Rheumatoid Arthritis

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

COPENHAGEN – New recommendations for the management of rheumatoid arthritis from the European Alliance of Associations for Rheumatology suggest starting short-term methotrexate and glucocorticoids when starting or changing conventional synthetic disease-modifying antirheumatic drugs (DMARDs), although rapid glucocorticoid dose reduction and discontinuation is also emphasized.

“In this respect we are at odds with the American College of Rheumatology guideline,” said Josef S. Smolen, MD, professor of internal medicine at the Medical University of Vienna, who presented the update at the annual European Congress of Rheumatology.

courtesy EULAR

More evidence supports the recommendation to start methotrexate plus glucocorticoids since this is not surpassed by several biologic DMARDs (bDMARDs) plus methotrexate, said Dr. Smolen, who spoke on behalf of his coauthors, Robert Landewe, MD, PhD, from Amsterdam Rheumatology and Clinical Immunology Center, and the rest of the Global Task Force for the 2022 Update of the EULAR RA-Management Recommendations.

In addition, “JAK [Janus kinase] inhibitors are now only recommended for patients who do not have risk factors for cardiovascular or malignant diseases, but otherwise they remain on the same level [phase 2] as bDMARDS,” he said.

“Registries hitherto do not observe what is reported in the ORAL Surveillance randomized controlled trial [RCT],” but, he added, “RCTs are the decisive studies and we await the baricitinib data on a similar population at risk.”

Dr. Smolen also noted that the ENTRACTE trial comparing tocilizumab with tumor necrosis factor (TNF)–alpha inhibitors did not report similar data as ORAL Surveillance.

“Tapering b/ts [biologic/targeted synthetic] and cs [conventional synthetic] DMARDs in sustained remission have been brought together with the need to discontinue glucocorticoids before other drugs are tapered has been more strongly emphasized,” he explained.

Most of the recommendations from the 2019 update remain unchanged, including all five overarching principles and 6 of the 12 individual items.

Rheumatologist Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, joined the meeting remotely and commented on the working draft of the treatment recommendations. “While much was retained from the previous version, there were several important updates,” he said. “Regarding the use of steroids, it is recommended that when they are used, they should be stopped as soon as possible. Regarding jakinibs, which EULAR considers as a class, they recommended consideration of risk factors for MACE events prior to their utilization,” he said.

Methotrexate plus glucocorticoids (Recommendation 6)

In recent years, many recommendations have suggested combining methotrexate with glucocorticoids as a first-treatment strategy upon diagnosis of RA, said Dr. Smolen, and initially “guidance from the ACR was in agreement.”

In 2021, however, “the ACR published a paper, albeit with a very low level of evidence, that one should not primarily use a combination of methotrexate plus glucocorticoids,” he added, with an emphasis on the “very low level of evidence.”

“Some people on the task force even interpreted it as being in favor of using expensive drugs,” he explained. “This needed to be addressed in the 2022 update.”

The global task force wanted to look further at the benefit-to-risk ratio, despite it being discussed in the 2019 recommendations. “We wanted to check that short-term use of glucocorticoids was not associated with major risks,” said Dr. Smolen. “Glucocorticoids are not used for a long time if used as a bridging therapy. We felt we had to more clearly define what we meant by short term.”

A systematic review of around 7,000 papers, led to consideration of 10 unique studies. “One study published a few years ago in PLOS One, did not find any evidence of increased cardiovascular risk,” Dr. Smolen reported, “however, use of over 1,000 mg of glucocorticoid was associated with a trend for high cardiovascular risk.”

“This trend was confirmed by data from the CorEvitas registry, which shows that up to 1,100 mg of cumulative dose was associated with no increased risk, but above this with increasing dose there was an increased and significant risk,” he added.

When the task force looked at trials that mandated and prespecified a reduction and stopping of glucocorticoids, they found less than 10% persistence of glucocorticoids at 12 months in all trials, some even reduced use to zero.

Dr. Smolen and colleagues also looked at data from the NORD-STAR trial, that compared methotrexate and glucocorticoids with methotrexate and three bDMARDs, namely an anti-TNF inhibitor, certolizumab pegol; anti–co-stimulation, abatacept; and an anti–interleukin-6 receptor, tocilizumab.

“These data prove the validity of the EULAR RA management recommendations regarding the unsurpassed benefit of methotrexate plus glucocorticoids in early RA,” Dr. Smolen said.

“This is confirmation of efficacy and that if you induce tapering and stopping it is not dangerous,” he added. “The level of evidence was very high, and it is the highest level of agreement we have had for any glucocorticoid recommendation over recent years.”

As such, Recommendation 6 says that shortening glucocorticoids should be considered when initiating or changing csDMARDS, in different dose regimens and routes of administration, but should be tapered and discontinued as rapidly as clinically feasible.
 

JAK inhibitor placed relative to DMARDs (Recommendation 10)

A paper published in the New England Journal of Medicine suggested cardiovascular risks and malignancy risks were higher with the JAK inhibitor, tofacitinib, compared with TNF-alpha inhibitors.

The task force therefore felt the need to evaluate the place of JAK inhibitors next to biologic DMARDs “once phase one with methotrexate plus glucocorticoids has failed,” Dr. Smolen said.

After a systematic literature review of around 4,500 papers, the researchers evaluated 88 safety papers including the ORAL Surveillance study. “This very clearly showed that tocilizumab was not noninferior according to the noninferiority criteria with an upper limit of 1.8 [hazard ratio] and this was independent of dose, compared with TNF-alpha inhibitor,” said Dr. Smolen. “The major adverse cardiovascular events [MACE] were not different, nor were malignancies and overall mortality.”

Dr. Smolen also referred to the ENTRACTE trial that compared etanercept with tocilizumab, and again, there was no evidence of an increased risk of MACE nor mortality for tocilizumab compared with a TNF-alpha inhibitor.

“The increased MACE risk in the ORAL Surveillance trial is unlikely due to inhibition of IL-6 and must be due to some other effects than IL-6 signaling,” he said.

As such, the agreed-on recommendation was that, “if the treatment target is not achieved with the first csDMARD strategy, when poor prognostic factors are present, a bDMARD should be added; JAK inhibitors may be considered but pertinent risk factors must be taken into account [aged over 65 years, history of current or past smoking, either cardiovascular or malignancy risk factors, and risk factors for thromboembolic events].”

There was a high level of agreement by the group for this recommendation.

Switching DMARDs

The task force considered their recommendations on switching DMARDs based on a systematic literature review of 47 papers.

EULAR previously strongly recommended a combination of csDMARDs with bDMARDs (including JAK inhibitors), and this recommendation remains the same except for a note added about risks of tsDMARDs.

Recommendation 10 relates to failure of phase 2 treatment and what to do when the first bDMARD or a tsDMARD has failed (including as per new recommendations, a JAK inhibitor), and if one TNF or IL-6 receptor inhibitor therapy has failed. In this case, patients may receive an agent with another mode of action or a second TNF/IL-6 receptor inhibitor, said Dr. Smolen.

Recommendation 11 has been combined with recommendation 12, he added. “If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, or tsDMARDs especially if this treatment is combined with a csDMARD.

“We decided to put more emphasis on the stopping of glucocorticoids, namely not saying ‘tapering’ but ‘discontinued,’ and if the patient is in sustained remission, then consider reduction of DMARDs [biologic, targeted synthetic or conventional synthetic DMARDs],” he explained. “This is left to the discretion of the patient and the physician as to which one should be tapered first. We don’t recommend to taper everything because the patient might be affected by flares but this needs further discussion.”

Dr. Smolen ended his presentation by looking ahead to the next set of recommendations: “With the current rate of evidence development, we expect an update of the recommendations to be necessary in about 3-4 years.”

This article was updated on 6/9/2022.

COPENHAGEN – New recommendations for the management of rheumatoid arthritis from the European Alliance of Associations for Rheumatology suggest starting short-term methotrexate and glucocorticoids when starting or changing conventional synthetic disease-modifying antirheumatic drugs (DMARDs), although rapid glucocorticoid dose reduction and discontinuation is also emphasized.

“In this respect we are at odds with the American College of Rheumatology guideline,” said Josef S. Smolen, MD, professor of internal medicine at the Medical University of Vienna, who presented the update at the annual European Congress of Rheumatology.

courtesy EULAR

More evidence supports the recommendation to start methotrexate plus glucocorticoids since this is not surpassed by several biologic DMARDs (bDMARDs) plus methotrexate, said Dr. Smolen, who spoke on behalf of his coauthors, Robert Landewe, MD, PhD, from Amsterdam Rheumatology and Clinical Immunology Center, and the rest of the Global Task Force for the 2022 Update of the EULAR RA-Management Recommendations.

In addition, “JAK [Janus kinase] inhibitors are now only recommended for patients who do not have risk factors for cardiovascular or malignant diseases, but otherwise they remain on the same level [phase 2] as bDMARDS,” he said.

“Registries hitherto do not observe what is reported in the ORAL Surveillance randomized controlled trial [RCT],” but, he added, “RCTs are the decisive studies and we await the baricitinib data on a similar population at risk.”

Dr. Smolen also noted that the ENTRACTE trial comparing tocilizumab with tumor necrosis factor (TNF)–alpha inhibitors did not report similar data as ORAL Surveillance.

“Tapering b/ts [biologic/targeted synthetic] and cs [conventional synthetic] DMARDs in sustained remission have been brought together with the need to discontinue glucocorticoids before other drugs are tapered has been more strongly emphasized,” he explained.

Most of the recommendations from the 2019 update remain unchanged, including all five overarching principles and 6 of the 12 individual items.

Rheumatologist Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, joined the meeting remotely and commented on the working draft of the treatment recommendations. “While much was retained from the previous version, there were several important updates,” he said. “Regarding the use of steroids, it is recommended that when they are used, they should be stopped as soon as possible. Regarding jakinibs, which EULAR considers as a class, they recommended consideration of risk factors for MACE events prior to their utilization,” he said.

Methotrexate plus glucocorticoids (Recommendation 6)

In recent years, many recommendations have suggested combining methotrexate with glucocorticoids as a first-treatment strategy upon diagnosis of RA, said Dr. Smolen, and initially “guidance from the ACR was in agreement.”

In 2021, however, “the ACR published a paper, albeit with a very low level of evidence, that one should not primarily use a combination of methotrexate plus glucocorticoids,” he added, with an emphasis on the “very low level of evidence.”

“Some people on the task force even interpreted it as being in favor of using expensive drugs,” he explained. “This needed to be addressed in the 2022 update.”

The global task force wanted to look further at the benefit-to-risk ratio, despite it being discussed in the 2019 recommendations. “We wanted to check that short-term use of glucocorticoids was not associated with major risks,” said Dr. Smolen. “Glucocorticoids are not used for a long time if used as a bridging therapy. We felt we had to more clearly define what we meant by short term.”

A systematic review of around 7,000 papers, led to consideration of 10 unique studies. “One study published a few years ago in PLOS One, did not find any evidence of increased cardiovascular risk,” Dr. Smolen reported, “however, use of over 1,000 mg of glucocorticoid was associated with a trend for high cardiovascular risk.”

“This trend was confirmed by data from the CorEvitas registry, which shows that up to 1,100 mg of cumulative dose was associated with no increased risk, but above this with increasing dose there was an increased and significant risk,” he added.

When the task force looked at trials that mandated and prespecified a reduction and stopping of glucocorticoids, they found less than 10% persistence of glucocorticoids at 12 months in all trials, some even reduced use to zero.

Dr. Smolen and colleagues also looked at data from the NORD-STAR trial, that compared methotrexate and glucocorticoids with methotrexate and three bDMARDs, namely an anti-TNF inhibitor, certolizumab pegol; anti–co-stimulation, abatacept; and an anti–interleukin-6 receptor, tocilizumab.

“These data prove the validity of the EULAR RA management recommendations regarding the unsurpassed benefit of methotrexate plus glucocorticoids in early RA,” Dr. Smolen said.

“This is confirmation of efficacy and that if you induce tapering and stopping it is not dangerous,” he added. “The level of evidence was very high, and it is the highest level of agreement we have had for any glucocorticoid recommendation over recent years.”

As such, Recommendation 6 says that shortening glucocorticoids should be considered when initiating or changing csDMARDS, in different dose regimens and routes of administration, but should be tapered and discontinued as rapidly as clinically feasible.
 

JAK inhibitor placed relative to DMARDs (Recommendation 10)

A paper published in the New England Journal of Medicine suggested cardiovascular risks and malignancy risks were higher with the JAK inhibitor, tofacitinib, compared with TNF-alpha inhibitors.

The task force therefore felt the need to evaluate the place of JAK inhibitors next to biologic DMARDs “once phase one with methotrexate plus glucocorticoids has failed,” Dr. Smolen said.

After a systematic literature review of around 4,500 papers, the researchers evaluated 88 safety papers including the ORAL Surveillance study. “This very clearly showed that tocilizumab was not noninferior according to the noninferiority criteria with an upper limit of 1.8 [hazard ratio] and this was independent of dose, compared with TNF-alpha inhibitor,” said Dr. Smolen. “The major adverse cardiovascular events [MACE] were not different, nor were malignancies and overall mortality.”

Dr. Smolen also referred to the ENTRACTE trial that compared etanercept with tocilizumab, and again, there was no evidence of an increased risk of MACE nor mortality for tocilizumab compared with a TNF-alpha inhibitor.

“The increased MACE risk in the ORAL Surveillance trial is unlikely due to inhibition of IL-6 and must be due to some other effects than IL-6 signaling,” he said.

As such, the agreed-on recommendation was that, “if the treatment target is not achieved with the first csDMARD strategy, when poor prognostic factors are present, a bDMARD should be added; JAK inhibitors may be considered but pertinent risk factors must be taken into account [aged over 65 years, history of current or past smoking, either cardiovascular or malignancy risk factors, and risk factors for thromboembolic events].”

There was a high level of agreement by the group for this recommendation.

Switching DMARDs

The task force considered their recommendations on switching DMARDs based on a systematic literature review of 47 papers.

EULAR previously strongly recommended a combination of csDMARDs with bDMARDs (including JAK inhibitors), and this recommendation remains the same except for a note added about risks of tsDMARDs.

Recommendation 10 relates to failure of phase 2 treatment and what to do when the first bDMARD or a tsDMARD has failed (including as per new recommendations, a JAK inhibitor), and if one TNF or IL-6 receptor inhibitor therapy has failed. In this case, patients may receive an agent with another mode of action or a second TNF/IL-6 receptor inhibitor, said Dr. Smolen.

Recommendation 11 has been combined with recommendation 12, he added. “If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, or tsDMARDs especially if this treatment is combined with a csDMARD.

“We decided to put more emphasis on the stopping of glucocorticoids, namely not saying ‘tapering’ but ‘discontinued,’ and if the patient is in sustained remission, then consider reduction of DMARDs [biologic, targeted synthetic or conventional synthetic DMARDs],” he explained. “This is left to the discretion of the patient and the physician as to which one should be tapered first. We don’t recommend to taper everything because the patient might be affected by flares but this needs further discussion.”

Dr. Smolen ended his presentation by looking ahead to the next set of recommendations: “With the current rate of evidence development, we expect an update of the recommendations to be necessary in about 3-4 years.”

This article was updated on 6/9/2022.

COPENHAGEN – New recommendations for the management of rheumatoid arthritis from the European Alliance of Associations for Rheumatology suggest starting short-term methotrexate and glucocorticoids when starting or changing conventional synthetic disease-modifying antirheumatic drugs (DMARDs), although rapid glucocorticoid dose reduction and discontinuation is also emphasized.

“In this respect we are at odds with the American College of Rheumatology guideline,” said Josef S. Smolen, MD, professor of internal medicine at the Medical University of Vienna, who presented the update at the annual European Congress of Rheumatology.

courtesy EULAR

More evidence supports the recommendation to start methotrexate plus glucocorticoids since this is not surpassed by several biologic DMARDs (bDMARDs) plus methotrexate, said Dr. Smolen, who spoke on behalf of his coauthors, Robert Landewe, MD, PhD, from Amsterdam Rheumatology and Clinical Immunology Center, and the rest of the Global Task Force for the 2022 Update of the EULAR RA-Management Recommendations.

In addition, “JAK [Janus kinase] inhibitors are now only recommended for patients who do not have risk factors for cardiovascular or malignant diseases, but otherwise they remain on the same level [phase 2] as bDMARDS,” he said.

“Registries hitherto do not observe what is reported in the ORAL Surveillance randomized controlled trial [RCT],” but, he added, “RCTs are the decisive studies and we await the baricitinib data on a similar population at risk.”

Dr. Smolen also noted that the ENTRACTE trial comparing tocilizumab with tumor necrosis factor (TNF)–alpha inhibitors did not report similar data as ORAL Surveillance.

“Tapering b/ts [biologic/targeted synthetic] and cs [conventional synthetic] DMARDs in sustained remission have been brought together with the need to discontinue glucocorticoids before other drugs are tapered has been more strongly emphasized,” he explained.

Most of the recommendations from the 2019 update remain unchanged, including all five overarching principles and 6 of the 12 individual items.

Rheumatologist Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, joined the meeting remotely and commented on the working draft of the treatment recommendations. “While much was retained from the previous version, there were several important updates,” he said. “Regarding the use of steroids, it is recommended that when they are used, they should be stopped as soon as possible. Regarding jakinibs, which EULAR considers as a class, they recommended consideration of risk factors for MACE events prior to their utilization,” he said.

Methotrexate plus glucocorticoids (Recommendation 6)

In recent years, many recommendations have suggested combining methotrexate with glucocorticoids as a first-treatment strategy upon diagnosis of RA, said Dr. Smolen, and initially “guidance from the ACR was in agreement.”

In 2021, however, “the ACR published a paper, albeit with a very low level of evidence, that one should not primarily use a combination of methotrexate plus glucocorticoids,” he added, with an emphasis on the “very low level of evidence.”

“Some people on the task force even interpreted it as being in favor of using expensive drugs,” he explained. “This needed to be addressed in the 2022 update.”

The global task force wanted to look further at the benefit-to-risk ratio, despite it being discussed in the 2019 recommendations. “We wanted to check that short-term use of glucocorticoids was not associated with major risks,” said Dr. Smolen. “Glucocorticoids are not used for a long time if used as a bridging therapy. We felt we had to more clearly define what we meant by short term.”

A systematic review of around 7,000 papers, led to consideration of 10 unique studies. “One study published a few years ago in PLOS One, did not find any evidence of increased cardiovascular risk,” Dr. Smolen reported, “however, use of over 1,000 mg of glucocorticoid was associated with a trend for high cardiovascular risk.”

“This trend was confirmed by data from the CorEvitas registry, which shows that up to 1,100 mg of cumulative dose was associated with no increased risk, but above this with increasing dose there was an increased and significant risk,” he added.

When the task force looked at trials that mandated and prespecified a reduction and stopping of glucocorticoids, they found less than 10% persistence of glucocorticoids at 12 months in all trials, some even reduced use to zero.

Dr. Smolen and colleagues also looked at data from the NORD-STAR trial, that compared methotrexate and glucocorticoids with methotrexate and three bDMARDs, namely an anti-TNF inhibitor, certolizumab pegol; anti–co-stimulation, abatacept; and an anti–interleukin-6 receptor, tocilizumab.

“These data prove the validity of the EULAR RA management recommendations regarding the unsurpassed benefit of methotrexate plus glucocorticoids in early RA,” Dr. Smolen said.

“This is confirmation of efficacy and that if you induce tapering and stopping it is not dangerous,” he added. “The level of evidence was very high, and it is the highest level of agreement we have had for any glucocorticoid recommendation over recent years.”

As such, Recommendation 6 says that shortening glucocorticoids should be considered when initiating or changing csDMARDS, in different dose regimens and routes of administration, but should be tapered and discontinued as rapidly as clinically feasible.
 

JAK inhibitor placed relative to DMARDs (Recommendation 10)

A paper published in the New England Journal of Medicine suggested cardiovascular risks and malignancy risks were higher with the JAK inhibitor, tofacitinib, compared with TNF-alpha inhibitors.

The task force therefore felt the need to evaluate the place of JAK inhibitors next to biologic DMARDs “once phase one with methotrexate plus glucocorticoids has failed,” Dr. Smolen said.

After a systematic literature review of around 4,500 papers, the researchers evaluated 88 safety papers including the ORAL Surveillance study. “This very clearly showed that tocilizumab was not noninferior according to the noninferiority criteria with an upper limit of 1.8 [hazard ratio] and this was independent of dose, compared with TNF-alpha inhibitor,” said Dr. Smolen. “The major adverse cardiovascular events [MACE] were not different, nor were malignancies and overall mortality.”

Dr. Smolen also referred to the ENTRACTE trial that compared etanercept with tocilizumab, and again, there was no evidence of an increased risk of MACE nor mortality for tocilizumab compared with a TNF-alpha inhibitor.

“The increased MACE risk in the ORAL Surveillance trial is unlikely due to inhibition of IL-6 and must be due to some other effects than IL-6 signaling,” he said.

As such, the agreed-on recommendation was that, “if the treatment target is not achieved with the first csDMARD strategy, when poor prognostic factors are present, a bDMARD should be added; JAK inhibitors may be considered but pertinent risk factors must be taken into account [aged over 65 years, history of current or past smoking, either cardiovascular or malignancy risk factors, and risk factors for thromboembolic events].”

There was a high level of agreement by the group for this recommendation.

Switching DMARDs

The task force considered their recommendations on switching DMARDs based on a systematic literature review of 47 papers.

EULAR previously strongly recommended a combination of csDMARDs with bDMARDs (including JAK inhibitors), and this recommendation remains the same except for a note added about risks of tsDMARDs.

Recommendation 10 relates to failure of phase 2 treatment and what to do when the first bDMARD or a tsDMARD has failed (including as per new recommendations, a JAK inhibitor), and if one TNF or IL-6 receptor inhibitor therapy has failed. In this case, patients may receive an agent with another mode of action or a second TNF/IL-6 receptor inhibitor, said Dr. Smolen.

Recommendation 11 has been combined with recommendation 12, he added. “If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, or tsDMARDs especially if this treatment is combined with a csDMARD.

“We decided to put more emphasis on the stopping of glucocorticoids, namely not saying ‘tapering’ but ‘discontinued,’ and if the patient is in sustained remission, then consider reduction of DMARDs [biologic, targeted synthetic or conventional synthetic DMARDs],” he explained. “This is left to the discretion of the patient and the physician as to which one should be tapered first. We don’t recommend to taper everything because the patient might be affected by flares but this needs further discussion.”

Dr. Smolen ended his presentation by looking ahead to the next set of recommendations: “With the current rate of evidence development, we expect an update of the recommendations to be necessary in about 3-4 years.”

This article was updated on 6/9/2022.

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

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

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

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

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

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

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

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

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

Obstetrician Beverly Gray, MD, is already seeing the effects of the Roe v. Wade abortion debate in her North Carolina practice.

The state allows abortion but requires that women get counseling with a qualified health professional 72 hours before the procedure. “Aside from that, we still have patients asking for more efficacious contraceptive methods just in case,” said Dr. Gray, residency director and division director for women’s community and population health and associate professor for obstetrics and gynecology at Duke University, Durham, N.C.

Patients and staff in her clinic have also been approaching her about tubal ligation. “They’re asking about additional birth control methods because they’re concerned about what’s going to happen” with the challenge to the historic Roe v. Wade decision in the Supreme Court and subsequent actions in the states to restrict or ban abortion, she said.

This has implications not just for abortion but for medications known to affect pregnancy. “What I’m really worried about is physicians will be withholding medicine because they’re concerned about teratogenic effects,” said Dr. Gray.

With more states issuing restrictions on abortion, doctors are worried that patients needing certain drugs to maintain their lupus flares, cancer, or other diseases may decide not to take them in the event they accidentally become pregnant. If the drug is known to affect the fetus, the fear is a patient who lives in a state with abortion restrictions will no longer have the option to terminate a pregnancy.

zoranm/Getty Images

The U.S. landscape on abortion restrictions

A leaked draft of a U.S. Supreme Court opinion on Mississippi’s 15-week abortion ban has sent the medical community into a tailspin. The case, Dobbs v. Jackson Women’s Health Organization, challenges the 1973 Roe v. Wade decision that affirms the constitutional right to abortion. It’s anticipated the high court will decide on the case in June.

Although the upcoming decision is subject to change, the draft indicated the high court would uphold the Mississippi ban. This would essentially overturn the 1973 ruling. An earlier Supreme Court decision allowing a Texas law banning abortion at 6 weeks suggests the court may already be heading in this direction. At the state level, legislatures have been moving on divergent paths – some taking steps to preserve abortion rights, others initiating restrictions.

More than 100 abortion restrictions in 19 states took effect in 2021, according to the Guttmacher Institute, which tracks such metrics. In 2022, “two key themes are anti-abortion policymakers’ continued pursuit of various types of abortion bans and restrictions on medication abortion,” the institute reported.

Forty-six states and the District of Columbia have introduced 2,025 restrictions or proactive measures on sexual and reproductive health and rights so far this year. The latest tally from Guttmacher, updated in late May, revealed that 11 states so far have enacted 42 abortion restrictions. A total of 6 states (Arizona, Florida, Idaho, Kentucky, Oklahoma, and Wyoming) have issued nine bans on abortion.

Comparatively, 11 states have enacted 19 protective abortion measures.

Twenty-two states have introduced 117 restrictions on medication abortions, which account for 54% of U.S. abortions. This includes seven measures that would ban medication abortion outright, according to Guttmacher. Kentucky and South Dakota collectively have enacted 14 restrictions on medication abortion, as well as provisions that ban mailing of abortion pills.
 

Chilling effect on prescribing

Some physicians anticipate that drugs such as the “morning-after” pill (levonorgestrel) will become less available as restrictions go into effect, since these are medications designed to prevent pregnancy.*

However, the ongoing effort to put a lid on abortion measures has prompted concerns about a trickle-down effect on other medications that are otherwise life-changing or lifesaving to patients but pose a risk to the fetus.

Several drugs are well documented to affect fetal growth and development of the fetus, ranging from mild, transitory effects to severe, permanent birth defects, said Ronald G. Grifka, MD, chief medical officer of University of Michigan Health-West and clinical professor of pediatrics at the University of Michigan Medical School, Ann Arbor. “As new medications are developed, we will need heightened attention to make sure they are safe for the fetus,” he added.

Christina Chambers

The iPLEDGE factor

Some rheumatology drugs like lenalidomide (Revlimid) require a valid negative pregnancy test in a lab every month. Similarly, the iPLEDGE Risk Evaluation and Mitigation Strategy seeks to reduce the teratogenicity of isotretinoin by requiring two types of birth control and regular pregnancy tests by users.

For isotretinoin specifically, abortion restrictions “could lead to increased adherence to pregnancy prevention measures which are already stringent in iPLEDGE. But on the other hand, it could lead to reduced willingness of physicians to prescribe or patients to take the medication,” said Dr. Chambers.

With programs like iPLEDGE in effect, the rate of pregnancies and abortions that occur in dermatology are relatively low, said Jenny Murase, MD, associate clinical professor of dermatology at the University of California, San Francisco.

Fewer women in clinical trials?

Abortion restrictions could possibly discourage women of reproductive age to participate in a clinical trial for a new medication, said Dr. Chambers.

A female patient with a chronic disease who’s randomized to receive a new medication may be required to use certain types of birth control because of unknown potential adverse effects the drug may have on the fetus. But in some cases, accidental pregnancies happen.

The participant in the trial may say, “I don’t know enough about the safety of this drug in pregnancy, and I’ve already taken it. I want to terminate the pregnancy,” said Dr. Chambers. Thinking ahead, a woman may decide not to do the trial to avoid the risk of getting pregnant and not having the option to terminate the pregnancy.

This could apply to new drugs such as antiviral treatments, or medications for severe chronic disease that typically have no clinical trial data in pregnancy prior to initial release into the market.

Women may start taking the drug without thinking about getting pregnant, then realize there are no safety data and become concerned about its effects on a future pregnancy.

The question is: Will abortion restrictions have a chilling effect on these new drugs as well? Patients and their doctors may decide not to try it until more data are available. “I can see where abortion restrictions would change the risk or benefit calculation in thinking about what you do or don’t prescribe or take during reproductive age,” said Dr. Chambers.
 

The upside of restrictions?

If there’s a positive side to these developments with abortion bans, it may encourage women taking new medications or joining clinical trials to think even more carefully about adherence to effective contraception, said Dr. Chambers.

Some methods are more effective than others, she emphasized. “When you have an unplanned pregnancy, it could mean that the method you used wasn’t optimal or you weren’t using it as recommended.” A goal moving forward is to encourage more thoughtful use of highly effective contraceptives, thus reducing the number of unplanned pregnancies, she added.

If patients are taking methotrexate, “the time to think about pregnancy is before getting pregnant so you can switch to a drug that’s compatible with pregnancy,” she said.

This whole thought process regarding pregnancy planning could work toward useful health goals, said Dr. Chambers. “Nobody thinks termination is the preferred method, but planning ahead should involve a discussion of what works best for the patient.”

Patients do have other choices, said Dr. Grifka. “Fortunately, there are many commonly prescribed medications which cross the placenta and have no ill effects on the fetus.”

Talking to patients about choices

Dr. Clowse, who spends a lot of time training rheumatologists, encourages them to have conversations with patients about pregnancy planning. It’s a lot to manage, getting the right drug to a female patient with chronic illness, especially in this current climate of abortion upheaval, she noted.

Her approach is to have an open and honest conversation with patients about their concerns and fears, what the realities are, and what the potential future options are for certain rheumatology drugs in the United States.

Some women who see what’s happening across the country may become so risk averse that they may choose to die rather than take a lifesaving drug that poses certain risks under new restrictions.

“I think that’s tragic,” said Dr. Clowse.

To help their patients, Dr. Gray believes physicians across specialties should better educate themselves about physiology in pregnancy and how to counsel patients on the impact of not taking medications in pregnancy.

In her view, it’s almost coercive to say to a patient, “You really need to have effective contraception if I’m going to give you this lifesaving or quality-of-life-improving medication.”

When confronting such scenarios, Dr. Gray doesn’t think physicians need to change how they counsel patients about contraception. “I don’t think we should be putting pressure on patients to consider other permanent methods just because there’s a lack of abortion options.”

Patients will eventually make those decisions for themselves, she said. “They’re going to want a more efficacious method because they’re worried about not having access to abortion if they get pregnant.”

Dr. Gray reports being a site principal investigator for a phase 3 trial for VeraCept IUD, funded by Sebela Pharmaceuticals. Dr. Clowse reports receiving research funding and doing consulting for GlaxoSmithKline.

*Correction, 6/2/2022: A previous version of this article misstated the intended use of drugs such as the “morning-after” pill (levonorgestrel). They are taken to prevent unintended pregnancy.

A version of this article first appeared on Medscape.com .

Obstetrician Beverly Gray, MD, is already seeing the effects of the Roe v. Wade abortion debate in her North Carolina practice.

The state allows abortion but requires that women get counseling with a qualified health professional 72 hours before the procedure. “Aside from that, we still have patients asking for more efficacious contraceptive methods just in case,” said Dr. Gray, residency director and division director for women’s community and population health and associate professor for obstetrics and gynecology at Duke University, Durham, N.C.

Patients and staff in her clinic have also been approaching her about tubal ligation. “They’re asking about additional birth control methods because they’re concerned about what’s going to happen” with the challenge to the historic Roe v. Wade decision in the Supreme Court and subsequent actions in the states to restrict or ban abortion, she said.

This has implications not just for abortion but for medications known to affect pregnancy. “What I’m really worried about is physicians will be withholding medicine because they’re concerned about teratogenic effects,” said Dr. Gray.

With more states issuing restrictions on abortion, doctors are worried that patients needing certain drugs to maintain their lupus flares, cancer, or other diseases may decide not to take them in the event they accidentally become pregnant. If the drug is known to affect the fetus, the fear is a patient who lives in a state with abortion restrictions will no longer have the option to terminate a pregnancy.

zoranm/Getty Images

The U.S. landscape on abortion restrictions

A leaked draft of a U.S. Supreme Court opinion on Mississippi’s 15-week abortion ban has sent the medical community into a tailspin. The case, Dobbs v. Jackson Women’s Health Organization, challenges the 1973 Roe v. Wade decision that affirms the constitutional right to abortion. It’s anticipated the high court will decide on the case in June.

Although the upcoming decision is subject to change, the draft indicated the high court would uphold the Mississippi ban. This would essentially overturn the 1973 ruling. An earlier Supreme Court decision allowing a Texas law banning abortion at 6 weeks suggests the court may already be heading in this direction. At the state level, legislatures have been moving on divergent paths – some taking steps to preserve abortion rights, others initiating restrictions.

More than 100 abortion restrictions in 19 states took effect in 2021, according to the Guttmacher Institute, which tracks such metrics. In 2022, “two key themes are anti-abortion policymakers’ continued pursuit of various types of abortion bans and restrictions on medication abortion,” the institute reported.

Forty-six states and the District of Columbia have introduced 2,025 restrictions or proactive measures on sexual and reproductive health and rights so far this year. The latest tally from Guttmacher, updated in late May, revealed that 11 states so far have enacted 42 abortion restrictions. A total of 6 states (Arizona, Florida, Idaho, Kentucky, Oklahoma, and Wyoming) have issued nine bans on abortion.

Comparatively, 11 states have enacted 19 protective abortion measures.

Twenty-two states have introduced 117 restrictions on medication abortions, which account for 54% of U.S. abortions. This includes seven measures that would ban medication abortion outright, according to Guttmacher. Kentucky and South Dakota collectively have enacted 14 restrictions on medication abortion, as well as provisions that ban mailing of abortion pills.
 

Chilling effect on prescribing

Some physicians anticipate that drugs such as the “morning-after” pill (levonorgestrel) will become less available as restrictions go into effect, since these are medications designed to prevent pregnancy.*

However, the ongoing effort to put a lid on abortion measures has prompted concerns about a trickle-down effect on other medications that are otherwise life-changing or lifesaving to patients but pose a risk to the fetus.

Several drugs are well documented to affect fetal growth and development of the fetus, ranging from mild, transitory effects to severe, permanent birth defects, said Ronald G. Grifka, MD, chief medical officer of University of Michigan Health-West and clinical professor of pediatrics at the University of Michigan Medical School, Ann Arbor. “As new medications are developed, we will need heightened attention to make sure they are safe for the fetus,” he added.

Christina Chambers

The iPLEDGE factor

Some rheumatology drugs like lenalidomide (Revlimid) require a valid negative pregnancy test in a lab every month. Similarly, the iPLEDGE Risk Evaluation and Mitigation Strategy seeks to reduce the teratogenicity of isotretinoin by requiring two types of birth control and regular pregnancy tests by users.

For isotretinoin specifically, abortion restrictions “could lead to increased adherence to pregnancy prevention measures which are already stringent in iPLEDGE. But on the other hand, it could lead to reduced willingness of physicians to prescribe or patients to take the medication,” said Dr. Chambers.

With programs like iPLEDGE in effect, the rate of pregnancies and abortions that occur in dermatology are relatively low, said Jenny Murase, MD, associate clinical professor of dermatology at the University of California, San Francisco.

Fewer women in clinical trials?

Abortion restrictions could possibly discourage women of reproductive age to participate in a clinical trial for a new medication, said Dr. Chambers.

A female patient with a chronic disease who’s randomized to receive a new medication may be required to use certain types of birth control because of unknown potential adverse effects the drug may have on the fetus. But in some cases, accidental pregnancies happen.

The participant in the trial may say, “I don’t know enough about the safety of this drug in pregnancy, and I’ve already taken it. I want to terminate the pregnancy,” said Dr. Chambers. Thinking ahead, a woman may decide not to do the trial to avoid the risk of getting pregnant and not having the option to terminate the pregnancy.

This could apply to new drugs such as antiviral treatments, or medications for severe chronic disease that typically have no clinical trial data in pregnancy prior to initial release into the market.

Women may start taking the drug without thinking about getting pregnant, then realize there are no safety data and become concerned about its effects on a future pregnancy.

The question is: Will abortion restrictions have a chilling effect on these new drugs as well? Patients and their doctors may decide not to try it until more data are available. “I can see where abortion restrictions would change the risk or benefit calculation in thinking about what you do or don’t prescribe or take during reproductive age,” said Dr. Chambers.
 

The upside of restrictions?

If there’s a positive side to these developments with abortion bans, it may encourage women taking new medications or joining clinical trials to think even more carefully about adherence to effective contraception, said Dr. Chambers.

Some methods are more effective than others, she emphasized. “When you have an unplanned pregnancy, it could mean that the method you used wasn’t optimal or you weren’t using it as recommended.” A goal moving forward is to encourage more thoughtful use of highly effective contraceptives, thus reducing the number of unplanned pregnancies, she added.

If patients are taking methotrexate, “the time to think about pregnancy is before getting pregnant so you can switch to a drug that’s compatible with pregnancy,” she said.

This whole thought process regarding pregnancy planning could work toward useful health goals, said Dr. Chambers. “Nobody thinks termination is the preferred method, but planning ahead should involve a discussion of what works best for the patient.”

Patients do have other choices, said Dr. Grifka. “Fortunately, there are many commonly prescribed medications which cross the placenta and have no ill effects on the fetus.”

Talking to patients about choices

Dr. Clowse, who spends a lot of time training rheumatologists, encourages them to have conversations with patients about pregnancy planning. It’s a lot to manage, getting the right drug to a female patient with chronic illness, especially in this current climate of abortion upheaval, she noted.

Her approach is to have an open and honest conversation with patients about their concerns and fears, what the realities are, and what the potential future options are for certain rheumatology drugs in the United States.

Some women who see what’s happening across the country may become so risk averse that they may choose to die rather than take a lifesaving drug that poses certain risks under new restrictions.

“I think that’s tragic,” said Dr. Clowse.

To help their patients, Dr. Gray believes physicians across specialties should better educate themselves about physiology in pregnancy and how to counsel patients on the impact of not taking medications in pregnancy.

In her view, it’s almost coercive to say to a patient, “You really need to have effective contraception if I’m going to give you this lifesaving or quality-of-life-improving medication.”

When confronting such scenarios, Dr. Gray doesn’t think physicians need to change how they counsel patients about contraception. “I don’t think we should be putting pressure on patients to consider other permanent methods just because there’s a lack of abortion options.”

Patients will eventually make those decisions for themselves, she said. “They’re going to want a more efficacious method because they’re worried about not having access to abortion if they get pregnant.”

Dr. Gray reports being a site principal investigator for a phase 3 trial for VeraCept IUD, funded by Sebela Pharmaceuticals. Dr. Clowse reports receiving research funding and doing consulting for GlaxoSmithKline.

*Correction, 6/2/2022: A previous version of this article misstated the intended use of drugs such as the “morning-after” pill (levonorgestrel). They are taken to prevent unintended pregnancy.

A version of this article first appeared on Medscape.com .

Obstetrician Beverly Gray, MD, is already seeing the effects of the Roe v. Wade abortion debate in her North Carolina practice.

The state allows abortion but requires that women get counseling with a qualified health professional 72 hours before the procedure. “Aside from that, we still have patients asking for more efficacious contraceptive methods just in case,” said Dr. Gray, residency director and division director for women’s community and population health and associate professor for obstetrics and gynecology at Duke University, Durham, N.C.

Patients and staff in her clinic have also been approaching her about tubal ligation. “They’re asking about additional birth control methods because they’re concerned about what’s going to happen” with the challenge to the historic Roe v. Wade decision in the Supreme Court and subsequent actions in the states to restrict or ban abortion, she said.

This has implications not just for abortion but for medications known to affect pregnancy. “What I’m really worried about is physicians will be withholding medicine because they’re concerned about teratogenic effects,” said Dr. Gray.

With more states issuing restrictions on abortion, doctors are worried that patients needing certain drugs to maintain their lupus flares, cancer, or other diseases may decide not to take them in the event they accidentally become pregnant. If the drug is known to affect the fetus, the fear is a patient who lives in a state with abortion restrictions will no longer have the option to terminate a pregnancy.

zoranm/Getty Images

The U.S. landscape on abortion restrictions

A leaked draft of a U.S. Supreme Court opinion on Mississippi’s 15-week abortion ban has sent the medical community into a tailspin. The case, Dobbs v. Jackson Women’s Health Organization, challenges the 1973 Roe v. Wade decision that affirms the constitutional right to abortion. It’s anticipated the high court will decide on the case in June.

Although the upcoming decision is subject to change, the draft indicated the high court would uphold the Mississippi ban. This would essentially overturn the 1973 ruling. An earlier Supreme Court decision allowing a Texas law banning abortion at 6 weeks suggests the court may already be heading in this direction. At the state level, legislatures have been moving on divergent paths – some taking steps to preserve abortion rights, others initiating restrictions.

More than 100 abortion restrictions in 19 states took effect in 2021, according to the Guttmacher Institute, which tracks such metrics. In 2022, “two key themes are anti-abortion policymakers’ continued pursuit of various types of abortion bans and restrictions on medication abortion,” the institute reported.

Forty-six states and the District of Columbia have introduced 2,025 restrictions or proactive measures on sexual and reproductive health and rights so far this year. The latest tally from Guttmacher, updated in late May, revealed that 11 states so far have enacted 42 abortion restrictions. A total of 6 states (Arizona, Florida, Idaho, Kentucky, Oklahoma, and Wyoming) have issued nine bans on abortion.

Comparatively, 11 states have enacted 19 protective abortion measures.

Twenty-two states have introduced 117 restrictions on medication abortions, which account for 54% of U.S. abortions. This includes seven measures that would ban medication abortion outright, according to Guttmacher. Kentucky and South Dakota collectively have enacted 14 restrictions on medication abortion, as well as provisions that ban mailing of abortion pills.
 

Chilling effect on prescribing

Some physicians anticipate that drugs such as the “morning-after” pill (levonorgestrel) will become less available as restrictions go into effect, since these are medications designed to prevent pregnancy.*

However, the ongoing effort to put a lid on abortion measures has prompted concerns about a trickle-down effect on other medications that are otherwise life-changing or lifesaving to patients but pose a risk to the fetus.

Several drugs are well documented to affect fetal growth and development of the fetus, ranging from mild, transitory effects to severe, permanent birth defects, said Ronald G. Grifka, MD, chief medical officer of University of Michigan Health-West and clinical professor of pediatrics at the University of Michigan Medical School, Ann Arbor. “As new medications are developed, we will need heightened attention to make sure they are safe for the fetus,” he added.

Christina Chambers

The iPLEDGE factor

Some rheumatology drugs like lenalidomide (Revlimid) require a valid negative pregnancy test in a lab every month. Similarly, the iPLEDGE Risk Evaluation and Mitigation Strategy seeks to reduce the teratogenicity of isotretinoin by requiring two types of birth control and regular pregnancy tests by users.

For isotretinoin specifically, abortion restrictions “could lead to increased adherence to pregnancy prevention measures which are already stringent in iPLEDGE. But on the other hand, it could lead to reduced willingness of physicians to prescribe or patients to take the medication,” said Dr. Chambers.

With programs like iPLEDGE in effect, the rate of pregnancies and abortions that occur in dermatology are relatively low, said Jenny Murase, MD, associate clinical professor of dermatology at the University of California, San Francisco.

Fewer women in clinical trials?

Abortion restrictions could possibly discourage women of reproductive age to participate in a clinical trial for a new medication, said Dr. Chambers.

A female patient with a chronic disease who’s randomized to receive a new medication may be required to use certain types of birth control because of unknown potential adverse effects the drug may have on the fetus. But in some cases, accidental pregnancies happen.

The participant in the trial may say, “I don’t know enough about the safety of this drug in pregnancy, and I’ve already taken it. I want to terminate the pregnancy,” said Dr. Chambers. Thinking ahead, a woman may decide not to do the trial to avoid the risk of getting pregnant and not having the option to terminate the pregnancy.

This could apply to new drugs such as antiviral treatments, or medications for severe chronic disease that typically have no clinical trial data in pregnancy prior to initial release into the market.

Women may start taking the drug without thinking about getting pregnant, then realize there are no safety data and become concerned about its effects on a future pregnancy.

The question is: Will abortion restrictions have a chilling effect on these new drugs as well? Patients and their doctors may decide not to try it until more data are available. “I can see where abortion restrictions would change the risk or benefit calculation in thinking about what you do or don’t prescribe or take during reproductive age,” said Dr. Chambers.
 

The upside of restrictions?

If there’s a positive side to these developments with abortion bans, it may encourage women taking new medications or joining clinical trials to think even more carefully about adherence to effective contraception, said Dr. Chambers.

Some methods are more effective than others, she emphasized. “When you have an unplanned pregnancy, it could mean that the method you used wasn’t optimal or you weren’t using it as recommended.” A goal moving forward is to encourage more thoughtful use of highly effective contraceptives, thus reducing the number of unplanned pregnancies, she added.

If patients are taking methotrexate, “the time to think about pregnancy is before getting pregnant so you can switch to a drug that’s compatible with pregnancy,” she said.

This whole thought process regarding pregnancy planning could work toward useful health goals, said Dr. Chambers. “Nobody thinks termination is the preferred method, but planning ahead should involve a discussion of what works best for the patient.”

Patients do have other choices, said Dr. Grifka. “Fortunately, there are many commonly prescribed medications which cross the placenta and have no ill effects on the fetus.”

Talking to patients about choices

Dr. Clowse, who spends a lot of time training rheumatologists, encourages them to have conversations with patients about pregnancy planning. It’s a lot to manage, getting the right drug to a female patient with chronic illness, especially in this current climate of abortion upheaval, she noted.

Her approach is to have an open and honest conversation with patients about their concerns and fears, what the realities are, and what the potential future options are for certain rheumatology drugs in the United States.

Some women who see what’s happening across the country may become so risk averse that they may choose to die rather than take a lifesaving drug that poses certain risks under new restrictions.

“I think that’s tragic,” said Dr. Clowse.

To help their patients, Dr. Gray believes physicians across specialties should better educate themselves about physiology in pregnancy and how to counsel patients on the impact of not taking medications in pregnancy.

In her view, it’s almost coercive to say to a patient, “You really need to have effective contraception if I’m going to give you this lifesaving or quality-of-life-improving medication.”

When confronting such scenarios, Dr. Gray doesn’t think physicians need to change how they counsel patients about contraception. “I don’t think we should be putting pressure on patients to consider other permanent methods just because there’s a lack of abortion options.”

Patients will eventually make those decisions for themselves, she said. “They’re going to want a more efficacious method because they’re worried about not having access to abortion if they get pregnant.”

Dr. Gray reports being a site principal investigator for a phase 3 trial for VeraCept IUD, funded by Sebela Pharmaceuticals. Dr. Clowse reports receiving research funding and doing consulting for GlaxoSmithKline.

*Correction, 6/2/2022: A previous version of this article misstated the intended use of drugs such as the “morning-after” pill (levonorgestrel). They are taken to prevent unintended pregnancy.

A version of this article first appeared on Medscape.com .

Key clinical point: A higher serum level of follicle-stimulating hormone (FSH) is an independent risk factor for rheumatoid arthritis (RA) and is positively associated with RA disease activity.

Major finding: Circulating FSH levels were significantly higher in women with RA vs age-matched healthy women (57.58 ± 15.94 vs 43.11 ± 19.46 mIU/mL; P = .025), with women with RA in the highest vs lowest quartiles of FSH levels having a significantly higher disease activity score of 28 joints with erythrocyte sedimentation rate (P < .001).

Study details: Findings are from a prospective analysis including 79 women with RA and 50 age-matched healthy women.

Disclosures: This study was supported by the Youth Foundation of Science and Technology Department of Shanxi Province and the National Natural Science Foundation of China. The authors declared no conflicts of interest.

Source: Zhang X et al. High follicle-stimulating hormone level associated with risk of rheumatoid arthritis and disease activity. Front Endocrinol. 2022;13:862849 (Apr 22). Doi: 10.3389/fendo.2022.862849

Key clinical point: A higher serum level of follicle-stimulating hormone (FSH) is an independent risk factor for rheumatoid arthritis (RA) and is positively associated with RA disease activity.

Major finding: Circulating FSH levels were significantly higher in women with RA vs age-matched healthy women (57.58 ± 15.94 vs 43.11 ± 19.46 mIU/mL; P = .025), with women with RA in the highest vs lowest quartiles of FSH levels having a significantly higher disease activity score of 28 joints with erythrocyte sedimentation rate (P < .001).

Study details: Findings are from a prospective analysis including 79 women with RA and 50 age-matched healthy women.

Disclosures: This study was supported by the Youth Foundation of Science and Technology Department of Shanxi Province and the National Natural Science Foundation of China. The authors declared no conflicts of interest.

Source: Zhang X et al. High follicle-stimulating hormone level associated with risk of rheumatoid arthritis and disease activity. Front Endocrinol. 2022;13:862849 (Apr 22). Doi: 10.3389/fendo.2022.862849

Key clinical point: A higher serum level of follicle-stimulating hormone (FSH) is an independent risk factor for rheumatoid arthritis (RA) and is positively associated with RA disease activity.

Major finding: Circulating FSH levels were significantly higher in women with RA vs age-matched healthy women (57.58 ± 15.94 vs 43.11 ± 19.46 mIU/mL; P = .025), with women with RA in the highest vs lowest quartiles of FSH levels having a significantly higher disease activity score of 28 joints with erythrocyte sedimentation rate (P < .001).

Study details: Findings are from a prospective analysis including 79 women with RA and 50 age-matched healthy women.

Disclosures: This study was supported by the Youth Foundation of Science and Technology Department of Shanxi Province and the National Natural Science Foundation of China. The authors declared no conflicts of interest.

Source: Zhang X et al. High follicle-stimulating hormone level associated with risk of rheumatoid arthritis and disease activity. Front Endocrinol. 2022;13:862849 (Apr 22). Doi: 10.3389/fendo.2022.862849

Key clinical point: Acupuncture relieves pain and improves the health index in patients with rheumatoid arthritis (RA) and can be considered an adjunctive nonpharmacological treatment in rehabilitation programs.

Major finding: Invasive acupuncture vs control interventions significantly reduced pain (mean difference [MD] −1.00; P ­= .04), Health Assessment Questionnaire score (MD −0.20; P < .001), Physician Global Assessment score (MD ­−0.98; P < .001), tender joint count (MD ­−1.24; P ­= .005), C-reactive protein level (MD, −1.81; P =­ .019), and erythrocyte sedimentation rate (MD, −3.03; P =­ .032). Similar benefits were observed with laser acupuncture. No adverse events were reported.

Study details: This was a meta-analysis of 11 randomized controlled trials including 796 patients with RA, of which 402 received acupuncture therapy and 394 received control interventions.

Disclosures: The study was supported by Beijing Jishuitan Hospital Elite Young Scholar Programme, Beijing, China. The authors declared no conflicts of interest.

Source: Li H et al. Clinical efficacy of acupuncture for the treatment of rheumatoid arthritis: Meta-analysis of randomized clinical trials. Evid Based Complementary Altern Med. 2022;5264977 (Apr 30). Doi: 10.1155/2022/5264977

Key clinical point: Acupuncture relieves pain and improves the health index in patients with rheumatoid arthritis (RA) and can be considered an adjunctive nonpharmacological treatment in rehabilitation programs.

Major finding: Invasive acupuncture vs control interventions significantly reduced pain (mean difference [MD] −1.00; P ­= .04), Health Assessment Questionnaire score (MD −0.20; P < .001), Physician Global Assessment score (MD ­−0.98; P < .001), tender joint count (MD ­−1.24; P ­= .005), C-reactive protein level (MD, −1.81; P =­ .019), and erythrocyte sedimentation rate (MD, −3.03; P =­ .032). Similar benefits were observed with laser acupuncture. No adverse events were reported.

Study details: This was a meta-analysis of 11 randomized controlled trials including 796 patients with RA, of which 402 received acupuncture therapy and 394 received control interventions.

Disclosures: The study was supported by Beijing Jishuitan Hospital Elite Young Scholar Programme, Beijing, China. The authors declared no conflicts of interest.

Source: Li H et al. Clinical efficacy of acupuncture for the treatment of rheumatoid arthritis: Meta-analysis of randomized clinical trials. Evid Based Complementary Altern Med. 2022;5264977 (Apr 30). Doi: 10.1155/2022/5264977

Key clinical point: Acupuncture relieves pain and improves the health index in patients with rheumatoid arthritis (RA) and can be considered an adjunctive nonpharmacological treatment in rehabilitation programs.

Major finding: Invasive acupuncture vs control interventions significantly reduced pain (mean difference [MD] −1.00; P ­= .04), Health Assessment Questionnaire score (MD −0.20; P < .001), Physician Global Assessment score (MD ­−0.98; P < .001), tender joint count (MD ­−1.24; P ­= .005), C-reactive protein level (MD, −1.81; P =­ .019), and erythrocyte sedimentation rate (MD, −3.03; P =­ .032). Similar benefits were observed with laser acupuncture. No adverse events were reported.

Study details: This was a meta-analysis of 11 randomized controlled trials including 796 patients with RA, of which 402 received acupuncture therapy and 394 received control interventions.

Disclosures: The study was supported by Beijing Jishuitan Hospital Elite Young Scholar Programme, Beijing, China. The authors declared no conflicts of interest.

Source: Li H et al. Clinical efficacy of acupuncture for the treatment of rheumatoid arthritis: Meta-analysis of randomized clinical trials. Evid Based Complementary Altern Med. 2022;5264977 (Apr 30). Doi: 10.1155/2022/5264977

Key clinical point: Acupuncture relieves pain and improves the health index in patients with rheumatoid arthritis (RA) and can be considered an adjunctive nonpharmacological treatment in rehabilitation programs.

Major finding: Invasive acupuncture vs control interventions significantly reduced pain (mean difference [MD] −1.00; P ­= .04), Health Assessment Questionnaire score (MD −0.20; P < .001), Physician Global Assessment score (MD ­−0.98; P < .001), tender joint count (MD ­−1.24; P ­= .005), C-reactive protein level (MD, −1.81; P =­ .019), and erythrocyte sedimentation rate (MD, −3.03; P =­ .032). Similar benefits were observed with laser acupuncture. No adverse events were reported.

Study details: This was a meta-analysis of 11 randomized controlled trials including 796 patients with RA, of which 402 received acupuncture therapy and 394 received control interventions.

Disclosures: The study was supported by Beijing Jishuitan Hospital Elite Young Scholar Programme, Beijing, China. The authors declared no conflicts of interest.

Source: Li H et al. Clinical efficacy of acupuncture for the treatment of rheumatoid arthritis: Meta-analysis of randomized clinical trials. Evid Based Complementary Altern Med. 2022;5264977 (Apr 30). Doi: 10.1155/2022/5264977

Key clinical point: Acupuncture relieves pain and improves the health index in patients with rheumatoid arthritis (RA) and can be considered an adjunctive nonpharmacological treatment in rehabilitation programs.

Major finding: Invasive acupuncture vs control interventions significantly reduced pain (mean difference [MD] −1.00; P ­= .04), Health Assessment Questionnaire score (MD −0.20; P < .001), Physician Global Assessment score (MD ­−0.98; P < .001), tender joint count (MD ­−1.24; P ­= .005), C-reactive protein level (MD, −1.81; P =­ .019), and erythrocyte sedimentation rate (MD, −3.03; P =­ .032). Similar benefits were observed with laser acupuncture. No adverse events were reported.

Study details: This was a meta-analysis of 11 randomized controlled trials including 796 patients with RA, of which 402 received acupuncture therapy and 394 received control interventions.

Disclosures: The study was supported by Beijing Jishuitan Hospital Elite Young Scholar Programme, Beijing, China. The authors declared no conflicts of interest.

Source: Li H et al. Clinical efficacy of acupuncture for the treatment of rheumatoid arthritis: Meta-analysis of randomized clinical trials. Evid Based Complementary Altern Med. 2022;5264977 (Apr 30). Doi: 10.1155/2022/5264977

Key clinical point: Acupuncture relieves pain and improves the health index in patients with rheumatoid arthritis (RA) and can be considered an adjunctive nonpharmacological treatment in rehabilitation programs.

Major finding: Invasive acupuncture vs control interventions significantly reduced pain (mean difference [MD] −1.00; P ­= .04), Health Assessment Questionnaire score (MD −0.20; P < .001), Physician Global Assessment score (MD ­−0.98; P < .001), tender joint count (MD ­−1.24; P ­= .005), C-reactive protein level (MD, −1.81; P =­ .019), and erythrocyte sedimentation rate (MD, −3.03; P =­ .032). Similar benefits were observed with laser acupuncture. No adverse events were reported.

Study details: This was a meta-analysis of 11 randomized controlled trials including 796 patients with RA, of which 402 received acupuncture therapy and 394 received control interventions.

Disclosures: The study was supported by Beijing Jishuitan Hospital Elite Young Scholar Programme, Beijing, China. The authors declared no conflicts of interest.

Source: Li H et al. Clinical efficacy of acupuncture for the treatment of rheumatoid arthritis: Meta-analysis of randomized clinical trials. Evid Based Complementary Altern Med. 2022;5264977 (Apr 30). Doi: 10.1155/2022/5264977

Key clinical point: The rates of achieving low disease activity (LDA) and clinical remission were almost 20%-40% lower in patients with rheumatoid arthritis (RA) and elevated levels of adipocytokines.

Major finding: Patients in the highest vs lowest quartile of adiponectin (adjusted hazard ratio [aHR] 0.69) and leptin (aHR 0.77; both P < .05) had a significantly lower rate of achieving LDA. The odds of achieving clinical remission were lower in patients in the highest vs lowest quartile of adiponectin (aHR 0.69) and leptin (aHR 0.64; both P < .05).

Study details: This was an observational cohort study including 1274 veterans with RA and a disease activity score in 28 joints of >3.2.

Disclosures: This study did not declare any specific funding. JF Baker, BR England, and TR Mikuls reported receiving funding, grants, research support, or consulting fees from various sources.

Source: Baker JF et al. Adipocytokines and achievement of low disease activity in rheumatoid arthritis. Semin Arthritis Rheum. 2022;55:152003 (Apr 12). Doi: 10.1016/j.semarthrit.2022.152003

Key clinical point: The rates of achieving low disease activity (LDA) and clinical remission were almost 20%-40% lower in patients with rheumatoid arthritis (RA) and elevated levels of adipocytokines.

Major finding: Patients in the highest vs lowest quartile of adiponectin (adjusted hazard ratio [aHR] 0.69) and leptin (aHR 0.77; both P < .05) had a significantly lower rate of achieving LDA. The odds of achieving clinical remission were lower in patients in the highest vs lowest quartile of adiponectin (aHR 0.69) and leptin (aHR 0.64; both P < .05).

Study details: This was an observational cohort study including 1274 veterans with RA and a disease activity score in 28 joints of >3.2.

Disclosures: This study did not declare any specific funding. JF Baker, BR England, and TR Mikuls reported receiving funding, grants, research support, or consulting fees from various sources.

Source: Baker JF et al. Adipocytokines and achievement of low disease activity in rheumatoid arthritis. Semin Arthritis Rheum. 2022;55:152003 (Apr 12). Doi: 10.1016/j.semarthrit.2022.152003

Key clinical point: The rates of achieving low disease activity (LDA) and clinical remission were almost 20%-40% lower in patients with rheumatoid arthritis (RA) and elevated levels of adipocytokines.

Major finding: Patients in the highest vs lowest quartile of adiponectin (adjusted hazard ratio [aHR] 0.69) and leptin (aHR 0.77; both P < .05) had a significantly lower rate of achieving LDA. The odds of achieving clinical remission were lower in patients in the highest vs lowest quartile of adiponectin (aHR 0.69) and leptin (aHR 0.64; both P < .05).

Study details: This was an observational cohort study including 1274 veterans with RA and a disease activity score in 28 joints of >3.2.

Disclosures: This study did not declare any specific funding. JF Baker, BR England, and TR Mikuls reported receiving funding, grants, research support, or consulting fees from various sources.

Source: Baker JF et al. Adipocytokines and achievement of low disease activity in rheumatoid arthritis. Semin Arthritis Rheum. 2022;55:152003 (Apr 12). Doi: 10.1016/j.semarthrit.2022.152003

Key clinical point: The risks for any serious bacterial, opportunistic, or herpes zoster infections were similar with add-on leflunomide or tacrolimus and tumor necrosis factor inhibitors (TNFi) in patients with seropositive rheumatoid arthritis (RA) receiving methotrexate.

Major finding: The risk for any serious infection was not significantly different with leflunomide (propensity score fine stratification-weighted hazard ratio [pHR, 1.03; 95% CI 0.89-1.22) or tacrolimus (pHR 0.91; 95% CI 0.77-1.08) compared to TNFi.

Study details: This was a population-based cohort study including 72,516 patients with seropositive RA who were taking methotrexate, of which 20,262 patients initiated leflunomide, tacrolimus, or TNFi therapy.

Disclosures: This study was supported by an investigator-sponsored grant from Hanlim pharmaceutical company. The authors declared no conflicts of interest.

Source: Shin A et al. Semin Arthritis Rheum. 2022 Apr 28. doi: 10.1016/j.semarthrit.2022.152019.

Key clinical point: The risks for any serious bacterial, opportunistic, or herpes zoster infections were similar with add-on leflunomide or tacrolimus and tumor necrosis factor inhibitors (TNFi) in patients with seropositive rheumatoid arthritis (RA) receiving methotrexate.

Major finding: The risk for any serious infection was not significantly different with leflunomide (propensity score fine stratification-weighted hazard ratio [pHR, 1.03; 95% CI 0.89-1.22) or tacrolimus (pHR 0.91; 95% CI 0.77-1.08) compared to TNFi.

Study details: This was a population-based cohort study including 72,516 patients with seropositive RA who were taking methotrexate, of which 20,262 patients initiated leflunomide, tacrolimus, or TNFi therapy.

Disclosures: This study was supported by an investigator-sponsored grant from Hanlim pharmaceutical company. The authors declared no conflicts of interest.

Source: Shin A et al. Semin Arthritis Rheum. 2022 Apr 28. doi: 10.1016/j.semarthrit.2022.152019.

Key clinical point: The risks for any serious bacterial, opportunistic, or herpes zoster infections were similar with add-on leflunomide or tacrolimus and tumor necrosis factor inhibitors (TNFi) in patients with seropositive rheumatoid arthritis (RA) receiving methotrexate.

Major finding: The risk for any serious infection was not significantly different with leflunomide (propensity score fine stratification-weighted hazard ratio [pHR, 1.03; 95% CI 0.89-1.22) or tacrolimus (pHR 0.91; 95% CI 0.77-1.08) compared to TNFi.

Study details: This was a population-based cohort study including 72,516 patients with seropositive RA who were taking methotrexate, of which 20,262 patients initiated leflunomide, tacrolimus, or TNFi therapy.

Disclosures: This study was supported by an investigator-sponsored grant from Hanlim pharmaceutical company. The authors declared no conflicts of interest.

Source: Shin A et al. Semin Arthritis Rheum. 2022 Apr 28. doi: 10.1016/j.semarthrit.2022.152019.

Key clinical point: Regular vitamin E supplementation in patients with rheumatoid arthritis (RA) may help reduce joint discomfort, edema, and stiffness, thus enhancing the overall quality of life.

Major finding: Patients with RA who received regular vitamin E supplementation showed improvements in uncomfortable joints (mean difference [MD] −0.62; 95% CI −12.59 to 11.36) and tender joints (MD −1.66; 95% CI −6.32 to 2.99) compared with those who received placebo, fish oil, or other medications, without any significant safety concerns.

Study details: This was a systematic review and meta-analysis of nine studies including 39,845 individuals with RA who received vitamin E (experimental group) or placebo, fish oil, or other medications (control group).

Disclosures: This study was supported by funding from the Natural Science Foundation of Shaanxi Province, China. The authors declared no competing interests.

Source: Kou H et al. Effect of vitamin E supplementation in rheumatoid arthritis: A systematic review and meta-analysis. Eur J Clin Nutr. 2022 (Apr 25). Doi: 10.1038/s41430-022-01148-9

Key clinical point: Regular vitamin E supplementation in patients with rheumatoid arthritis (RA) may help reduce joint discomfort, edema, and stiffness, thus enhancing the overall quality of life.

Major finding: Patients with RA who received regular vitamin E supplementation showed improvements in uncomfortable joints (mean difference [MD] −0.62; 95% CI −12.59 to 11.36) and tender joints (MD −1.66; 95% CI −6.32 to 2.99) compared with those who received placebo, fish oil, or other medications, without any significant safety concerns.

Study details: This was a systematic review and meta-analysis of nine studies including 39,845 individuals with RA who received vitamin E (experimental group) or placebo, fish oil, or other medications (control group).

Disclosures: This study was supported by funding from the Natural Science Foundation of Shaanxi Province, China. The authors declared no competing interests.

Source: Kou H et al. Effect of vitamin E supplementation in rheumatoid arthritis: A systematic review and meta-analysis. Eur J Clin Nutr. 2022 (Apr 25). Doi: 10.1038/s41430-022-01148-9

Key clinical point: Regular vitamin E supplementation in patients with rheumatoid arthritis (RA) may help reduce joint discomfort, edema, and stiffness, thus enhancing the overall quality of life.

Major finding: Patients with RA who received regular vitamin E supplementation showed improvements in uncomfortable joints (mean difference [MD] −0.62; 95% CI −12.59 to 11.36) and tender joints (MD −1.66; 95% CI −6.32 to 2.99) compared with those who received placebo, fish oil, or other medications, without any significant safety concerns.

Study details: This was a systematic review and meta-analysis of nine studies including 39,845 individuals with RA who received vitamin E (experimental group) or placebo, fish oil, or other medications (control group).

Disclosures: This study was supported by funding from the Natural Science Foundation of Shaanxi Province, China. The authors declared no competing interests.

Source: Kou H et al. Effect of vitamin E supplementation in rheumatoid arthritis: A systematic review and meta-analysis. Eur J Clin Nutr. 2022 (Apr 25). Doi: 10.1038/s41430-022-01148-9