Arundathi Jayatilleke, MD

In the approach to treatment of patients with rheumatoid arthritis (RA), methotrexate monotherapy is often followed by addition of a biologic disease modifying anti-rheumatic drugs (bDMARDs) for best disease outcomes. Combination DMARDs therapy with methotrexate, hydroxychloroquine, and sulfasalazine (triple therapy) has been proposed as an alternative to biologic therapy. Combination methotrexate and leflunomide is not as frequently addressed in the literature, perhaps due in part to concerns about hepatotoxicity. Bredemeier et al address safety concerns regarding combination methotrexate and leflunomide in the treatment of patients with RA. In this multicenter Brazilian registry study, they compared adverse events (including infection) among patients receiving bDMARDs or JAK inhibitors. Patients treated with combination methotrexate and leflunomide had comparable rates of adverse effects as patients treated with either medication alone; infectious and serious adverse events were fewer compared to patients treated with bDMARDs or JAK inhibitors. Given this reassuring information, further study of the efficacy and durability of combination methotrexate and leflunomide therapy would be helpful to firmly establish its place in treatment of RA, especially among newer biologic choices.

Tofacitinib and tocilizumab, for example, have been under investigation for safety and efficacy, alone and in combination with conventional synthetic DMARDs (csDMARDs). Prior studies have suggested that tofacitinib is more effective in bDMARD-naïve patients than patients who have had inadequate efficacy with one or more bDMARDs. In this multicenter Japanese cohort study, Mori et al examine RA outcomes in new users of tofacitinib and tocilizumab. Clinical disease activity index (CDAI) responses and remission rates were significantly better among bDMARD-naïve patients receiving tofacitinib compared to those receiving tocilizumab; interestingly, this difference was not seen in patients who had previously received bDMARDs. Interpretation of these results is somewhat hampered by the use of the lower every-other-week tocilizimab injection dose, but they still raise the question as to whether timing and sequence of biologics can affect future response to therapy.

The role of conventional DMARDs has also been questioned in the converse role: tapering of therapy. Lillegraven et al compare tapering of csDMARDs to continuing therapy in this randomized multicenter Norwegian study. The possibility of biologic tapering in RA has previously been addressed with some evidence of success in the form of reduced frequency of administration. Unfortunately, despite being in stable remission, patients assigned to reduce csDMARDs to half-dose had more flares than those continuing therapy, suggesting that reducing csDMARDs to half-dose in RA patients in remission may not be easily accomplished. Whether this changes in patients with prolonged or “deep” remission is as yet unknown.

Finally, with all of these options for tailored therapy, how does our treatment of early RA fare? Combe et al report the 10-year outcomes of a French early RA cohort (ESPOIR), including patients with RA for <6 months recruited from 2003-2005. 521 patients were followed; at year 10, half were in DAS28 remission, and 14% in drug-free remission. Compared to outcomes from an earlier community- based study, patients in the ESPOIR cohort have better outcomes, possibly due to more aggressive treatment for RA, use of bDMARDs, or perhaps even earlier identification of patients for treatment. Due to the sizeable proportion of patients in drug-free remission, the impact of stringency of entry criteria should be considered, and a comparison to a later cohort with patients identified using 2019 ACR/EULAR criteria would be of great interest.

In the approach to treatment of patients with rheumatoid arthritis (RA), methotrexate monotherapy is often followed by addition of a biologic disease modifying anti-rheumatic drugs (bDMARDs) for best disease outcomes. Combination DMARDs therapy with methotrexate, hydroxychloroquine, and sulfasalazine (triple therapy) has been proposed as an alternative to biologic therapy. Combination methotrexate and leflunomide is not as frequently addressed in the literature, perhaps due in part to concerns about hepatotoxicity. Bredemeier et al address safety concerns regarding combination methotrexate and leflunomide in the treatment of patients with RA. In this multicenter Brazilian registry study, they compared adverse events (including infection) among patients receiving bDMARDs or JAK inhibitors. Patients treated with combination methotrexate and leflunomide had comparable rates of adverse effects as patients treated with either medication alone; infectious and serious adverse events were fewer compared to patients treated with bDMARDs or JAK inhibitors. Given this reassuring information, further study of the efficacy and durability of combination methotrexate and leflunomide therapy would be helpful to firmly establish its place in treatment of RA, especially among newer biologic choices.

Tofacitinib and tocilizumab, for example, have been under investigation for safety and efficacy, alone and in combination with conventional synthetic DMARDs (csDMARDs). Prior studies have suggested that tofacitinib is more effective in bDMARD-naïve patients than patients who have had inadequate efficacy with one or more bDMARDs. In this multicenter Japanese cohort study, Mori et al examine RA outcomes in new users of tofacitinib and tocilizumab. Clinical disease activity index (CDAI) responses and remission rates were significantly better among bDMARD-naïve patients receiving tofacitinib compared to those receiving tocilizumab; interestingly, this difference was not seen in patients who had previously received bDMARDs. Interpretation of these results is somewhat hampered by the use of the lower every-other-week tocilizimab injection dose, but they still raise the question as to whether timing and sequence of biologics can affect future response to therapy.

The role of conventional DMARDs has also been questioned in the converse role: tapering of therapy. Lillegraven et al compare tapering of csDMARDs to continuing therapy in this randomized multicenter Norwegian study. The possibility of biologic tapering in RA has previously been addressed with some evidence of success in the form of reduced frequency of administration. Unfortunately, despite being in stable remission, patients assigned to reduce csDMARDs to half-dose had more flares than those continuing therapy, suggesting that reducing csDMARDs to half-dose in RA patients in remission may not be easily accomplished. Whether this changes in patients with prolonged or “deep” remission is as yet unknown.

Finally, with all of these options for tailored therapy, how does our treatment of early RA fare? Combe et al report the 10-year outcomes of a French early RA cohort (ESPOIR), including patients with RA for <6 months recruited from 2003-2005. 521 patients were followed; at year 10, half were in DAS28 remission, and 14% in drug-free remission. Compared to outcomes from an earlier community- based study, patients in the ESPOIR cohort have better outcomes, possibly due to more aggressive treatment for RA, use of bDMARDs, or perhaps even earlier identification of patients for treatment. Due to the sizeable proportion of patients in drug-free remission, the impact of stringency of entry criteria should be considered, and a comparison to a later cohort with patients identified using 2019 ACR/EULAR criteria would be of great interest.

In the approach to treatment of patients with rheumatoid arthritis (RA), methotrexate monotherapy is often followed by addition of a biologic disease modifying anti-rheumatic drugs (bDMARDs) for best disease outcomes. Combination DMARDs therapy with methotrexate, hydroxychloroquine, and sulfasalazine (triple therapy) has been proposed as an alternative to biologic therapy. Combination methotrexate and leflunomide is not as frequently addressed in the literature, perhaps due in part to concerns about hepatotoxicity. Bredemeier et al address safety concerns regarding combination methotrexate and leflunomide in the treatment of patients with RA. In this multicenter Brazilian registry study, they compared adverse events (including infection) among patients receiving bDMARDs or JAK inhibitors. Patients treated with combination methotrexate and leflunomide had comparable rates of adverse effects as patients treated with either medication alone; infectious and serious adverse events were fewer compared to patients treated with bDMARDs or JAK inhibitors. Given this reassuring information, further study of the efficacy and durability of combination methotrexate and leflunomide therapy would be helpful to firmly establish its place in treatment of RA, especially among newer biologic choices.

Tofacitinib and tocilizumab, for example, have been under investigation for safety and efficacy, alone and in combination with conventional synthetic DMARDs (csDMARDs). Prior studies have suggested that tofacitinib is more effective in bDMARD-naïve patients than patients who have had inadequate efficacy with one or more bDMARDs. In this multicenter Japanese cohort study, Mori et al examine RA outcomes in new users of tofacitinib and tocilizumab. Clinical disease activity index (CDAI) responses and remission rates were significantly better among bDMARD-naïve patients receiving tofacitinib compared to those receiving tocilizumab; interestingly, this difference was not seen in patients who had previously received bDMARDs. Interpretation of these results is somewhat hampered by the use of the lower every-other-week tocilizimab injection dose, but they still raise the question as to whether timing and sequence of biologics can affect future response to therapy.

The role of conventional DMARDs has also been questioned in the converse role: tapering of therapy. Lillegraven et al compare tapering of csDMARDs to continuing therapy in this randomized multicenter Norwegian study. The possibility of biologic tapering in RA has previously been addressed with some evidence of success in the form of reduced frequency of administration. Unfortunately, despite being in stable remission, patients assigned to reduce csDMARDs to half-dose had more flares than those continuing therapy, suggesting that reducing csDMARDs to half-dose in RA patients in remission may not be easily accomplished. Whether this changes in patients with prolonged or “deep” remission is as yet unknown.

Finally, with all of these options for tailored therapy, how does our treatment of early RA fare? Combe et al report the 10-year outcomes of a French early RA cohort (ESPOIR), including patients with RA for <6 months recruited from 2003-2005. 521 patients were followed; at year 10, half were in DAS28 remission, and 14% in drug-free remission. Compared to outcomes from an earlier community- based study, patients in the ESPOIR cohort have better outcomes, possibly due to more aggressive treatment for RA, use of bDMARDs, or perhaps even earlier identification of patients for treatment. Due to the sizeable proportion of patients in drug-free remission, the impact of stringency of entry criteria should be considered, and a comparison to a later cohort with patients identified using 2019 ACR/EULAR criteria would be of great interest.

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

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

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

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

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

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

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

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

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

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

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

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

Iguratimod (IGU) is a novel small-molecule synthetic DMARD being studied for RA; its exact mechanism is unknown, but it inhibits NF-kB activation and seems to reduce bone resorption via RANKL and cartilage erosion via matrix metalloproteinases. Currently, it is approved in Japan and China for treatment of RA; initial studies from 2008-2010 showed improved ACR20 rates compared to placebo and comparable rates with methotrexate monotherapy; combination therapy with methotrexate appears to be more effective than either methotrexate or IGU monotherapy. Yoshikawa et al present a small study of 47 patients receiving methotrexate or methotrexate with IGU and show promising results regarding tapering of methotrexate with sustained remission/low disease activity and decrease in ultrasound evidence of synovitis in patients receiving IGU, suggesting that it is a reasonable longer-term option for RA patients. However, the medication is not approved in the US, nor have studies in patients in the US been published, so generalizability in patients outside of Japan and China is uncertain, in addition to concerns related to the small sample size.

In contrast, tocilizumab is an established therapy for RA; Pappas et al present real-world clinical practice data from the Corrona RA registry. Among nearly 1800 RA patients who initiated tocilizumab therapy, the mean durability of response was over 3 years in terms of maintaining minimum clinically important difference (MCID) over baseline CDAI and over 1 year in terms of maintaining low disease activity. Most patients in the study had previously received biologic therapy. Though the observational nature of the study limits its generalizability, the addition of efficacy data to persistence on therapy lend weight to this evidence regarding durability of response to tocilizumab, as the proportion of patients maintaining MCID was >50% at 3 years.

Treatment options are limited for RA patients who have ILD or other pulmonary complications. The fear of causing or exacerbating pulmonary toxicity limits the use of methotrexate, leflunomide, and anti-TNF biologics. Some data support the safety of rituximab and abatacept. A retrospective observational study looked at outcomes in RA patients on rituximab and JAK inhibitors. Reassuringly, respiratory event rates were no different between the two groups though number of patients and trial design prevents wider generalization; it is also unknown whether RA-ILD improves with ritixumab or JAK-inhibition. However, given these results, studying JAK inhibitors in larger prospective studies would be reasonable.

Iguratimod (IGU) is a novel small-molecule synthetic DMARD being studied for RA; its exact mechanism is unknown, but it inhibits NF-kB activation and seems to reduce bone resorption via RANKL and cartilage erosion via matrix metalloproteinases. Currently, it is approved in Japan and China for treatment of RA; initial studies from 2008-2010 showed improved ACR20 rates compared to placebo and comparable rates with methotrexate monotherapy; combination therapy with methotrexate appears to be more effective than either methotrexate or IGU monotherapy. Yoshikawa et al present a small study of 47 patients receiving methotrexate or methotrexate with IGU and show promising results regarding tapering of methotrexate with sustained remission/low disease activity and decrease in ultrasound evidence of synovitis in patients receiving IGU, suggesting that it is a reasonable longer-term option for RA patients. However, the medication is not approved in the US, nor have studies in patients in the US been published, so generalizability in patients outside of Japan and China is uncertain, in addition to concerns related to the small sample size.

In contrast, tocilizumab is an established therapy for RA; Pappas et al present real-world clinical practice data from the Corrona RA registry. Among nearly 1800 RA patients who initiated tocilizumab therapy, the mean durability of response was over 3 years in terms of maintaining minimum clinically important difference (MCID) over baseline CDAI and over 1 year in terms of maintaining low disease activity. Most patients in the study had previously received biologic therapy. Though the observational nature of the study limits its generalizability, the addition of efficacy data to persistence on therapy lend weight to this evidence regarding durability of response to tocilizumab, as the proportion of patients maintaining MCID was >50% at 3 years.

Treatment options are limited for RA patients who have ILD or other pulmonary complications. The fear of causing or exacerbating pulmonary toxicity limits the use of methotrexate, leflunomide, and anti-TNF biologics. Some data support the safety of rituximab and abatacept. A retrospective observational study looked at outcomes in RA patients on rituximab and JAK inhibitors. Reassuringly, respiratory event rates were no different between the two groups though number of patients and trial design prevents wider generalization; it is also unknown whether RA-ILD improves with ritixumab or JAK-inhibition. However, given these results, studying JAK inhibitors in larger prospective studies would be reasonable.

Iguratimod (IGU) is a novel small-molecule synthetic DMARD being studied for RA; its exact mechanism is unknown, but it inhibits NF-kB activation and seems to reduce bone resorption via RANKL and cartilage erosion via matrix metalloproteinases. Currently, it is approved in Japan and China for treatment of RA; initial studies from 2008-2010 showed improved ACR20 rates compared to placebo and comparable rates with methotrexate monotherapy; combination therapy with methotrexate appears to be more effective than either methotrexate or IGU monotherapy. Yoshikawa et al present a small study of 47 patients receiving methotrexate or methotrexate with IGU and show promising results regarding tapering of methotrexate with sustained remission/low disease activity and decrease in ultrasound evidence of synovitis in patients receiving IGU, suggesting that it is a reasonable longer-term option for RA patients. However, the medication is not approved in the US, nor have studies in patients in the US been published, so generalizability in patients outside of Japan and China is uncertain, in addition to concerns related to the small sample size.

In contrast, tocilizumab is an established therapy for RA; Pappas et al present real-world clinical practice data from the Corrona RA registry. Among nearly 1800 RA patients who initiated tocilizumab therapy, the mean durability of response was over 3 years in terms of maintaining minimum clinically important difference (MCID) over baseline CDAI and over 1 year in terms of maintaining low disease activity. Most patients in the study had previously received biologic therapy. Though the observational nature of the study limits its generalizability, the addition of efficacy data to persistence on therapy lend weight to this evidence regarding durability of response to tocilizumab, as the proportion of patients maintaining MCID was >50% at 3 years.

Treatment options are limited for RA patients who have ILD or other pulmonary complications. The fear of causing or exacerbating pulmonary toxicity limits the use of methotrexate, leflunomide, and anti-TNF biologics. Some data support the safety of rituximab and abatacept. A retrospective observational study looked at outcomes in RA patients on rituximab and JAK inhibitors. Reassuringly, respiratory event rates were no different between the two groups though number of patients and trial design prevents wider generalization; it is also unknown whether RA-ILD improves with ritixumab or JAK-inhibition. However, given these results, studying JAK inhibitors in larger prospective studies would be reasonable.

Salliot et al examine the relationship between female sex hormone exposure and risk of RA in a large cohort of French women. Based on a biannual questionnaire, 698 RA cases were diagnosed among 78,452 women and examined for association with endogenous and exogenous sex hormone exposure (e.g., age at menarche, parity, age at menopause, use of oral contraceptives, and use of hormone replacement therapy). Early age at menopause (≤45 vs >53 years) and early age at first pregnancy (<22 vs ≥27 years) were associated with increased risk of incident RA. Among exogenous hormone exposure, duration of perimenopausal progestogen use >24 months was inversely associated with risk of RA (HR 0.77). The results of this study are difficult to fit into a simple narrative regarding cumulative hormonal exposure or lifetime reproductive events, and the hazard ratios in question are relatively low. Even taking into account the fact that the study only looked at RA incidence after menopause, a larger cohort size may be necessary to determine whether type and timing of hormone exposure influences RA risk.

New biomarkers remain of high interest in RA in order to better predict severity and tailor treatment. ACPA positivity is known to be associated with joint damage in RA; however, ACPA-negative RA patients have similar outcomes in terms of pain and fatigue. Lamachia et al analyze the predictive value of anti-carbamylated protein (anti-CarP) and anti-peptidyl-arginine deiminase type-3 (anti-PAD3) antibodies in identifying patients at risk of severe RA outcomes. Anti-PAD3, but not anti-CarP, positivity was associated with higher baseline swollen joint counts and DAS28-ESR, as well as higher overall disease activity and joint damage scores, but not radiographic progression. While there was significant overlap between RF- and ACPA-positive and anti-PAD3 positive RA patients, the existence of a subset of nearly 20% of anti-PAD3 positive patients who were anti-CCP3 negative suggests that anti-PAD3 could have diagnostic in addition to predictive utility.

In addition to risk of joint damage, people with RA also have an increased risk of fracture due to low bone density, glucocorticoid use, and other factors. While we may recognize this in older patients, the risk in younger patients may be less frequently recognized. In this retrospective cohort study, Erwin et al examined risk of fracture and risk of first fracture before age 50 in RA patients compared to matched controls. Overall, fracture risk was higher in RA patients even after adjusting for age at diagnosis, gender, glucocorticoid risk, smoking, and alcohol use. Women in particular had a higher risk of first fracture before age 50 compared to women without RA; men did not have a similar risk. Hopefully awareness of this increased risk among younger RA patients will lead to better preventative strategies as well.

Salliot et al examine the relationship between female sex hormone exposure and risk of RA in a large cohort of French women. Based on a biannual questionnaire, 698 RA cases were diagnosed among 78,452 women and examined for association with endogenous and exogenous sex hormone exposure (e.g., age at menarche, parity, age at menopause, use of oral contraceptives, and use of hormone replacement therapy). Early age at menopause (≤45 vs >53 years) and early age at first pregnancy (<22 vs ≥27 years) were associated with increased risk of incident RA. Among exogenous hormone exposure, duration of perimenopausal progestogen use >24 months was inversely associated with risk of RA (HR 0.77). The results of this study are difficult to fit into a simple narrative regarding cumulative hormonal exposure or lifetime reproductive events, and the hazard ratios in question are relatively low. Even taking into account the fact that the study only looked at RA incidence after menopause, a larger cohort size may be necessary to determine whether type and timing of hormone exposure influences RA risk.

New biomarkers remain of high interest in RA in order to better predict severity and tailor treatment. ACPA positivity is known to be associated with joint damage in RA; however, ACPA-negative RA patients have similar outcomes in terms of pain and fatigue. Lamachia et al analyze the predictive value of anti-carbamylated protein (anti-CarP) and anti-peptidyl-arginine deiminase type-3 (anti-PAD3) antibodies in identifying patients at risk of severe RA outcomes. Anti-PAD3, but not anti-CarP, positivity was associated with higher baseline swollen joint counts and DAS28-ESR, as well as higher overall disease activity and joint damage scores, but not radiographic progression. While there was significant overlap between RF- and ACPA-positive and anti-PAD3 positive RA patients, the existence of a subset of nearly 20% of anti-PAD3 positive patients who were anti-CCP3 negative suggests that anti-PAD3 could have diagnostic in addition to predictive utility.

In addition to risk of joint damage, people with RA also have an increased risk of fracture due to low bone density, glucocorticoid use, and other factors. While we may recognize this in older patients, the risk in younger patients may be less frequently recognized. In this retrospective cohort study, Erwin et al examined risk of fracture and risk of first fracture before age 50 in RA patients compared to matched controls. Overall, fracture risk was higher in RA patients even after adjusting for age at diagnosis, gender, glucocorticoid risk, smoking, and alcohol use. Women in particular had a higher risk of first fracture before age 50 compared to women without RA; men did not have a similar risk. Hopefully awareness of this increased risk among younger RA patients will lead to better preventative strategies as well.

Salliot et al examine the relationship between female sex hormone exposure and risk of RA in a large cohort of French women. Based on a biannual questionnaire, 698 RA cases were diagnosed among 78,452 women and examined for association with endogenous and exogenous sex hormone exposure (e.g., age at menarche, parity, age at menopause, use of oral contraceptives, and use of hormone replacement therapy). Early age at menopause (≤45 vs >53 years) and early age at first pregnancy (<22 vs ≥27 years) were associated with increased risk of incident RA. Among exogenous hormone exposure, duration of perimenopausal progestogen use >24 months was inversely associated with risk of RA (HR 0.77). The results of this study are difficult to fit into a simple narrative regarding cumulative hormonal exposure or lifetime reproductive events, and the hazard ratios in question are relatively low. Even taking into account the fact that the study only looked at RA incidence after menopause, a larger cohort size may be necessary to determine whether type and timing of hormone exposure influences RA risk.

New biomarkers remain of high interest in RA in order to better predict severity and tailor treatment. ACPA positivity is known to be associated with joint damage in RA; however, ACPA-negative RA patients have similar outcomes in terms of pain and fatigue. Lamachia et al analyze the predictive value of anti-carbamylated protein (anti-CarP) and anti-peptidyl-arginine deiminase type-3 (anti-PAD3) antibodies in identifying patients at risk of severe RA outcomes. Anti-PAD3, but not anti-CarP, positivity was associated with higher baseline swollen joint counts and DAS28-ESR, as well as higher overall disease activity and joint damage scores, but not radiographic progression. While there was significant overlap between RF- and ACPA-positive and anti-PAD3 positive RA patients, the existence of a subset of nearly 20% of anti-PAD3 positive patients who were anti-CCP3 negative suggests that anti-PAD3 could have diagnostic in addition to predictive utility.

In addition to risk of joint damage, people with RA also have an increased risk of fracture due to low bone density, glucocorticoid use, and other factors. While we may recognize this in older patients, the risk in younger patients may be less frequently recognized. In this retrospective cohort study, Erwin et al examined risk of fracture and risk of first fracture before age 50 in RA patients compared to matched controls. Overall, fracture risk was higher in RA patients even after adjusting for age at diagnosis, gender, glucocorticoid risk, smoking, and alcohol use. Women in particular had a higher risk of first fracture before age 50 compared to women without RA; men did not have a similar risk. Hopefully awareness of this increased risk among younger RA patients will lead to better preventative strategies as well.

Li et al looked at risk of thromboembolic disease in patients with RA within the first 5 years of diagnosis compared to those without RA. Using a population database in British Columbia, Canada, 39,142 RA patients were matched to 78,078 non-RA patients and those with prior venous thromboembolism (VTE) were excluded. Incidence rates of VTE, pulmonary embolism (PE), and deep venous thrombosis (DVT) were higher among the RA cohort than the non-RA cohort; this observation held true after adjusting for age, sex, glucocorticoid, and contraceptive use. It would be interesting to know if the increased risk holds true after control of inflammation (i.e. in patients with established RA in low vs. high disease activity states). In the absence of information about BMI and tobacco use, more studies are necessary to provide further support for this finding.

As noted above, RA is associated with cardiovascular disease (CVD), along with risk of death from cardiovascular complications. Because CVD is itself a risk factor for dementia, Sattui et al examined the potential for systemic inflammation and CVD to increase risk of developing dementia in RA patients. Using CMS claims data from 2006 to 2014, they studied 56,000 RA patients age 65 or older and looked at risk of dementia according to CVD status (no CVD or risk factors, CVD risk factors without disease, and CVD). Incidence rates for dementia were higher among RA patients with CVD risk factors than those without, and highest among RA patients with CVD. This effect was age-dependent, with a more significant risk among RA patients age 65-74, perhaps because of a general increase in dementia in older adults. As RA disease activity was not obtainable in this study, the effects of systemic inflammation are difficult to attribute. In addition, there may be some misclassification of data regarding coding of dementia subtypes (i.e. vascular and Alzheimer dementia). However, as there are limited studies in this area, this study provides credible evidence for an increase in dementia in RA patients with CVD, which should be further investigated.

Finally, hydroxychloroquine (HCQ) has come under increased scrutiny in the past year in terms of its potential use outside of treatment of lupus and RA as well as potential side effects. Cardiac toxicity related to HCQ is thought to be rare; Sorour et al looked at the association between chronic HCQ use in patients with RA and the development of heart failure (HF) using a retrospective study comparing patients who developed HF after RA diagnosis to those who did not develop HF. HCQ use was similar in both groups and a higher cumulative HCQ dose was not associated with increased risk of HF. As it is small and retrospective, larger prospective studies would be helpful, but this remains reassuring as to the safety of HCQ in RA patients.

Li et al looked at risk of thromboembolic disease in patients with RA within the first 5 years of diagnosis compared to those without RA. Using a population database in British Columbia, Canada, 39,142 RA patients were matched to 78,078 non-RA patients and those with prior venous thromboembolism (VTE) were excluded. Incidence rates of VTE, pulmonary embolism (PE), and deep venous thrombosis (DVT) were higher among the RA cohort than the non-RA cohort; this observation held true after adjusting for age, sex, glucocorticoid, and contraceptive use. It would be interesting to know if the increased risk holds true after control of inflammation (i.e. in patients with established RA in low vs. high disease activity states). In the absence of information about BMI and tobacco use, more studies are necessary to provide further support for this finding.

As noted above, RA is associated with cardiovascular disease (CVD), along with risk of death from cardiovascular complications. Because CVD is itself a risk factor for dementia, Sattui et al examined the potential for systemic inflammation and CVD to increase risk of developing dementia in RA patients. Using CMS claims data from 2006 to 2014, they studied 56,000 RA patients age 65 or older and looked at risk of dementia according to CVD status (no CVD or risk factors, CVD risk factors without disease, and CVD). Incidence rates for dementia were higher among RA patients with CVD risk factors than those without, and highest among RA patients with CVD. This effect was age-dependent, with a more significant risk among RA patients age 65-74, perhaps because of a general increase in dementia in older adults. As RA disease activity was not obtainable in this study, the effects of systemic inflammation are difficult to attribute. In addition, there may be some misclassification of data regarding coding of dementia subtypes (i.e. vascular and Alzheimer dementia). However, as there are limited studies in this area, this study provides credible evidence for an increase in dementia in RA patients with CVD, which should be further investigated.

Finally, hydroxychloroquine (HCQ) has come under increased scrutiny in the past year in terms of its potential use outside of treatment of lupus and RA as well as potential side effects. Cardiac toxicity related to HCQ is thought to be rare; Sorour et al looked at the association between chronic HCQ use in patients with RA and the development of heart failure (HF) using a retrospective study comparing patients who developed HF after RA diagnosis to those who did not develop HF. HCQ use was similar in both groups and a higher cumulative HCQ dose was not associated with increased risk of HF. As it is small and retrospective, larger prospective studies would be helpful, but this remains reassuring as to the safety of HCQ in RA patients.

Li et al looked at risk of thromboembolic disease in patients with RA within the first 5 years of diagnosis compared to those without RA. Using a population database in British Columbia, Canada, 39,142 RA patients were matched to 78,078 non-RA patients and those with prior venous thromboembolism (VTE) were excluded. Incidence rates of VTE, pulmonary embolism (PE), and deep venous thrombosis (DVT) were higher among the RA cohort than the non-RA cohort; this observation held true after adjusting for age, sex, glucocorticoid, and contraceptive use. It would be interesting to know if the increased risk holds true after control of inflammation (i.e. in patients with established RA in low vs. high disease activity states). In the absence of information about BMI and tobacco use, more studies are necessary to provide further support for this finding.

As noted above, RA is associated with cardiovascular disease (CVD), along with risk of death from cardiovascular complications. Because CVD is itself a risk factor for dementia, Sattui et al examined the potential for systemic inflammation and CVD to increase risk of developing dementia in RA patients. Using CMS claims data from 2006 to 2014, they studied 56,000 RA patients age 65 or older and looked at risk of dementia according to CVD status (no CVD or risk factors, CVD risk factors without disease, and CVD). Incidence rates for dementia were higher among RA patients with CVD risk factors than those without, and highest among RA patients with CVD. This effect was age-dependent, with a more significant risk among RA patients age 65-74, perhaps because of a general increase in dementia in older adults. As RA disease activity was not obtainable in this study, the effects of systemic inflammation are difficult to attribute. In addition, there may be some misclassification of data regarding coding of dementia subtypes (i.e. vascular and Alzheimer dementia). However, as there are limited studies in this area, this study provides credible evidence for an increase in dementia in RA patients with CVD, which should be further investigated.

Finally, hydroxychloroquine (HCQ) has come under increased scrutiny in the past year in terms of its potential use outside of treatment of lupus and RA as well as potential side effects. Cardiac toxicity related to HCQ is thought to be rare; Sorour et al looked at the association between chronic HCQ use in patients with RA and the development of heart failure (HF) using a retrospective study comparing patients who developed HF after RA diagnosis to those who did not develop HF. HCQ use was similar in both groups and a higher cumulative HCQ dose was not associated with increased risk of HF. As it is small and retrospective, larger prospective studies would be helpful, but this remains reassuring as to the safety of HCQ in RA patients.

The availability of biologic DMARDs such as TNF-alpha inhibitors has expanded the therapies available to patient with RA. However, these agents have been associated with immunogenicity and the development of anti-drug antibodies that can in turn be associated with allergic reactions as well as secondary non-response to the medication. This observational study analyzes the potential relationship between the presence of anti-nuclear antibodies before and after administration of different TNF-alpha inhibitors (infliximab (IFX), adalimumab (ADA), and etanercept (ADA)) with the development of anti-drug antibodies, with the aim of predicting treatment failure. Interestingly, patients who were ANA negative (by immunofluorescence) prior to initiation of therapy did not develop antibodies to ADA or IFX (antibodies to ETN were not measured). How this is related to treatment efficacy is not clear; more patients who had anti-drug antibodies discontinued therapy within 52 weeks and were classified as non-responders to therapy, but whether there was a secondary non-response was not examined in this study. As many patients with RA are also ANA positive and have SSA antibodies, these findings could potentially greatly alter treatment algorithms if proven in longer-term randomized trials and should be examined in other biologic DMARDs as well.

The Leiden Early Arthritis Cohort (EAC) is an inception cohort that was established to study inflammatory arthritis early in the disease state, with a particular interest in RA. This cross-sectional study evaluates the frequency of intermetatarsal and submetatarsal bursitis (IMB and SMB) in early RA. The presence of these forefoot disorders on MRI was evaluated in 441 consecutive patients presenting to the EAC and in 193 healthy controls. IMB and SMB were found more frequently in RA than in other inflammatory arthritides or healthy controls, with a specificity of 70-97%. Sensitivity was higher for IMB than SMB. While the study was not designed to evaluate MRI of the forefoot as a predictive test for development of RA, these findings raise the possibility that this could be used as a diagnostic test in early arthritis and would be worthwhile studying prospectively.

Another question with regard to prediction of response of RA to therapy is that of the possibility of maintaining sustained DMARD-free remission (SDFR). Another study from the Leiden EAC examined 772 RA patients treated with synthetic and biologic DMARDs who had achieved clinical remission (DAS < 2.4) without synovitis. Taper and discontinuation of therapy was attempted, and patients were followed to evaluate whether absence of synovitis on exam was sustained on followup for at least 1 year. Of these patients, 149 achieved SDFR within 7 years of followup; 130 of these patients were seronegative for ACPA. Baseline DAS was similar between patients who did and did not achieve SDFR, but a better early DAS response (larger decrease between baseline and 4 months) was associated an increased chance of SDFR. As the study is observational without a control, it is hard to evaluate how SDFR may proceed in the natural course of the disease. Although the importance of treatment response at 4 months places a premium on early reduction of inflammation, achievement of SDFR in these patients may also be related to other baseline characteristics of the group, especially as ACPA-positive patients less frequently achieved SDFR.

The availability of biologic DMARDs such as TNF-alpha inhibitors has expanded the therapies available to patient with RA. However, these agents have been associated with immunogenicity and the development of anti-drug antibodies that can in turn be associated with allergic reactions as well as secondary non-response to the medication. This observational study analyzes the potential relationship between the presence of anti-nuclear antibodies before and after administration of different TNF-alpha inhibitors (infliximab (IFX), adalimumab (ADA), and etanercept (ADA)) with the development of anti-drug antibodies, with the aim of predicting treatment failure. Interestingly, patients who were ANA negative (by immunofluorescence) prior to initiation of therapy did not develop antibodies to ADA or IFX (antibodies to ETN were not measured). How this is related to treatment efficacy is not clear; more patients who had anti-drug antibodies discontinued therapy within 52 weeks and were classified as non-responders to therapy, but whether there was a secondary non-response was not examined in this study. As many patients with RA are also ANA positive and have SSA antibodies, these findings could potentially greatly alter treatment algorithms if proven in longer-term randomized trials and should be examined in other biologic DMARDs as well.

The Leiden Early Arthritis Cohort (EAC) is an inception cohort that was established to study inflammatory arthritis early in the disease state, with a particular interest in RA. This cross-sectional study evaluates the frequency of intermetatarsal and submetatarsal bursitis (IMB and SMB) in early RA. The presence of these forefoot disorders on MRI was evaluated in 441 consecutive patients presenting to the EAC and in 193 healthy controls. IMB and SMB were found more frequently in RA than in other inflammatory arthritides or healthy controls, with a specificity of 70-97%. Sensitivity was higher for IMB than SMB. While the study was not designed to evaluate MRI of the forefoot as a predictive test for development of RA, these findings raise the possibility that this could be used as a diagnostic test in early arthritis and would be worthwhile studying prospectively.

Another question with regard to prediction of response of RA to therapy is that of the possibility of maintaining sustained DMARD-free remission (SDFR). Another study from the Leiden EAC examined 772 RA patients treated with synthetic and biologic DMARDs who had achieved clinical remission (DAS < 2.4) without synovitis. Taper and discontinuation of therapy was attempted, and patients were followed to evaluate whether absence of synovitis on exam was sustained on followup for at least 1 year. Of these patients, 149 achieved SDFR within 7 years of followup; 130 of these patients were seronegative for ACPA. Baseline DAS was similar between patients who did and did not achieve SDFR, but a better early DAS response (larger decrease between baseline and 4 months) was associated an increased chance of SDFR. As the study is observational without a control, it is hard to evaluate how SDFR may proceed in the natural course of the disease. Although the importance of treatment response at 4 months places a premium on early reduction of inflammation, achievement of SDFR in these patients may also be related to other baseline characteristics of the group, especially as ACPA-positive patients less frequently achieved SDFR.

The availability of biologic DMARDs such as TNF-alpha inhibitors has expanded the therapies available to patient with RA. However, these agents have been associated with immunogenicity and the development of anti-drug antibodies that can in turn be associated with allergic reactions as well as secondary non-response to the medication. This observational study analyzes the potential relationship between the presence of anti-nuclear antibodies before and after administration of different TNF-alpha inhibitors (infliximab (IFX), adalimumab (ADA), and etanercept (ADA)) with the development of anti-drug antibodies, with the aim of predicting treatment failure. Interestingly, patients who were ANA negative (by immunofluorescence) prior to initiation of therapy did not develop antibodies to ADA or IFX (antibodies to ETN were not measured). How this is related to treatment efficacy is not clear; more patients who had anti-drug antibodies discontinued therapy within 52 weeks and were classified as non-responders to therapy, but whether there was a secondary non-response was not examined in this study. As many patients with RA are also ANA positive and have SSA antibodies, these findings could potentially greatly alter treatment algorithms if proven in longer-term randomized trials and should be examined in other biologic DMARDs as well.

The Leiden Early Arthritis Cohort (EAC) is an inception cohort that was established to study inflammatory arthritis early in the disease state, with a particular interest in RA. This cross-sectional study evaluates the frequency of intermetatarsal and submetatarsal bursitis (IMB and SMB) in early RA. The presence of these forefoot disorders on MRI was evaluated in 441 consecutive patients presenting to the EAC and in 193 healthy controls. IMB and SMB were found more frequently in RA than in other inflammatory arthritides or healthy controls, with a specificity of 70-97%. Sensitivity was higher for IMB than SMB. While the study was not designed to evaluate MRI of the forefoot as a predictive test for development of RA, these findings raise the possibility that this could be used as a diagnostic test in early arthritis and would be worthwhile studying prospectively.

Another question with regard to prediction of response of RA to therapy is that of the possibility of maintaining sustained DMARD-free remission (SDFR). Another study from the Leiden EAC examined 772 RA patients treated with synthetic and biologic DMARDs who had achieved clinical remission (DAS < 2.4) without synovitis. Taper and discontinuation of therapy was attempted, and patients were followed to evaluate whether absence of synovitis on exam was sustained on followup for at least 1 year. Of these patients, 149 achieved SDFR within 7 years of followup; 130 of these patients were seronegative for ACPA. Baseline DAS was similar between patients who did and did not achieve SDFR, but a better early DAS response (larger decrease between baseline and 4 months) was associated an increased chance of SDFR. As the study is observational without a control, it is hard to evaluate how SDFR may proceed in the natural course of the disease. Although the importance of treatment response at 4 months places a premium on early reduction of inflammation, achievement of SDFR in these patients may also be related to other baseline characteristics of the group, especially as ACPA-positive patients less frequently achieved SDFR.