Commentary: RA August 2021

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.