreased in RA subjects, suggesting reduced humoral immunity. Whether a pause in JAK inhibitor treatment, as recommended by the American College of Rheumatology, makes an appreciable difference in these assessments of vaccine response is as yet unknown. Further, given the limited data, it is unclear whether having RA on its own, rather than the treatments involved, was the causative factor. Research is already underway on SARS-CoV-2 vaccine response in people with RA and other rheumatic diseases, but studies such as these also imply a relative immunodeficiency due to the diseases and their treatment that could extend to other vaccines or infections.

In addition to impacts on SARS-CoV-2 vaccine response, treatment with JAK inhibitors is known to increase risk of herpes zoster (HZ). A post hoc analysis of pooled data from 21 RA and 3 psoriatic arthritis (PsA) tofacitinib trials by Winthrop et al.³ evaluated the number and severity of HZ infections. Interestingly, HZ infections occurred more frequently in participants in the RA clinical trials, with about 11% having an infection compared to 5% in the PsA studies, once again highlighting a potential immunodeficiency particular to people with RA. Most patients had mild to moderate infections, but a small proportion of patients (<5%) had severe infections. Given the possibility of a reduced vaccine response, though unknown, after HZ vaccination in people with RA, consideration should be given not only to vaccination prior to initiation of JAK inhibitor therapy, but to assessment of vaccine efficacy and the ideal dosing schedules in these patients.

References

1. Wang Y et al. Increased risk of COVID-19 in patients with rheumatoid arthritis: a general population-based cohort study. Arthritis Care Res (Hoboken) 2021(Dec 7). 
2. Iancovici L et al. Rheumatoid arthritis patients treated with Janus kinase inhibitors show reduced humoral immune responses following BNT162b2 vaccination. Rheumatology (Oxford). 2021:keab879 (Nov 25).
3. Winthrop KL et al. Clinical management of herpes zoster in patients with rheumatoid arthritis or psoriatic arthritis receiving tofacitinib treatment. Rheumatol Ther. 2021 (Dec 6).

Many people with rheumatoid arthritis (RA) have concomitant hand osteoarthritis (OA). This Swiss cohort study by Lechtenboehmer et al¹ using a longitudinal registry of RA patients examined characteristics of RA patients who had progression of radiographic hand OA. Of over 1,300 patients who had radiographic distal interphalangeal (DIP) OA at baseline, a substantial fraction had progression of OA with osteophyte formation, joint space narrowing, and subchondral sclerosis. In subgroup analysis, biologic disease-modifying antirheumatic drug (bDMARD) use was associated with osteophyte formation, while of nearly 900 patients without radiographic OA at baseline, bDMARD use was not associated with development of DIP OA. While the authors postulate that this may be due to osteoanabolic effects of bDMARDs, in this real-world analysis the association does not imply a causative role for bDMARDs as additional confounders may exist and the onset/timing of progression is unknown. Still, the association deserves attention in controlled and long-term studies.

Another condition known to affect older adults is sarcopenia; in addition to aging, poor nutrition, lack of exercise, and autoimmune disease are thought to contribute to sarcopenia. RA is associated with an increased risk of sarcopenia. A cross-sectional study of cohort of Japanese women by Minamino et al.² of RA examines the potential relationship between 25-OH vitamin D levels and sarcopenia. Participants were over the age of 60 and not taking vitamin D supplements. Low vitamin D levels, as well as age, 28-Joint RA Disease Activity Score (DAS-28), and health assessment questionnaire disability index (HAQ), were associated with the prevalence of severe sarcopenia, including the separate components of muscle mass, physical performance, and strength. Although this does not prove causation, the known decrease in vitamin D receptors in muscle nuclei with aging lends pathophysiologic support to vitamin D’s role in sarcopenia. Whether this plays a larger role in RA-related sarcopenia also remains to be seen.

Several recent studies have expanded our awareness of respiratory illness and exposure outside of cigarette smoking as potentially associated with RA risk. This single-center case control study by Kronzer et al³ looked at respiratory disease diagnosis (based on ICD10 code) at least two years prior to RA diagnosis. Acute and chronic sinusitis, as well as pharyngitis, were associated with increased risk of RA, even adjusting for the known risk of smoking, raising the possibility of a role for the upper respiratory mucosa in RA pathogenesis. Whether this association is a sign of immune dysregulation instead or a result of other respiratory exposures is a question that should be further investigated given this growing body of evidence of respiratory involvement in RA pathogenesis.

In terms of other factors that influence the development of autoimmune disease, there is evidence of the involvement of the gut microbiome in RA pathogenesis, as well as public interest in the possibility of an optimal diet, such as the “Mediterranean diet” for control of arthritis symptoms. The recent Swedish crossover Anti-inflammatory Diet In Rheumatoid Arthritis (ADIRA) study by Turesson Wadell et al⁴ examined effects of a “typical” and “anti-inflammatory” diet with whole grains, fruits, nuts, legumes, fatty fish, and probiotics in patients with RA. Prior work suggested that the anti-inflammatory diet was associated with lower RA disease activity and inflammatory markers. Only 44 patients completed the 10 week study, perhaps contributing to the lack of differences seen in functional measures, pain, fatigue, and morning stiffness at the end of the intervention. Changes in medications may have masked dietary effects in this small study and a longer study period may be necessary to assess effects. Given the lack of evidence in this area, further research is of course needed, but this study represents an initial attempt at rigorous examination and could be suggested to interested and motivated patients as generally safe.

References

1. Lechtenboehmer CA et al. Increased radiographic progression of distal hand osteoarthritis occurring during biologic DMARD monotherapy for concomitant rheumatoid arthritis. Arthritis Res Ther. 2021;23:267 (Oct 26).
2. Minamino H et al. Serum vitamin D status inversely associates with a prevalence of severe sarcopenia among female patients with rheumatoid arthritis. Sci Rep. 2021;11:20485 (Oct 14).
3. Kronzer VL et al. Association of sinusitis and upper respiratory tract diseases with incident rheumatoid arthritis: A case-control study. J Rheumatol 2021(Oct 15).
4. Turesson Wadell A et al. Effects on health-related quality of life in the randomized, controlled crossover trial ADIRA (Anti-inflammatory Diet In Rheumatoid Arthritis). PLoS One. 2021(Oct 14).

Many people with rheumatoid arthritis (RA) have concomitant hand osteoarthritis (OA). This Swiss cohort study by Lechtenboehmer et al¹ using a longitudinal registry of RA patients examined characteristics of RA patients who had progression of radiographic hand OA. Of over 1,300 patients who had radiographic distal interphalangeal (DIP) OA at baseline, a substantial fraction had progression of OA with osteophyte formation, joint space narrowing, and subchondral sclerosis. In subgroup analysis, biologic disease-modifying antirheumatic drug (bDMARD) use was associated with osteophyte formation, while of nearly 900 patients without radiographic OA at baseline, bDMARD use was not associated with development of DIP OA. While the authors postulate that this may be due to osteoanabolic effects of bDMARDs, in this real-world analysis the association does not imply a causative role for bDMARDs as additional confounders may exist and the onset/timing of progression is unknown. Still, the association deserves attention in controlled and long-term studies.

Another condition known to affect older adults is sarcopenia; in addition to aging, poor nutrition, lack of exercise, and autoimmune disease are thought to contribute to sarcopenia. RA is associated with an increased risk of sarcopenia. A cross-sectional study of cohort of Japanese women by Minamino et al.² of RA examines the potential relationship between 25-OH vitamin D levels and sarcopenia. Participants were over the age of 60 and not taking vitamin D supplements. Low vitamin D levels, as well as age, 28-Joint RA Disease Activity Score (DAS-28), and health assessment questionnaire disability index (HAQ), were associated with the prevalence of severe sarcopenia, including the separate components of muscle mass, physical performance, and strength. Although this does not prove causation, the known decrease in vitamin D receptors in muscle nuclei with aging lends pathophysiologic support to vitamin D’s role in sarcopenia. Whether this plays a larger role in RA-related sarcopenia also remains to be seen.

Several recent studies have expanded our awareness of respiratory illness and exposure outside of cigarette smoking as potentially associated with RA risk. This single-center case control study by Kronzer et al³ looked at respiratory disease diagnosis (based on ICD10 code) at least two years prior to RA diagnosis. Acute and chronic sinusitis, as well as pharyngitis, were associated with increased risk of RA, even adjusting for the known risk of smoking, raising the possibility of a role for the upper respiratory mucosa in RA pathogenesis. Whether this association is a sign of immune dysregulation instead or a result of other respiratory exposures is a question that should be further investigated given this growing body of evidence of respiratory involvement in RA pathogenesis.

In terms of other factors that influence the development of autoimmune disease, there is evidence of the involvement of the gut microbiome in RA pathogenesis, as well as public interest in the possibility of an optimal diet, such as the “Mediterranean diet” for control of arthritis symptoms. The recent Swedish crossover Anti-inflammatory Diet In Rheumatoid Arthritis (ADIRA) study by Turesson Wadell et al⁴ examined effects of a “typical” and “anti-inflammatory” diet with whole grains, fruits, nuts, legumes, fatty fish, and probiotics in patients with RA. Prior work suggested that the anti-inflammatory diet was associated with lower RA disease activity and inflammatory markers. Only 44 patients completed the 10 week study, perhaps contributing to the lack of differences seen in functional measures, pain, fatigue, and morning stiffness at the end of the intervention. Changes in medications may have masked dietary effects in this small study and a longer study period may be necessary to assess effects. Given the lack of evidence in this area, further research is of course needed, but this study represents an initial attempt at rigorous examination and could be suggested to interested and motivated patients as generally safe.

References

1. Lechtenboehmer CA et al. Increased radiographic progression of distal hand osteoarthritis occurring during biologic DMARD monotherapy for concomitant rheumatoid arthritis. Arthritis Res Ther. 2021;23:267 (Oct 26).
2. Minamino H et al. Serum vitamin D status inversely associates with a prevalence of severe sarcopenia among female patients with rheumatoid arthritis. Sci Rep. 2021;11:20485 (Oct 14).
3. Kronzer VL et al. Association of sinusitis and upper respiratory tract diseases with incident rheumatoid arthritis: A case-control study. J Rheumatol 2021(Oct 15).
4. Turesson Wadell A et al. Effects on health-related quality of life in the randomized, controlled crossover trial ADIRA (Anti-inflammatory Diet In Rheumatoid Arthritis). PLoS One. 2021(Oct 14).

Many people with rheumatoid arthritis (RA) have concomitant hand osteoarthritis (OA). This Swiss cohort study by Lechtenboehmer et al¹ using a longitudinal registry of RA patients examined characteristics of RA patients who had progression of radiographic hand OA. Of over 1,300 patients who had radiographic distal interphalangeal (DIP) OA at baseline, a substantial fraction had progression of OA with osteophyte formation, joint space narrowing, and subchondral sclerosis. In subgroup analysis, biologic disease-modifying antirheumatic drug (bDMARD) use was associated with osteophyte formation, while of nearly 900 patients without radiographic OA at baseline, bDMARD use was not associated with development of DIP OA. While the authors postulate that this may be due to osteoanabolic effects of bDMARDs, in this real-world analysis the association does not imply a causative role for bDMARDs as additional confounders may exist and the onset/timing of progression is unknown. Still, the association deserves attention in controlled and long-term studies.

Another condition known to affect older adults is sarcopenia; in addition to aging, poor nutrition, lack of exercise, and autoimmune disease are thought to contribute to sarcopenia. RA is associated with an increased risk of sarcopenia. A cross-sectional study of cohort of Japanese women by Minamino et al.² of RA examines the potential relationship between 25-OH vitamin D levels and sarcopenia. Participants were over the age of 60 and not taking vitamin D supplements. Low vitamin D levels, as well as age, 28-Joint RA Disease Activity Score (DAS-28), and health assessment questionnaire disability index (HAQ), were associated with the prevalence of severe sarcopenia, including the separate components of muscle mass, physical performance, and strength. Although this does not prove causation, the known decrease in vitamin D receptors in muscle nuclei with aging lends pathophysiologic support to vitamin D’s role in sarcopenia. Whether this plays a larger role in RA-related sarcopenia also remains to be seen.

Several recent studies have expanded our awareness of respiratory illness and exposure outside of cigarette smoking as potentially associated with RA risk. This single-center case control study by Kronzer et al³ looked at respiratory disease diagnosis (based on ICD10 code) at least two years prior to RA diagnosis. Acute and chronic sinusitis, as well as pharyngitis, were associated with increased risk of RA, even adjusting for the known risk of smoking, raising the possibility of a role for the upper respiratory mucosa in RA pathogenesis. Whether this association is a sign of immune dysregulation instead or a result of other respiratory exposures is a question that should be further investigated given this growing body of evidence of respiratory involvement in RA pathogenesis.

In terms of other factors that influence the development of autoimmune disease, there is evidence of the involvement of the gut microbiome in RA pathogenesis, as well as public interest in the possibility of an optimal diet, such as the “Mediterranean diet” for control of arthritis symptoms. The recent Swedish crossover Anti-inflammatory Diet In Rheumatoid Arthritis (ADIRA) study by Turesson Wadell et al⁴ examined effects of a “typical” and “anti-inflammatory” diet with whole grains, fruits, nuts, legumes, fatty fish, and probiotics in patients with RA. Prior work suggested that the anti-inflammatory diet was associated with lower RA disease activity and inflammatory markers. Only 44 patients completed the 10 week study, perhaps contributing to the lack of differences seen in functional measures, pain, fatigue, and morning stiffness at the end of the intervention. Changes in medications may have masked dietary effects in this small study and a longer study period may be necessary to assess effects. Given the lack of evidence in this area, further research is of course needed, but this study represents an initial attempt at rigorous examination and could be suggested to interested and motivated patients as generally safe.

References

1. Lechtenboehmer CA et al. Increased radiographic progression of distal hand osteoarthritis occurring during biologic DMARD monotherapy for concomitant rheumatoid arthritis. Arthritis Res Ther. 2021;23:267 (Oct 26).
2. Minamino H et al. Serum vitamin D status inversely associates with a prevalence of severe sarcopenia among female patients with rheumatoid arthritis. Sci Rep. 2021;11:20485 (Oct 14).
3. Kronzer VL et al. Association of sinusitis and upper respiratory tract diseases with incident rheumatoid arthritis: A case-control study. J Rheumatol 2021(Oct 15).
4. Turesson Wadell A et al. Effects on health-related quality of life in the randomized, controlled crossover trial ADIRA (Anti-inflammatory Diet In Rheumatoid Arthritis). PLoS One. 2021(Oct 14).

Biosimilar medications have received significant attention recently in the treatment of rheumatoid arthritis (RA), though the effects of switching from the reference drug to a biosimilar is not known. The study by Fleischmann et al¹ looks at the safety and efficacy, as well as immunogenicity, of biosimilar adalimumab (ADL-PF) compared to the reference ADL-EU (European Union sourced adalimumab) in a randomized double-blind study. Patients were randomized to start and continue ADL-PF or start ADL-EU and switch to ADL-PF at week 26 or 52. Immunogenicity was measured using anti-drug antibodies (ADA). American College of Rheumatology (ACR20) response rates were similar among all groups, while ACR50 and ACR70 response rates were numerically lower in the week 52 switch group. ADA development was comparable between groups. Data were analyzed using descriptive statistics, but overall, safety, efficacy, and immunogenicity were similar between patients maintained on ADL-PF and those switched from ADL-EU at week 26 or 52.

Statins have long been associated with musculoskeletal symptoms in patients, but have also been postulated to have anti-inflammatory and immunomodulatory effects. Complicating the relationship is the knowledge that inflammation increases cardiovascular risk in RA patients. In a case-control study, Peterson et al² used an administrative database to examine the influence of statin use on development of RA. Cases were identified based on ICD-9 coding as well as a prescription for methotrexate after diagnosis. They were matched 1:1 with controls based on demographics and year of diagnosis. Statin use was evaluated. Statin use was associated with a small increase in risk of RA, which was diminished after adjusting for hyperlipidemia; a trend towards increase in risk with higher dose and duration of statin use was not statistically significant. Beyond this, the reduced risk after adjustment for hyperlipidemia is hard to interpret as an explanation of cause or effect of autoimmunity, and, given the small magnitude of increases and decreases in risk, may not be clinically meaningful.

In addition to patients with RA having a higher burden of cardiovascular disease necessitating use of statins, they also have a high risk of progressive secondary osteoarthritis requiring joint replacement surgery. Chang et al³ used a national claims-based dataset from China to examine risk of total knee or hip replacement (TKR and THR, respectively) in patients with RA. From 2000-2013 (ie, the onset of the biologic era), TKR and THR rates were examined in a cohort of biologic disease-modifying antirheumatic drug (bDMARD) users compared to conventional synthetic DMARD (csDMARD) users. Adjusted hazard ratios (HR) were lower for both TKD and THR in bDMARD users. Though RA activity was not examined, combined with the knowledge of the association of disease severity with bDMARD use, this study lends evidence to the benefits of more aggressive treatment.

Finally, much is made of the link between bDMARD and targeted synthetic DMARD use and malignancy due to reduced immunosurveillance, but concrete evidence is conflicting. Wetzman et al⁴ performed a systematic review of studies of patients with inflammatory arthritis (RA, psoriatic arthritis, and Ankylosing spondylitis) looking at cancer relapse or occurrence of new cancer. An increase in skin cancers (HR 1.32) was noted, but reassuringly no other increase in risk of recurrent or new cancer was seen.

References

1. Fleischmann R et al. Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52–92 data from a randomized, double-blind, phase 3 trialArthritis Res Ther. 2021(Sep 25);23:248.
2. Peterson MN et al. Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study. Arthritis Res Ther. 2021(Sep 18):23:244.
3. Chang YS et al. Effects of biologics on reducing the risks of total knee replacement and total hip replacement in rheumatoid arthritis. Rheumatology (Oxford). 2021(Sep 17):keab671.
4. Wetzman A et al. Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthritis and a prior cancer: systematic review with meta-analysis. Arthritis Care Res (Hoboken). 2021(Sep 21): acr.24784.

Biosimilar medications have received significant attention recently in the treatment of rheumatoid arthritis (RA), though the effects of switching from the reference drug to a biosimilar is not known. The study by Fleischmann et al¹ looks at the safety and efficacy, as well as immunogenicity, of biosimilar adalimumab (ADL-PF) compared to the reference ADL-EU (European Union sourced adalimumab) in a randomized double-blind study. Patients were randomized to start and continue ADL-PF or start ADL-EU and switch to ADL-PF at week 26 or 52. Immunogenicity was measured using anti-drug antibodies (ADA). American College of Rheumatology (ACR20) response rates were similar among all groups, while ACR50 and ACR70 response rates were numerically lower in the week 52 switch group. ADA development was comparable between groups. Data were analyzed using descriptive statistics, but overall, safety, efficacy, and immunogenicity were similar between patients maintained on ADL-PF and those switched from ADL-EU at week 26 or 52.

Statins have long been associated with musculoskeletal symptoms in patients, but have also been postulated to have anti-inflammatory and immunomodulatory effects. Complicating the relationship is the knowledge that inflammation increases cardiovascular risk in RA patients. In a case-control study, Peterson et al² used an administrative database to examine the influence of statin use on development of RA. Cases were identified based on ICD-9 coding as well as a prescription for methotrexate after diagnosis. They were matched 1:1 with controls based on demographics and year of diagnosis. Statin use was evaluated. Statin use was associated with a small increase in risk of RA, which was diminished after adjusting for hyperlipidemia; a trend towards increase in risk with higher dose and duration of statin use was not statistically significant. Beyond this, the reduced risk after adjustment for hyperlipidemia is hard to interpret as an explanation of cause or effect of autoimmunity, and, given the small magnitude of increases and decreases in risk, may not be clinically meaningful.

In addition to patients with RA having a higher burden of cardiovascular disease necessitating use of statins, they also have a high risk of progressive secondary osteoarthritis requiring joint replacement surgery. Chang et al³ used a national claims-based dataset from China to examine risk of total knee or hip replacement (TKR and THR, respectively) in patients with RA. From 2000-2013 (ie, the onset of the biologic era), TKR and THR rates were examined in a cohort of biologic disease-modifying antirheumatic drug (bDMARD) users compared to conventional synthetic DMARD (csDMARD) users. Adjusted hazard ratios (HR) were lower for both TKD and THR in bDMARD users. Though RA activity was not examined, combined with the knowledge of the association of disease severity with bDMARD use, this study lends evidence to the benefits of more aggressive treatment.

Finally, much is made of the link between bDMARD and targeted synthetic DMARD use and malignancy due to reduced immunosurveillance, but concrete evidence is conflicting. Wetzman et al⁴ performed a systematic review of studies of patients with inflammatory arthritis (RA, psoriatic arthritis, and Ankylosing spondylitis) looking at cancer relapse or occurrence of new cancer. An increase in skin cancers (HR 1.32) was noted, but reassuringly no other increase in risk of recurrent or new cancer was seen.

References

1. Fleischmann R et al. Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52–92 data from a randomized, double-blind, phase 3 trialArthritis Res Ther. 2021(Sep 25);23:248.
2. Peterson MN et al. Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study. Arthritis Res Ther. 2021(Sep 18):23:244.
3. Chang YS et al. Effects of biologics on reducing the risks of total knee replacement and total hip replacement in rheumatoid arthritis. Rheumatology (Oxford). 2021(Sep 17):keab671.
4. Wetzman A et al. Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthritis and a prior cancer: systematic review with meta-analysis. Arthritis Care Res (Hoboken). 2021(Sep 21): acr.24784.

Biosimilar medications have received significant attention recently in the treatment of rheumatoid arthritis (RA), though the effects of switching from the reference drug to a biosimilar is not known. The study by Fleischmann et al¹ looks at the safety and efficacy, as well as immunogenicity, of biosimilar adalimumab (ADL-PF) compared to the reference ADL-EU (European Union sourced adalimumab) in a randomized double-blind study. Patients were randomized to start and continue ADL-PF or start ADL-EU and switch to ADL-PF at week 26 or 52. Immunogenicity was measured using anti-drug antibodies (ADA). American College of Rheumatology (ACR20) response rates were similar among all groups, while ACR50 and ACR70 response rates were numerically lower in the week 52 switch group. ADA development was comparable between groups. Data were analyzed using descriptive statistics, but overall, safety, efficacy, and immunogenicity were similar between patients maintained on ADL-PF and those switched from ADL-EU at week 26 or 52.

Statins have long been associated with musculoskeletal symptoms in patients, but have also been postulated to have anti-inflammatory and immunomodulatory effects. Complicating the relationship is the knowledge that inflammation increases cardiovascular risk in RA patients. In a case-control study, Peterson et al² used an administrative database to examine the influence of statin use on development of RA. Cases were identified based on ICD-9 coding as well as a prescription for methotrexate after diagnosis. They were matched 1:1 with controls based on demographics and year of diagnosis. Statin use was evaluated. Statin use was associated with a small increase in risk of RA, which was diminished after adjusting for hyperlipidemia; a trend towards increase in risk with higher dose and duration of statin use was not statistically significant. Beyond this, the reduced risk after adjustment for hyperlipidemia is hard to interpret as an explanation of cause or effect of autoimmunity, and, given the small magnitude of increases and decreases in risk, may not be clinically meaningful.

In addition to patients with RA having a higher burden of cardiovascular disease necessitating use of statins, they also have a high risk of progressive secondary osteoarthritis requiring joint replacement surgery. Chang et al³ used a national claims-based dataset from China to examine risk of total knee or hip replacement (TKR and THR, respectively) in patients with RA. From 2000-2013 (ie, the onset of the biologic era), TKR and THR rates were examined in a cohort of biologic disease-modifying antirheumatic drug (bDMARD) users compared to conventional synthetic DMARD (csDMARD) users. Adjusted hazard ratios (HR) were lower for both TKD and THR in bDMARD users. Though RA activity was not examined, combined with the knowledge of the association of disease severity with bDMARD use, this study lends evidence to the benefits of more aggressive treatment.

Finally, much is made of the link between bDMARD and targeted synthetic DMARD use and malignancy due to reduced immunosurveillance, but concrete evidence is conflicting. Wetzman et al⁴ performed a systematic review of studies of patients with inflammatory arthritis (RA, psoriatic arthritis, and Ankylosing spondylitis) looking at cancer relapse or occurrence of new cancer. An increase in skin cancers (HR 1.32) was noted, but reassuringly no other increase in risk of recurrent or new cancer was seen.

References

1. Fleischmann R et al. Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52–92 data from a randomized, double-blind, phase 3 trialArthritis Res Ther. 2021(Sep 25);23:248.
2. Peterson MN et al. Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study. Arthritis Res Ther. 2021(Sep 18):23:244.
3. Chang YS et al. Effects of biologics on reducing the risks of total knee replacement and total hip replacement in rheumatoid arthritis. Rheumatology (Oxford). 2021(Sep 17):keab671.
4. Wetzman A et al. Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthritis and a prior cancer: systematic review with meta-analysis. Arthritis Care Res (Hoboken). 2021(Sep 21): acr.24784.

Cigarette smoking is a well-known modifiable risk factor for the development of rheumatoid arthritis (RA). Studies have suggested not only an elevated risk but possible pathogenetic role in the development of autoantibodies, as well as effects on disease outcomes. Passive cigarette smoking has also been proposed as a potential risk factor for RA, though studies are harder to evaluate. This review of prospective data from the Nurses Health Study (NHS) by Yoshida et al looks at incident RA among women enrolled in the study and the influence of in utero, childhood, and adulthood exposure to cigarettes. Childhood exposure to parental smoking was associated with seropositive RA (hazard ratio 1.75) even after controlling for adult personal smoking, and maternal smoking during pregnancy was associated with RA, though the latter effect was not seen after controlling for subsequent smoking exposure. As the authors point out, verifiable prospective data is difficult to obtain regarding exposure to smoking in utero or in childhood and recall bias is possible in obtaining historical information in this prospective study given the use of questionnaires, though it remains plausible given prior studies on the association of personal smoking with RA.

The involvement of gut microbiota in development of autoimmunity has also been postulated but not well-explained. Several recent studies have examined the impact of antibiotic use on the development of RA, including a recent large UK-based case-control study suggesting an increase in RA incidence in people with antibiotic exposure. While a systematic review is ongoing, this prospective cohort study by Liu et al also examines data from NHSI and NHSII and RA risk in patients exposed to antibiotics, stratified by duration of use (none, ≤14 days, ≥15 days). It is reassuring that in this study neither short term (≤14 days) nor long term (≥15 days) antibiotic use was associated with RA risk. Comparison with prior studies with prescription data, however, is limited given the use of questionnaires to establish duration of recent antibiotic exposure.

Fatigue is a common symptom of RA and has a high impact on quality of life in terms of function. The study by Holten et al examines data from the ARCTIC trial in terms of associations between disease activity and fatigue in early RA, as well as change in fatigue with therapy for RA. Fatigue was measured via a visual analog scale (VAS) and did decrease with therapy from baseline; 80% of patients in the study had moderate or high disease activity based on disease activity score (DAS) at baseline and 69% of patients reported fatigue, while 9% of patients had moderate or high disease activity based on DAS at  24 months and 38% reported fatigue. Interestingly, patients who were in remission (per DAS) at 6 months had a reduced risk of fatigue at 24 months. It is hard to interpret this information in a granular way as fatigue is not measured in a standardized way across clinical studies and the only instrument of measure in the ARCTIC trial was the VAS. An alternate view, for example examining the impact of baseline fatigue on response to therapy, may also be reasonable, or fatigue may be a residual symptom similar to chronic myofascial or “non-inflammatory” pain not responsive to treatment in RA.

Finally, another associated extra-articular manifestation of RA is bronchiectasis. Martin et al performed a systematic review and meta-analysis of the literature and found that the prevalence of bronchiectasis was about 18% in RA patients, suggesting that it is more common than previously thought. However, inclusion of CT imaging may detect subclinical bronchiectasis and other secondary causes were not determined. Still, given the effects on quality of life and mortality, further research into causes and risk factors for bronchiectasis in RA is warranted.

Cigarette smoking is a well-known modifiable risk factor for the development of rheumatoid arthritis (RA). Studies have suggested not only an elevated risk but possible pathogenetic role in the development of autoantibodies, as well as effects on disease outcomes. Passive cigarette smoking has also been proposed as a potential risk factor for RA, though studies are harder to evaluate. This review of prospective data from the Nurses Health Study (NHS) by Yoshida et al looks at incident RA among women enrolled in the study and the influence of in utero, childhood, and adulthood exposure to cigarettes. Childhood exposure to parental smoking was associated with seropositive RA (hazard ratio 1.75) even after controlling for adult personal smoking, and maternal smoking during pregnancy was associated with RA, though the latter effect was not seen after controlling for subsequent smoking exposure. As the authors point out, verifiable prospective data is difficult to obtain regarding exposure to smoking in utero or in childhood and recall bias is possible in obtaining historical information in this prospective study given the use of questionnaires, though it remains plausible given prior studies on the association of personal smoking with RA.

The involvement of gut microbiota in development of autoimmunity has also been postulated but not well-explained. Several recent studies have examined the impact of antibiotic use on the development of RA, including a recent large UK-based case-control study suggesting an increase in RA incidence in people with antibiotic exposure. While a systematic review is ongoing, this prospective cohort study by Liu et al also examines data from NHSI and NHSII and RA risk in patients exposed to antibiotics, stratified by duration of use (none, ≤14 days, ≥15 days). It is reassuring that in this study neither short term (≤14 days) nor long term (≥15 days) antibiotic use was associated with RA risk. Comparison with prior studies with prescription data, however, is limited given the use of questionnaires to establish duration of recent antibiotic exposure.

Fatigue is a common symptom of RA and has a high impact on quality of life in terms of function. The study by Holten et al examines data from the ARCTIC trial in terms of associations between disease activity and fatigue in early RA, as well as change in fatigue with therapy for RA. Fatigue was measured via a visual analog scale (VAS) and did decrease with therapy from baseline; 80% of patients in the study had moderate or high disease activity based on disease activity score (DAS) at baseline and 69% of patients reported fatigue, while 9% of patients had moderate or high disease activity based on DAS at  24 months and 38% reported fatigue. Interestingly, patients who were in remission (per DAS) at 6 months had a reduced risk of fatigue at 24 months. It is hard to interpret this information in a granular way as fatigue is not measured in a standardized way across clinical studies and the only instrument of measure in the ARCTIC trial was the VAS. An alternate view, for example examining the impact of baseline fatigue on response to therapy, may also be reasonable, or fatigue may be a residual symptom similar to chronic myofascial or “non-inflammatory” pain not responsive to treatment in RA.

Finally, another associated extra-articular manifestation of RA is bronchiectasis. Martin et al performed a systematic review and meta-analysis of the literature and found that the prevalence of bronchiectasis was about 18% in RA patients, suggesting that it is more common than previously thought. However, inclusion of CT imaging may detect subclinical bronchiectasis and other secondary causes were not determined. Still, given the effects on quality of life and mortality, further research into causes and risk factors for bronchiectasis in RA is warranted.

Cigarette smoking is a well-known modifiable risk factor for the development of rheumatoid arthritis (RA). Studies have suggested not only an elevated risk but possible pathogenetic role in the development of autoantibodies, as well as effects on disease outcomes. Passive cigarette smoking has also been proposed as a potential risk factor for RA, though studies are harder to evaluate. This review of prospective data from the Nurses Health Study (NHS) by Yoshida et al looks at incident RA among women enrolled in the study and the influence of in utero, childhood, and adulthood exposure to cigarettes. Childhood exposure to parental smoking was associated with seropositive RA (hazard ratio 1.75) even after controlling for adult personal smoking, and maternal smoking during pregnancy was associated with RA, though the latter effect was not seen after controlling for subsequent smoking exposure. As the authors point out, verifiable prospective data is difficult to obtain regarding exposure to smoking in utero or in childhood and recall bias is possible in obtaining historical information in this prospective study given the use of questionnaires, though it remains plausible given prior studies on the association of personal smoking with RA.

The involvement of gut microbiota in development of autoimmunity has also been postulated but not well-explained. Several recent studies have examined the impact of antibiotic use on the development of RA, including a recent large UK-based case-control study suggesting an increase in RA incidence in people with antibiotic exposure. While a systematic review is ongoing, this prospective cohort study by Liu et al also examines data from NHSI and NHSII and RA risk in patients exposed to antibiotics, stratified by duration of use (none, ≤14 days, ≥15 days). It is reassuring that in this study neither short term (≤14 days) nor long term (≥15 days) antibiotic use was associated with RA risk. Comparison with prior studies with prescription data, however, is limited given the use of questionnaires to establish duration of recent antibiotic exposure.

Fatigue is a common symptom of RA and has a high impact on quality of life in terms of function. The study by Holten et al examines data from the ARCTIC trial in terms of associations between disease activity and fatigue in early RA, as well as change in fatigue with therapy for RA. Fatigue was measured via a visual analog scale (VAS) and did decrease with therapy from baseline; 80% of patients in the study had moderate or high disease activity based on disease activity score (DAS) at baseline and 69% of patients reported fatigue, while 9% of patients had moderate or high disease activity based on DAS at  24 months and 38% reported fatigue. Interestingly, patients who were in remission (per DAS) at 6 months had a reduced risk of fatigue at 24 months. It is hard to interpret this information in a granular way as fatigue is not measured in a standardized way across clinical studies and the only instrument of measure in the ARCTIC trial was the VAS. An alternate view, for example examining the impact of baseline fatigue on response to therapy, may also be reasonable, or fatigue may be a residual symptom similar to chronic myofascial or “non-inflammatory” pain not responsive to treatment in RA.

Finally, another associated extra-articular manifestation of RA is bronchiectasis. Martin et al performed a systematic review and meta-analysis of the literature and found that the prevalence of bronchiectasis was about 18% in RA patients, suggesting that it is more common than previously thought. However, inclusion of CT imaging may detect subclinical bronchiectasis and other secondary causes were not determined. Still, given the effects on quality of life and mortality, further research into causes and risk factors for bronchiectasis in RA is warranted.

Herpes zoster infection is another well-known complication of RA and its treatment, including glucocorticoid therapy. An increased incidence has recently been noted in people who use JAK inhibitors, though other bDMARDs including TNF inhibitors are also known to increase risk. Redeker et al. compare the incidence of herpes zoster in people with RA using csDMARDs, bDMARDs, and tsDMARDs using a German prospective RA registry. In nearly 14,000 patients, 559 cases of herpes zoster were documented; after adjusting for age, sex, and glucocorticoid use, an increased risk was noted for treatment with monoclonal anti-TNF therapy, B-cell directed therapy, and JAK inhibitors compared to csDMARDs, whereas soluble TNF receptor fusion protein, T cell costimulation modulators and IL-6 inhibitors were not associated with a higher risk of herpes zoster compared with csDMARDs. Unfortunately, zoster vaccination status was not extracted for all patients. The study confirms what we already know with direct risk comparison between different agents and underscores the importance of vaccination in RA patients, especially those being treated with glucocorticoids and tsDMARDs.

Finally, another important consideration in the use of bDMARDs is the increase in cancer risk due to a potential reduction in immunosurveillance. Initial meta-analyses of clinical trials of anti-TNF agents highlighted an early increase in cancer risk, though later studies including meta-analyses and registry studies with longer follow-up durations have been equivocal. Huss et al. examine a Swedish registry of people with RA and no prior history of cancer and found a small increase in cancer-risk in patients with RA compared to the general population (HR 1.2). However, there was no increase in overall cancer incidence in patients treated with TNF inhibitors, rituximab, abatacept, or JAK inhibitors compared to RA patients naïve to bDMARDs and tsDMARDs. Interestingly, urinary tract cancer risk was slightly increased in several treatment groups, though the effect size was small. Considering the generally long duration of follow-up (with the exception of JAK inhibitors), this study is very reassuring regarding long-term risk of cancer of bDMARD use and useful in counseling people with RA on therapeutic risks.

Herpes zoster infection is another well-known complication of RA and its treatment, including glucocorticoid therapy. An increased incidence has recently been noted in people who use JAK inhibitors, though other bDMARDs including TNF inhibitors are also known to increase risk. Redeker et al. compare the incidence of herpes zoster in people with RA using csDMARDs, bDMARDs, and tsDMARDs using a German prospective RA registry. In nearly 14,000 patients, 559 cases of herpes zoster were documented; after adjusting for age, sex, and glucocorticoid use, an increased risk was noted for treatment with monoclonal anti-TNF therapy, B-cell directed therapy, and JAK inhibitors compared to csDMARDs, whereas soluble TNF receptor fusion protein, T cell costimulation modulators and IL-6 inhibitors were not associated with a higher risk of herpes zoster compared with csDMARDs. Unfortunately, zoster vaccination status was not extracted for all patients. The study confirms what we already know with direct risk comparison between different agents and underscores the importance of vaccination in RA patients, especially those being treated with glucocorticoids and tsDMARDs.

Finally, another important consideration in the use of bDMARDs is the increase in cancer risk due to a potential reduction in immunosurveillance. Initial meta-analyses of clinical trials of anti-TNF agents highlighted an early increase in cancer risk, though later studies including meta-analyses and registry studies with longer follow-up durations have been equivocal. Huss et al. examine a Swedish registry of people with RA and no prior history of cancer and found a small increase in cancer-risk in patients with RA compared to the general population (HR 1.2). However, there was no increase in overall cancer incidence in patients treated with TNF inhibitors, rituximab, abatacept, or JAK inhibitors compared to RA patients naïve to bDMARDs and tsDMARDs. Interestingly, urinary tract cancer risk was slightly increased in several treatment groups, though the effect size was small. Considering the generally long duration of follow-up (with the exception of JAK inhibitors), this study is very reassuring regarding long-term risk of cancer of bDMARD use and useful in counseling people with RA on therapeutic risks.

Herpes zoster infection is another well-known complication of RA and its treatment, including glucocorticoid therapy. An increased incidence has recently been noted in people who use JAK inhibitors, though other bDMARDs including TNF inhibitors are also known to increase risk. Redeker et al. compare the incidence of herpes zoster in people with RA using csDMARDs, bDMARDs, and tsDMARDs using a German prospective RA registry. In nearly 14,000 patients, 559 cases of herpes zoster were documented; after adjusting for age, sex, and glucocorticoid use, an increased risk was noted for treatment with monoclonal anti-TNF therapy, B-cell directed therapy, and JAK inhibitors compared to csDMARDs, whereas soluble TNF receptor fusion protein, T cell costimulation modulators and IL-6 inhibitors were not associated with a higher risk of herpes zoster compared with csDMARDs. Unfortunately, zoster vaccination status was not extracted for all patients. The study confirms what we already know with direct risk comparison between different agents and underscores the importance of vaccination in RA patients, especially those being treated with glucocorticoids and tsDMARDs.

Finally, another important consideration in the use of bDMARDs is the increase in cancer risk due to a potential reduction in immunosurveillance. Initial meta-analyses of clinical trials of anti-TNF agents highlighted an early increase in cancer risk, though later studies including meta-analyses and registry studies with longer follow-up durations have been equivocal. Huss et al. examine a Swedish registry of people with RA and no prior history of cancer and found a small increase in cancer-risk in patients with RA compared to the general population (HR 1.2). However, there was no increase in overall cancer incidence in patients treated with TNF inhibitors, rituximab, abatacept, or JAK inhibitors compared to RA patients naïve to bDMARDs and tsDMARDs. Interestingly, urinary tract cancer risk was slightly increased in several treatment groups, though the effect size was small. Considering the generally long duration of follow-up (with the exception of JAK inhibitors), this study is very reassuring regarding long-term risk of cancer of bDMARD use and useful in counseling people with RA on therapeutic risks.

Recently, ACR guidelines were published on the prevention and treatment of glucocorticoid-induced osteoporosis, emphasizing use of supplemental calcium and vitamin D and antiresorptive therapy. This randomized, controlled, open-label trial by Cho et al looks at the efficacy of selective estrogen receptor modulators (SERMs) in preventing bone loss and fractures in postmenopausal RA patients with osteopenia on long-term glucocorticoids. Patients were randomized to bazedoxefine, a 3^rd-generation SERM vs no therapy in addition to background calcium and vitamin D supplementation and bone mineral density (BMD) and trabecular bone score (TBS). Bone turnover markers were assessed over the course of 48 weeks, in addition to adverse events. Prednisone dose was relatively low, with a baseline of ~3 mg/day. Bone density increased by almost 2% in the L spine (P < 0.05), but the increases in BMD at the femoral neck and TBS were not significant. Bone turnover markers did decrease in the bazedoxefine group, though not in the control group. These findings are not striking but are promising given the short duration of the study (<1 year), and potentially deserves longer-term follow-up, both for evaluation of efficacy as well as long-term safety. In the US, the medication is only available in combination with estrogen, and thus it is not currently a practical option for RA patients with GIOP.

Despite wider availability of both synthetic and biologic DMARDs for treatment of RA in recent years, persistent pain is an issue for many patients, perhaps due to peripheral sensitization. Though it seems almost unnecessary to investigate the utility of glucocorticoids for treatment of RA-related pain, the magnitude and duration of their benefit is unknown. McWilliams et al take the approach of quantitatively analyzing the benefit of glucocorticoids in RA over time in their systematic review and meta-analysis. The study looked at both spontaneous and evoked pain, and evaluated 65 studies that mostly used pain visual analogue scale, tender joint count, and Ritchie Articular Index. Reduction in spontaneous pain was greatest in the 0-3-month time period, with smaller reductions in 3-6 months and >6 month. A similar pattern was seen in evaluation of the time course of evoked pain. As such, the benefits of long-term systemic glucocorticoid therapy may not outweigh its well-known risks, especially in patients with persistent pain. Whether this is due to non-inflammatory sources of pain or other mechanisms remains unknown and is likely heavily impacted by the specific clinical scenario.

Due to the potential long-terms side effects of chronic immunosuppression, including long-term glucocorticoid therapy in patients with persistent pain in RA, the course and predictors of unacceptable pain are of interest. Eberhard et al examined an inception cohort of RA patients in a single center in Sweden over the course of 5 years. They were found to have reduction of VAS pain from inclusion to 6 months, but pain levels largely stayed the same during the rest of the follow-up period. The proportion of patients with unacceptable pain also decreased but remained stable at about 30% after 1 year, with 20% having unacceptable pain and low inflammation and about 10% having high inflammation and unacceptable pain. The study found seropositivity, high inflammatory parameters, high DAS28 and severe patient-reported outcomes to be predictive of high inflammation and unacceptable pain and lower age, higher VAS pain, and low ESR to be predictive of low inflammation and unacceptable pain. These findings highlight the importance of examining non-inflammatory mechanisms of pain as well as identifying treatments; however, in evaluating the risk of immunosuppression and glucocorticoid therapy, it does not guide increasing or reducing treatment in RA patients with persistent pain.

Recently, ACR guidelines were published on the prevention and treatment of glucocorticoid-induced osteoporosis, emphasizing use of supplemental calcium and vitamin D and antiresorptive therapy. This randomized, controlled, open-label trial by Cho et al looks at the efficacy of selective estrogen receptor modulators (SERMs) in preventing bone loss and fractures in postmenopausal RA patients with osteopenia on long-term glucocorticoids. Patients were randomized to bazedoxefine, a 3^rd-generation SERM vs no therapy in addition to background calcium and vitamin D supplementation and bone mineral density (BMD) and trabecular bone score (TBS). Bone turnover markers were assessed over the course of 48 weeks, in addition to adverse events. Prednisone dose was relatively low, with a baseline of ~3 mg/day. Bone density increased by almost 2% in the L spine (P < 0.05), but the increases in BMD at the femoral neck and TBS were not significant. Bone turnover markers did decrease in the bazedoxefine group, though not in the control group. These findings are not striking but are promising given the short duration of the study (<1 year), and potentially deserves longer-term follow-up, both for evaluation of efficacy as well as long-term safety. In the US, the medication is only available in combination with estrogen, and thus it is not currently a practical option for RA patients with GIOP.

Despite wider availability of both synthetic and biologic DMARDs for treatment of RA in recent years, persistent pain is an issue for many patients, perhaps due to peripheral sensitization. Though it seems almost unnecessary to investigate the utility of glucocorticoids for treatment of RA-related pain, the magnitude and duration of their benefit is unknown. McWilliams et al take the approach of quantitatively analyzing the benefit of glucocorticoids in RA over time in their systematic review and meta-analysis. The study looked at both spontaneous and evoked pain, and evaluated 65 studies that mostly used pain visual analogue scale, tender joint count, and Ritchie Articular Index. Reduction in spontaneous pain was greatest in the 0-3-month time period, with smaller reductions in 3-6 months and >6 month. A similar pattern was seen in evaluation of the time course of evoked pain. As such, the benefits of long-term systemic glucocorticoid therapy may not outweigh its well-known risks, especially in patients with persistent pain. Whether this is due to non-inflammatory sources of pain or other mechanisms remains unknown and is likely heavily impacted by the specific clinical scenario.

Due to the potential long-terms side effects of chronic immunosuppression, including long-term glucocorticoid therapy in patients with persistent pain in RA, the course and predictors of unacceptable pain are of interest. Eberhard et al examined an inception cohort of RA patients in a single center in Sweden over the course of 5 years. They were found to have reduction of VAS pain from inclusion to 6 months, but pain levels largely stayed the same during the rest of the follow-up period. The proportion of patients with unacceptable pain also decreased but remained stable at about 30% after 1 year, with 20% having unacceptable pain and low inflammation and about 10% having high inflammation and unacceptable pain. The study found seropositivity, high inflammatory parameters, high DAS28 and severe patient-reported outcomes to be predictive of high inflammation and unacceptable pain and lower age, higher VAS pain, and low ESR to be predictive of low inflammation and unacceptable pain. These findings highlight the importance of examining non-inflammatory mechanisms of pain as well as identifying treatments; however, in evaluating the risk of immunosuppression and glucocorticoid therapy, it does not guide increasing or reducing treatment in RA patients with persistent pain.

Recently, ACR guidelines were published on the prevention and treatment of glucocorticoid-induced osteoporosis, emphasizing use of supplemental calcium and vitamin D and antiresorptive therapy. This randomized, controlled, open-label trial by Cho et al looks at the efficacy of selective estrogen receptor modulators (SERMs) in preventing bone loss and fractures in postmenopausal RA patients with osteopenia on long-term glucocorticoids. Patients were randomized to bazedoxefine, a 3^rd-generation SERM vs no therapy in addition to background calcium and vitamin D supplementation and bone mineral density (BMD) and trabecular bone score (TBS). Bone turnover markers were assessed over the course of 48 weeks, in addition to adverse events. Prednisone dose was relatively low, with a baseline of ~3 mg/day. Bone density increased by almost 2% in the L spine (P < 0.05), but the increases in BMD at the femoral neck and TBS were not significant. Bone turnover markers did decrease in the bazedoxefine group, though not in the control group. These findings are not striking but are promising given the short duration of the study (<1 year), and potentially deserves longer-term follow-up, both for evaluation of efficacy as well as long-term safety. In the US, the medication is only available in combination with estrogen, and thus it is not currently a practical option for RA patients with GIOP.

Despite wider availability of both synthetic and biologic DMARDs for treatment of RA in recent years, persistent pain is an issue for many patients, perhaps due to peripheral sensitization. Though it seems almost unnecessary to investigate the utility of glucocorticoids for treatment of RA-related pain, the magnitude and duration of their benefit is unknown. McWilliams et al take the approach of quantitatively analyzing the benefit of glucocorticoids in RA over time in their systematic review and meta-analysis. The study looked at both spontaneous and evoked pain, and evaluated 65 studies that mostly used pain visual analogue scale, tender joint count, and Ritchie Articular Index. Reduction in spontaneous pain was greatest in the 0-3-month time period, with smaller reductions in 3-6 months and >6 month. A similar pattern was seen in evaluation of the time course of evoked pain. As such, the benefits of long-term systemic glucocorticoid therapy may not outweigh its well-known risks, especially in patients with persistent pain. Whether this is due to non-inflammatory sources of pain or other mechanisms remains unknown and is likely heavily impacted by the specific clinical scenario.

Due to the potential long-terms side effects of chronic immunosuppression, including long-term glucocorticoid therapy in patients with persistent pain in RA, the course and predictors of unacceptable pain are of interest. Eberhard et al examined an inception cohort of RA patients in a single center in Sweden over the course of 5 years. They were found to have reduction of VAS pain from inclusion to 6 months, but pain levels largely stayed the same during the rest of the follow-up period. The proportion of patients with unacceptable pain also decreased but remained stable at about 30% after 1 year, with 20% having unacceptable pain and low inflammation and about 10% having high inflammation and unacceptable pain. The study found seropositivity, high inflammatory parameters, high DAS28 and severe patient-reported outcomes to be predictive of high inflammation and unacceptable pain and lower age, higher VAS pain, and low ESR to be predictive of low inflammation and unacceptable pain. These findings highlight the importance of examining non-inflammatory mechanisms of pain as well as identifying treatments; however, in evaluating the risk of immunosuppression and glucocorticoid therapy, it does not guide increasing or reducing treatment in RA patients with persistent pain.

Several recent studies have evaluated risks of therapy in rheumatoid arthritis (RA). One question regarding treatment of early RA is whether different initial treatment strategies confer different risks. In a systematic review with network meta-analysis, Adas et al reviewed differences between methotrexate, biologic disease-modifying antirheumatic drug (bDMARD), and steroid use in early RA. Overall, risk of serious adverse events was higher with bDMARD monotherapy than methotrexate monotherapy. Of note, while generally long-term steroid use is disfavored due to adverse effects, serious adverse events were not increased in patients treated with methotrexate and steroids together. The size of differences in risk was small and study heterogeneity, including the class of bDMARDs, limits generalizability of this information; thus, variations in the studies themselves may account for these differences.

Pazmino et al also looked at treatment strategies in early RA in a post hoc analysis of participants at “low-risk” for poor prognosis in the CareRA trial, in which patients were randomized to step-up methotrexate without glucocorticoids or step-down with glucocorticoids. While pain scores and disease activity scores were similar among the two groups, analgesic use (including non-steroidal anti-inflammatory drugs [NSAIDs] and opioids) was significantly lower among those randomized to the glucocorticoid-bridging arm. Though this information is reassuring as to the utility of glucocorticoids, it is not clear that this correlation is broadly applicable, for example, among the “higher-risk” patients who might otherwise be more likely to receive glucocorticoids.

A recent analysis of the COVID-19 global rheumatology alliance physician registry by Sparks et al of cases of COVID-19 in patients with rheumatic disease looked more specifically at COVID-19 outcomes in patients with RA on biologic therapy. These are of interest due both to the risk of immunosuppression overall as well as the use of immunosuppressive medications in COVID-19-associated hyperinflammation. The study evaluated outcomes of hospitalization (including respiratory support and mortality). While hospitalization is difficult to evaluate as an outcome without knowing the background rate of COVID in the different areas, of the hospitalized patients, patients who used Janus kinase inhibitors (JAKi) and rituximab received oxygen or ventilator support and had higher mortality than those who were on abatacept, IL-6 inhibitors, or TNF inhibitors. Wider interpretation is difficult due to lack of knowledge of when medications were given (including rituximab dosing), but the results suggest that concern is warranted in improving outcomes for patients with RA on these therapies.

Finally, regarding the well-known cardiovascular risk associated with RA, several observational studies have suggested that methotrexate is associated with reduction in risk of cardiovascular events. This cohort study of the Veterans Affairs RA registry followed over 2000 patients for a mean of about 5 years; a reduction in incidence of cardiovascular events was associated with methotrexate use, independent of age, body mass index (BMI), cardiovascular risk factors, RA disease activity, and other RA therapies. It may be that methotrexate use is associated with an unknown mediator of cardiovascular disease not evaluated in this study, such as reduced glucocorticoid or NSAID use, but this area deserves further investigation.

Several recent studies have evaluated risks of therapy in rheumatoid arthritis (RA). One question regarding treatment of early RA is whether different initial treatment strategies confer different risks. In a systematic review with network meta-analysis, Adas et al reviewed differences between methotrexate, biologic disease-modifying antirheumatic drug (bDMARD), and steroid use in early RA. Overall, risk of serious adverse events was higher with bDMARD monotherapy than methotrexate monotherapy. Of note, while generally long-term steroid use is disfavored due to adverse effects, serious adverse events were not increased in patients treated with methotrexate and steroids together. The size of differences in risk was small and study heterogeneity, including the class of bDMARDs, limits generalizability of this information; thus, variations in the studies themselves may account for these differences.

Pazmino et al also looked at treatment strategies in early RA in a post hoc analysis of participants at “low-risk” for poor prognosis in the CareRA trial, in which patients were randomized to step-up methotrexate without glucocorticoids or step-down with glucocorticoids. While pain scores and disease activity scores were similar among the two groups, analgesic use (including non-steroidal anti-inflammatory drugs [NSAIDs] and opioids) was significantly lower among those randomized to the glucocorticoid-bridging arm. Though this information is reassuring as to the utility of glucocorticoids, it is not clear that this correlation is broadly applicable, for example, among the “higher-risk” patients who might otherwise be more likely to receive glucocorticoids.

A recent analysis of the COVID-19 global rheumatology alliance physician registry by Sparks et al of cases of COVID-19 in patients with rheumatic disease looked more specifically at COVID-19 outcomes in patients with RA on biologic therapy. These are of interest due both to the risk of immunosuppression overall as well as the use of immunosuppressive medications in COVID-19-associated hyperinflammation. The study evaluated outcomes of hospitalization (including respiratory support and mortality). While hospitalization is difficult to evaluate as an outcome without knowing the background rate of COVID in the different areas, of the hospitalized patients, patients who used Janus kinase inhibitors (JAKi) and rituximab received oxygen or ventilator support and had higher mortality than those who were on abatacept, IL-6 inhibitors, or TNF inhibitors. Wider interpretation is difficult due to lack of knowledge of when medications were given (including rituximab dosing), but the results suggest that concern is warranted in improving outcomes for patients with RA on these therapies.

Finally, regarding the well-known cardiovascular risk associated with RA, several observational studies have suggested that methotrexate is associated with reduction in risk of cardiovascular events. This cohort study of the Veterans Affairs RA registry followed over 2000 patients for a mean of about 5 years; a reduction in incidence of cardiovascular events was associated with methotrexate use, independent of age, body mass index (BMI), cardiovascular risk factors, RA disease activity, and other RA therapies. It may be that methotrexate use is associated with an unknown mediator of cardiovascular disease not evaluated in this study, such as reduced glucocorticoid or NSAID use, but this area deserves further investigation.

Several recent studies have evaluated risks of therapy in rheumatoid arthritis (RA). One question regarding treatment of early RA is whether different initial treatment strategies confer different risks. In a systematic review with network meta-analysis, Adas et al reviewed differences between methotrexate, biologic disease-modifying antirheumatic drug (bDMARD), and steroid use in early RA. Overall, risk of serious adverse events was higher with bDMARD monotherapy than methotrexate monotherapy. Of note, while generally long-term steroid use is disfavored due to adverse effects, serious adverse events were not increased in patients treated with methotrexate and steroids together. The size of differences in risk was small and study heterogeneity, including the class of bDMARDs, limits generalizability of this information; thus, variations in the studies themselves may account for these differences.

Pazmino et al also looked at treatment strategies in early RA in a post hoc analysis of participants at “low-risk” for poor prognosis in the CareRA trial, in which patients were randomized to step-up methotrexate without glucocorticoids or step-down with glucocorticoids. While pain scores and disease activity scores were similar among the two groups, analgesic use (including non-steroidal anti-inflammatory drugs [NSAIDs] and opioids) was significantly lower among those randomized to the glucocorticoid-bridging arm. Though this information is reassuring as to the utility of glucocorticoids, it is not clear that this correlation is broadly applicable, for example, among the “higher-risk” patients who might otherwise be more likely to receive glucocorticoids.

A recent analysis of the COVID-19 global rheumatology alliance physician registry by Sparks et al of cases of COVID-19 in patients with rheumatic disease looked more specifically at COVID-19 outcomes in patients with RA on biologic therapy. These are of interest due both to the risk of immunosuppression overall as well as the use of immunosuppressive medications in COVID-19-associated hyperinflammation. The study evaluated outcomes of hospitalization (including respiratory support and mortality). While hospitalization is difficult to evaluate as an outcome without knowing the background rate of COVID in the different areas, of the hospitalized patients, patients who used Janus kinase inhibitors (JAKi) and rituximab received oxygen or ventilator support and had higher mortality than those who were on abatacept, IL-6 inhibitors, or TNF inhibitors. Wider interpretation is difficult due to lack of knowledge of when medications were given (including rituximab dosing), but the results suggest that concern is warranted in improving outcomes for patients with RA on these therapies.

Finally, regarding the well-known cardiovascular risk associated with RA, several observational studies have suggested that methotrexate is associated with reduction in risk of cardiovascular events. This cohort study of the Veterans Affairs RA registry followed over 2000 patients for a mean of about 5 years; a reduction in incidence of cardiovascular events was associated with methotrexate use, independent of age, body mass index (BMI), cardiovascular risk factors, RA disease activity, and other RA therapies. It may be that methotrexate use is associated with an unknown mediator of cardiovascular disease not evaluated in this study, such as reduced glucocorticoid or NSAID use, but this area deserves further investigation.