Psoriatic Arthritis

Key clinical point: Bimekizumab (160 mg/4 weeks) demonstrated favorable efficacy outcomes over secukinumab (150 mg or 300 mg/4 weeks) in patients with psoriatic arthritis (PsA) who were naive to biologic disease-modifying anti-rheumatic drugs (bDMARD) or had prior inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR).

Major finding: In the bDMARD naive subgroup, the probability of achieving at least 70% improvement in American College of Rheumatology (ACR) response was higher with bimekizumab vs secukinumab (odds ratio > 2; P < .05) at week 52, with similar response in the TNFi-IR subgroup for ACR70 and minimal disease activity outcomes (all P < .05).

Study details: This study included data of bDMARD naive or TNFi-IR patients with PsA who received bimekizumab from BE OPTIMAL (n = 236) and BE COMPLETE (n = 146) and secukinumab from FUTURE 2 trial (n = 200).

Disclosures: This study was sponsored by UCB Pharma. Four authors declared being employees and stockholders of UCB Pharma. Several authors declared receiving research grants, and other ties with various sources, including UCB Pharma.

Source: Mease PJ, Warren RB, Nash P, et al. Comparative effectiveness of bimekizumab and secukinumab in patients with psoriatic arthritis at 52 weeks using a matching-adjusted indirect comparison. Rheumatol Ther. 2024 (Mar 6). Source 

Key clinical point: Bimekizumab (160 mg/4 weeks) demonstrated favorable efficacy outcomes over secukinumab (150 mg or 300 mg/4 weeks) in patients with psoriatic arthritis (PsA) who were naive to biologic disease-modifying anti-rheumatic drugs (bDMARD) or had prior inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR).

Major finding: In the bDMARD naive subgroup, the probability of achieving at least 70% improvement in American College of Rheumatology (ACR) response was higher with bimekizumab vs secukinumab (odds ratio > 2; P < .05) at week 52, with similar response in the TNFi-IR subgroup for ACR70 and minimal disease activity outcomes (all P < .05).

Study details: This study included data of bDMARD naive or TNFi-IR patients with PsA who received bimekizumab from BE OPTIMAL (n = 236) and BE COMPLETE (n = 146) and secukinumab from FUTURE 2 trial (n = 200).

Disclosures: This study was sponsored by UCB Pharma. Four authors declared being employees and stockholders of UCB Pharma. Several authors declared receiving research grants, and other ties with various sources, including UCB Pharma.

Source: Mease PJ, Warren RB, Nash P, et al. Comparative effectiveness of bimekizumab and secukinumab in patients with psoriatic arthritis at 52 weeks using a matching-adjusted indirect comparison. Rheumatol Ther. 2024 (Mar 6). Source 

Key clinical point: Bimekizumab (160 mg/4 weeks) demonstrated favorable efficacy outcomes over secukinumab (150 mg or 300 mg/4 weeks) in patients with psoriatic arthritis (PsA) who were naive to biologic disease-modifying anti-rheumatic drugs (bDMARD) or had prior inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR).

Major finding: In the bDMARD naive subgroup, the probability of achieving at least 70% improvement in American College of Rheumatology (ACR) response was higher with bimekizumab vs secukinumab (odds ratio > 2; P < .05) at week 52, with similar response in the TNFi-IR subgroup for ACR70 and minimal disease activity outcomes (all P < .05).

Study details: This study included data of bDMARD naive or TNFi-IR patients with PsA who received bimekizumab from BE OPTIMAL (n = 236) and BE COMPLETE (n = 146) and secukinumab from FUTURE 2 trial (n = 200).

Disclosures: This study was sponsored by UCB Pharma. Four authors declared being employees and stockholders of UCB Pharma. Several authors declared receiving research grants, and other ties with various sources, including UCB Pharma.

Source: Mease PJ, Warren RB, Nash P, et al. Comparative effectiveness of bimekizumab and secukinumab in patients with psoriatic arthritis at 52 weeks using a matching-adjusted indirect comparison. Rheumatol Ther. 2024 (Mar 6). Source 

Key clinical point: Real-world treatment with guselkumab for ≥6 months was effective and safe in patients with longstanding active psoriatic arthritis (PsA) who had median disease duration of 6 years.

Major finding: Disease Activity Index for Psoriatic Arthritis (DAPSA) scores reduced significantly by 15.47 points in guselkumab-treated patients with PsA (P  =  .001), with 39.6% of patients achieving low disease activity, as assessed by achievement of DAPSA ≤ 14 at 6 months of follow-up. Guselkumab was well tolerated, with no reports of new safety signals.

Study details: This was a prospective real-world cohort study including 111 patients with active, longstanding PsA with a median disease duration of 6 years, who received guselkumab for ≥6 months.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Ruscitti P, Cataldi G, Gentile M, et al. The evaluation of effectiveness and safety of guselkumab in patients with psoriatic arthritis in a prospective multicentre "real-life" cohort study. Rheumatol Ther. 2024 (Mar 4). doi: 10.1007/s40744-024-00649-2 Source

Key clinical point: Real-world treatment with guselkumab for ≥6 months was effective and safe in patients with longstanding active psoriatic arthritis (PsA) who had median disease duration of 6 years.

Major finding: Disease Activity Index for Psoriatic Arthritis (DAPSA) scores reduced significantly by 15.47 points in guselkumab-treated patients with PsA (P  =  .001), with 39.6% of patients achieving low disease activity, as assessed by achievement of DAPSA ≤ 14 at 6 months of follow-up. Guselkumab was well tolerated, with no reports of new safety signals.

Study details: This was a prospective real-world cohort study including 111 patients with active, longstanding PsA with a median disease duration of 6 years, who received guselkumab for ≥6 months.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Ruscitti P, Cataldi G, Gentile M, et al. The evaluation of effectiveness and safety of guselkumab in patients with psoriatic arthritis in a prospective multicentre "real-life" cohort study. Rheumatol Ther. 2024 (Mar 4). doi: 10.1007/s40744-024-00649-2 Source

Key clinical point: Real-world treatment with guselkumab for ≥6 months was effective and safe in patients with longstanding active psoriatic arthritis (PsA) who had median disease duration of 6 years.

Major finding: Disease Activity Index for Psoriatic Arthritis (DAPSA) scores reduced significantly by 15.47 points in guselkumab-treated patients with PsA (P  =  .001), with 39.6% of patients achieving low disease activity, as assessed by achievement of DAPSA ≤ 14 at 6 months of follow-up. Guselkumab was well tolerated, with no reports of new safety signals.

Study details: This was a prospective real-world cohort study including 111 patients with active, longstanding PsA with a median disease duration of 6 years, who received guselkumab for ≥6 months.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Ruscitti P, Cataldi G, Gentile M, et al. The evaluation of effectiveness and safety of guselkumab in patients with psoriatic arthritis in a prospective multicentre "real-life" cohort study. Rheumatol Ther. 2024 (Mar 4). doi: 10.1007/s40744-024-00649-2 Source

Key clinical point: Guselkumab was more effective than ustekinumab in improving joint and skin outcomes in patients with psoriatic arthritis (PsA), regardless of prior exposure to biologics.

Major finding: A higher proportion of patients with prior exposure to biologics receiving guselkumab (dosage 100 mg/2 weeks or 100 mg/4 weeks) vs ustekinumab (dosage 45/90 mg) achieved the American College of Rheumatology-20 response (> 58% vs 35.6%) and Psoriasis Area Severity Index-90 response (> 50.0% vs 25.9%) at week 52, with similar outcomes in patients naive to biologics.

Study details: This study included pooled individual data from four trials of patients having PsA with (n  =  197) or without prior exposure to biologics (n  =  1170) who received either guselkumab or ustekinumab.

Disclosures: This study was sponsored by Janssen Research and Development (HEMAR Department, High Wycombe, United Kingdom). All authors reported being employees of Janssen Research and Development or EVERSANA, which received funding from Janssen Research and Development for this study.

Source: Thilakarathne P, Schubert A, Peterson S, et al. Comparing efficacy of guselkumab versus ustekinumab in patients with psoriatic arthritis: An adjusted comparison using individual patient data from the DISCOVER and PSUMMIT trials. Rheumatol Ther. 2024;11:457-474 (Feb 28). doi: 10.1007/s40744-024-00644-7 Source

Key clinical point: Guselkumab was more effective than ustekinumab in improving joint and skin outcomes in patients with psoriatic arthritis (PsA), regardless of prior exposure to biologics.

Major finding: A higher proportion of patients with prior exposure to biologics receiving guselkumab (dosage 100 mg/2 weeks or 100 mg/4 weeks) vs ustekinumab (dosage 45/90 mg) achieved the American College of Rheumatology-20 response (> 58% vs 35.6%) and Psoriasis Area Severity Index-90 response (> 50.0% vs 25.9%) at week 52, with similar outcomes in patients naive to biologics.

Study details: This study included pooled individual data from four trials of patients having PsA with (n  =  197) or without prior exposure to biologics (n  =  1170) who received either guselkumab or ustekinumab.

Disclosures: This study was sponsored by Janssen Research and Development (HEMAR Department, High Wycombe, United Kingdom). All authors reported being employees of Janssen Research and Development or EVERSANA, which received funding from Janssen Research and Development for this study.

Source: Thilakarathne P, Schubert A, Peterson S, et al. Comparing efficacy of guselkumab versus ustekinumab in patients with psoriatic arthritis: An adjusted comparison using individual patient data from the DISCOVER and PSUMMIT trials. Rheumatol Ther. 2024;11:457-474 (Feb 28). doi: 10.1007/s40744-024-00644-7 Source

Key clinical point: Guselkumab was more effective than ustekinumab in improving joint and skin outcomes in patients with psoriatic arthritis (PsA), regardless of prior exposure to biologics.

Major finding: A higher proportion of patients with prior exposure to biologics receiving guselkumab (dosage 100 mg/2 weeks or 100 mg/4 weeks) vs ustekinumab (dosage 45/90 mg) achieved the American College of Rheumatology-20 response (> 58% vs 35.6%) and Psoriasis Area Severity Index-90 response (> 50.0% vs 25.9%) at week 52, with similar outcomes in patients naive to biologics.

Study details: This study included pooled individual data from four trials of patients having PsA with (n  =  197) or without prior exposure to biologics (n  =  1170) who received either guselkumab or ustekinumab.

Disclosures: This study was sponsored by Janssen Research and Development (HEMAR Department, High Wycombe, United Kingdom). All authors reported being employees of Janssen Research and Development or EVERSANA, which received funding from Janssen Research and Development for this study.

Source: Thilakarathne P, Schubert A, Peterson S, et al. Comparing efficacy of guselkumab versus ustekinumab in patients with psoriatic arthritis: An adjusted comparison using individual patient data from the DISCOVER and PSUMMIT trials. Rheumatol Ther. 2024;11:457-474 (Feb 28). doi: 10.1007/s40744-024-00644-7 Source

Key clinical point: A long delay (>1 year) in diagnosing psoriatic arthritis (PsA) is associated with worse clinical outcomes, especially in women and patients with enthesitis, chronic back pain, and lower C-reactive protein (CRP) levels.

Major finding: Patients with a short (<12 weeks) vs long delay (>1 year) in PsA diagnosis after symptom onset was more likely to achieve minimum disease activity (odds ratio 2.55; 95% CI 1.37-4.76). Female sex, chronic back pain (age < 45 years), enthesitis, and lower CRP levels were associated with a diagnostic delay > 1 year in patients with PsA (all P < .05).

Study details: This study included 708 newly diagnosed patients with PsA who were followed up for ≥3 years; were naive to disease-modifying antirheumatic drugs; and were categorized into groups having short (n  =  136), intermediate (12 weeks to 1 year; n  =  237), or long (n  =  335) delay to diagnosis after symptom onset.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Snoeck Henkemans SVJ, de Jong PHP, Luime JJ, et al. Window of opportunity in psoriatic arthritis: The earlier the better? RMD Open. 2024;10:e004062 (Feb 27). doi: 10.1136/rmdopen-2023-004062 Source

Key clinical point: A long delay (>1 year) in diagnosing psoriatic arthritis (PsA) is associated with worse clinical outcomes, especially in women and patients with enthesitis, chronic back pain, and lower C-reactive protein (CRP) levels.

Major finding: Patients with a short (<12 weeks) vs long delay (>1 year) in PsA diagnosis after symptom onset was more likely to achieve minimum disease activity (odds ratio 2.55; 95% CI 1.37-4.76). Female sex, chronic back pain (age < 45 years), enthesitis, and lower CRP levels were associated with a diagnostic delay > 1 year in patients with PsA (all P < .05).

Study details: This study included 708 newly diagnosed patients with PsA who were followed up for ≥3 years; were naive to disease-modifying antirheumatic drugs; and were categorized into groups having short (n  =  136), intermediate (12 weeks to 1 year; n  =  237), or long (n  =  335) delay to diagnosis after symptom onset.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Snoeck Henkemans SVJ, de Jong PHP, Luime JJ, et al. Window of opportunity in psoriatic arthritis: The earlier the better? RMD Open. 2024;10:e004062 (Feb 27). doi: 10.1136/rmdopen-2023-004062 Source

Key clinical point: A long delay (>1 year) in diagnosing psoriatic arthritis (PsA) is associated with worse clinical outcomes, especially in women and patients with enthesitis, chronic back pain, and lower C-reactive protein (CRP) levels.

Major finding: Patients with a short (<12 weeks) vs long delay (>1 year) in PsA diagnosis after symptom onset was more likely to achieve minimum disease activity (odds ratio 2.55; 95% CI 1.37-4.76). Female sex, chronic back pain (age < 45 years), enthesitis, and lower CRP levels were associated with a diagnostic delay > 1 year in patients with PsA (all P < .05).

Study details: This study included 708 newly diagnosed patients with PsA who were followed up for ≥3 years; were naive to disease-modifying antirheumatic drugs; and were categorized into groups having short (n  =  136), intermediate (12 weeks to 1 year; n  =  237), or long (n  =  335) delay to diagnosis after symptom onset.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Snoeck Henkemans SVJ, de Jong PHP, Luime JJ, et al. Window of opportunity in psoriatic arthritis: The earlier the better? RMD Open. 2024;10:e004062 (Feb 27). doi: 10.1136/rmdopen-2023-004062 Source

Key clinical point: Higher relative abundance of gut microbiota belonging to family Rikenellaceae and an unidentified metabolite X-11538 were associated with a reduced risk for psoriatic arthritis (PsA), highlighting the potential of gut microbiota taxa and metabolites as biomarkers for treatment and prevention of PsA.

Major finding: Adjusted multivariable Mendelian randomization analysis showed that a higher relative abundance of microbiota belonging to the family Rikenellaceae (odds ratio [OR] 0.5; 95% CI 0.320-0.780) and elevated serum levels of X-11538 (OR 0.448; 95% CI 0.244-0.821) were causally associated with a reduced risk for PsA.

Study details: This Mendelian randomization study included summary level data of gut microbiota taxa (n  =  18,340), PsA (n  =  339,050), and metabolites (n  =  7824) from participants included in the MiBioGen consortium, FinnGen Biobank, and TwinsUK and KORA cohorts, respectively.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Xu X, Wu LY, Wang SY, et al. Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: A Mendelian randomization study. Front Microbiol. 2024;15:1287637 (Feb 14). doi: 10.3389/fmicb.2024.1287637 Source

Key clinical point: Higher relative abundance of gut microbiota belonging to family Rikenellaceae and an unidentified metabolite X-11538 were associated with a reduced risk for psoriatic arthritis (PsA), highlighting the potential of gut microbiota taxa and metabolites as biomarkers for treatment and prevention of PsA.

Major finding: Adjusted multivariable Mendelian randomization analysis showed that a higher relative abundance of microbiota belonging to the family Rikenellaceae (odds ratio [OR] 0.5; 95% CI 0.320-0.780) and elevated serum levels of X-11538 (OR 0.448; 95% CI 0.244-0.821) were causally associated with a reduced risk for PsA.

Study details: This Mendelian randomization study included summary level data of gut microbiota taxa (n  =  18,340), PsA (n  =  339,050), and metabolites (n  =  7824) from participants included in the MiBioGen consortium, FinnGen Biobank, and TwinsUK and KORA cohorts, respectively.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Xu X, Wu LY, Wang SY, et al. Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: A Mendelian randomization study. Front Microbiol. 2024;15:1287637 (Feb 14). doi: 10.3389/fmicb.2024.1287637 Source

Key clinical point: Higher relative abundance of gut microbiota belonging to family Rikenellaceae and an unidentified metabolite X-11538 were associated with a reduced risk for psoriatic arthritis (PsA), highlighting the potential of gut microbiota taxa and metabolites as biomarkers for treatment and prevention of PsA.

Major finding: Adjusted multivariable Mendelian randomization analysis showed that a higher relative abundance of microbiota belonging to the family Rikenellaceae (odds ratio [OR] 0.5; 95% CI 0.320-0.780) and elevated serum levels of X-11538 (OR 0.448; 95% CI 0.244-0.821) were causally associated with a reduced risk for PsA.

Study details: This Mendelian randomization study included summary level data of gut microbiota taxa (n  =  18,340), PsA (n  =  339,050), and metabolites (n  =  7824) from participants included in the MiBioGen consortium, FinnGen Biobank, and TwinsUK and KORA cohorts, respectively.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Xu X, Wu LY, Wang SY, et al. Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: A Mendelian randomization study. Front Microbiol. 2024;15:1287637 (Feb 14). doi: 10.3389/fmicb.2024.1287637 Source

Key clinical point: Bimekizumab led to long-term improvements in efficacy outcomes and had a manageable safety profile in patients with active psoriatic arthritis (PsA) and prior inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR).

Major finding: At week 16, a significantly higher number of patients achieved ≥50% improvement in American College of Rheumatology response with bimekizumab vs placebo (43.4% vs 6.8%; P < .0001), with improvements sustained up to week 52 by >40% of patients receiving bimekizumab. No new safety signals were observed.

Study details: Findings are from the BE VITAL open-label extension study including 377 patients with active PsA and TNFi-IR who received bimekizumab or placebo for 16 weeks followed by only bimekizumab up to week 52.

Disclosures: This study was sponsored by UCB Pharma. Four authors reported being employees or shareholders of UCB Pharma. Several authors declared receiving research support or consulting fees or having other ties with various sources, including UCB Pharma.

Source: Coates LC, Landewe R, McInnes IB, et al. Bimekizumab treatment in patients with active psoriatic arthritis and prior inadequate response to tumour necrosis factor inhibitors: 52-week safety and efficacy from the phase III BE COMPLETE study and its open-label extension BE VITAL. RMD Open. 2024;10:e003855 (Feb 22). doi: 10.1136/rmdopen-2023-003855 Source

Key clinical point: Bimekizumab led to long-term improvements in efficacy outcomes and had a manageable safety profile in patients with active psoriatic arthritis (PsA) and prior inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR).

Major finding: At week 16, a significantly higher number of patients achieved ≥50% improvement in American College of Rheumatology response with bimekizumab vs placebo (43.4% vs 6.8%; P < .0001), with improvements sustained up to week 52 by >40% of patients receiving bimekizumab. No new safety signals were observed.

Study details: Findings are from the BE VITAL open-label extension study including 377 patients with active PsA and TNFi-IR who received bimekizumab or placebo for 16 weeks followed by only bimekizumab up to week 52.

Disclosures: This study was sponsored by UCB Pharma. Four authors reported being employees or shareholders of UCB Pharma. Several authors declared receiving research support or consulting fees or having other ties with various sources, including UCB Pharma.

Source: Coates LC, Landewe R, McInnes IB, et al. Bimekizumab treatment in patients with active psoriatic arthritis and prior inadequate response to tumour necrosis factor inhibitors: 52-week safety and efficacy from the phase III BE COMPLETE study and its open-label extension BE VITAL. RMD Open. 2024;10:e003855 (Feb 22). doi: 10.1136/rmdopen-2023-003855 Source

Key clinical point: Bimekizumab led to long-term improvements in efficacy outcomes and had a manageable safety profile in patients with active psoriatic arthritis (PsA) and prior inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR).

Major finding: At week 16, a significantly higher number of patients achieved ≥50% improvement in American College of Rheumatology response with bimekizumab vs placebo (43.4% vs 6.8%; P < .0001), with improvements sustained up to week 52 by >40% of patients receiving bimekizumab. No new safety signals were observed.

Study details: Findings are from the BE VITAL open-label extension study including 377 patients with active PsA and TNFi-IR who received bimekizumab or placebo for 16 weeks followed by only bimekizumab up to week 52.

Disclosures: This study was sponsored by UCB Pharma. Four authors reported being employees or shareholders of UCB Pharma. Several authors declared receiving research support or consulting fees or having other ties with various sources, including UCB Pharma.

Source: Coates LC, Landewe R, McInnes IB, et al. Bimekizumab treatment in patients with active psoriatic arthritis and prior inadequate response to tumour necrosis factor inhibitors: 52-week safety and efficacy from the phase III BE COMPLETE study and its open-label extension BE VITAL. RMD Open. 2024;10:e003855 (Feb 22). doi: 10.1136/rmdopen-2023-003855 Source

Key clinical point: The incidence rates of major adverse cardiovascular events (MACE) were similar in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA), suggesting that both inflammatory disorders share a common atherogenic mechanism.

Major finding: After a total of 119,571 patient-years of follow-up, 6.7% of patients with RA or PsA developed MACE for the first time. The rates of MACE incidence (adjusted incidence rate ratio 0.96; P  =  .767) and MACE-free survival (P  =  .987) were comparable between patients with PsA and RA. Higher time-varying erythrocyte sedimentation rate, C-reactive protein levels, and exposure to glucocorticoids increased the risk for MACE in both patients with PsA and RA (all P < .05).

Study details: This population based retrospective cohort study included 13,905 patients with PsA (n  =  1672) or RA (n  =  12,233) who did not have any previous history of MACE.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Meng H, Lam SH, So H, Tam LS. Incidence and risk factors of major cardiovascular events in rheumatoid arthritis and psoriatic arthritis: A population-based cohort study. Semin Arthritis Rheum. 2024;65:152416 (Feb 17). Source

Key clinical point: The incidence rates of major adverse cardiovascular events (MACE) were similar in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA), suggesting that both inflammatory disorders share a common atherogenic mechanism.

Major finding: After a total of 119,571 patient-years of follow-up, 6.7% of patients with RA or PsA developed MACE for the first time. The rates of MACE incidence (adjusted incidence rate ratio 0.96; P  =  .767) and MACE-free survival (P  =  .987) were comparable between patients with PsA and RA. Higher time-varying erythrocyte sedimentation rate, C-reactive protein levels, and exposure to glucocorticoids increased the risk for MACE in both patients with PsA and RA (all P < .05).

Study details: This population based retrospective cohort study included 13,905 patients with PsA (n  =  1672) or RA (n  =  12,233) who did not have any previous history of MACE.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Meng H, Lam SH, So H, Tam LS. Incidence and risk factors of major cardiovascular events in rheumatoid arthritis and psoriatic arthritis: A population-based cohort study. Semin Arthritis Rheum. 2024;65:152416 (Feb 17). Source

Key clinical point: The incidence rates of major adverse cardiovascular events (MACE) were similar in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA), suggesting that both inflammatory disorders share a common atherogenic mechanism.

Major finding: After a total of 119,571 patient-years of follow-up, 6.7% of patients with RA or PsA developed MACE for the first time. The rates of MACE incidence (adjusted incidence rate ratio 0.96; P  =  .767) and MACE-free survival (P  =  .987) were comparable between patients with PsA and RA. Higher time-varying erythrocyte sedimentation rate, C-reactive protein levels, and exposure to glucocorticoids increased the risk for MACE in both patients with PsA and RA (all P < .05).

Study details: This population based retrospective cohort study included 13,905 patients with PsA (n  =  1672) or RA (n  =  12,233) who did not have any previous history of MACE.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Meng H, Lam SH, So H, Tam LS. Incidence and risk factors of major cardiovascular events in rheumatoid arthritis and psoriatic arthritis: A population-based cohort study. Semin Arthritis Rheum. 2024;65:152416 (Feb 17). Source

Key clinical point: Ixekizumab was more effective than adalimumab in resolving distal interphalangeal (DIP) joint tenderness, swelling, and adjacent nail psoriasis in patients with psoriatic arthritis (PsA) and DIP joint involvement who nearly invariably had adjacent nail psoriasis.

Major finding: More than 96% of patients with PsA and simultaneous DIP joint involvement reported adjacent nail psoriasis in at least one digit in the finger unit. Ixekizumab vs adalimumab led to greater improvements in DIP involvement and adjacent nail psoriasis as early as week 12 (38.8% vs 28.4%; P < .0001), with improvements sustained up to week 52 (64.9% vs 57.5%; P  =  .0055).

Study details: This post hoc analysis of the SPIRIT-H2H study included 354 patients with PsA who had simultaneous DIP joint involvement and adjacent nail psoriasis and were randomly assigned to receive ixekizumab or adalimumab.

Disclosures: This study was supported by Eli Lilly and Company. Four authors declared being employees and shareholders of Eli Lilly and Company. The other authors reported ties with various sources, including Eli Lilly and Company.

Source: McGonagle D, Kavanaugh A, McInnes IB, et al. Association of the clinical components in the distal interphalangeal joint synovio-entheseal complex and subsequent response to ixekizumab or adalimumab in psoriatic arthritis. Rheumatology (Oxford). 2024 (Feb 10). doi: 10.1093/rheumatology/keae060 Source

Key clinical point: Ixekizumab was more effective than adalimumab in resolving distal interphalangeal (DIP) joint tenderness, swelling, and adjacent nail psoriasis in patients with psoriatic arthritis (PsA) and DIP joint involvement who nearly invariably had adjacent nail psoriasis.

Major finding: More than 96% of patients with PsA and simultaneous DIP joint involvement reported adjacent nail psoriasis in at least one digit in the finger unit. Ixekizumab vs adalimumab led to greater improvements in DIP involvement and adjacent nail psoriasis as early as week 12 (38.8% vs 28.4%; P < .0001), with improvements sustained up to week 52 (64.9% vs 57.5%; P  =  .0055).

Study details: This post hoc analysis of the SPIRIT-H2H study included 354 patients with PsA who had simultaneous DIP joint involvement and adjacent nail psoriasis and were randomly assigned to receive ixekizumab or adalimumab.

Disclosures: This study was supported by Eli Lilly and Company. Four authors declared being employees and shareholders of Eli Lilly and Company. The other authors reported ties with various sources, including Eli Lilly and Company.

Source: McGonagle D, Kavanaugh A, McInnes IB, et al. Association of the clinical components in the distal interphalangeal joint synovio-entheseal complex and subsequent response to ixekizumab or adalimumab in psoriatic arthritis. Rheumatology (Oxford). 2024 (Feb 10). doi: 10.1093/rheumatology/keae060 Source

Key clinical point: Ixekizumab was more effective than adalimumab in resolving distal interphalangeal (DIP) joint tenderness, swelling, and adjacent nail psoriasis in patients with psoriatic arthritis (PsA) and DIP joint involvement who nearly invariably had adjacent nail psoriasis.

Major finding: More than 96% of patients with PsA and simultaneous DIP joint involvement reported adjacent nail psoriasis in at least one digit in the finger unit. Ixekizumab vs adalimumab led to greater improvements in DIP involvement and adjacent nail psoriasis as early as week 12 (38.8% vs 28.4%; P < .0001), with improvements sustained up to week 52 (64.9% vs 57.5%; P  =  .0055).

Study details: This post hoc analysis of the SPIRIT-H2H study included 354 patients with PsA who had simultaneous DIP joint involvement and adjacent nail psoriasis and were randomly assigned to receive ixekizumab or adalimumab.

Disclosures: This study was supported by Eli Lilly and Company. Four authors declared being employees and shareholders of Eli Lilly and Company. The other authors reported ties with various sources, including Eli Lilly and Company.

Source: McGonagle D, Kavanaugh A, McInnes IB, et al. Association of the clinical components in the distal interphalangeal joint synovio-entheseal complex and subsequent response to ixekizumab or adalimumab in psoriatic arthritis. Rheumatology (Oxford). 2024 (Feb 10). doi: 10.1093/rheumatology/keae060 Source

The rheumatologist of the future will see patients who have been assessed and triaged with artificial intelligence utilizing data from remote kiosk-placed ultrasound scanners and physician-directed algorithms. Practices will be broadly fueled by AI, which will screen charts, produce notes, handle prior authorizations and insurance issues, aid in earlier diagnoses, find patients for clinical trials, and maybe even suggest the next best therapy for individual patients.

Such is the future envisioned by Alvin F. Wells, MD, PhD, and John J. Cush, MD, who discussed the current and forthcoming reach of AI — and their own uses of it — at the 2024 Rheumatology Winter Clinical Symposium.

“We’re not at the stage where ChatGPT and AI can tell us what the next best therapy is, but we’re getting there,” said Dr. Cush, a rheumatologist based in Dallas and executive director of RheumNow.com. For now, he said, “AI affords us a truly big-time increase in efficiency. It helps you deal with your time constraints in managing information overload and task overload.”

Bruce Jancin/MDedge News

At a time when “PubMed doubles every 73 days ... and it’s getting harder and harder to stay abreast,” for example, new applications such as Scite, SciSpace, and Consensus can help curate, focus, and analyze the literature to match one’s own clinical interests. Such review tools are “just now getting into play and are evolving,” Dr. Cush said, noting that many but not all of them are based on ChatGPT, OpenAI’s chatbot that had a over 100 million users by January 2023 — just over a month after its version 3.5 was released.

For Dr. Wells, a rheumatologist and Midwest Region director in the department of rheumatology for the Advocate Health Medical Group in Franklin, Wisconsin, clinician-developed algorithms are helping his group assess patients — often remotely — and triage them to be seen fairly immediately by a rheumatologist versus in 4-6 weeks or in several months. “You can use AI to guide your access,” he said.

A patient “with a family history of RA, sed rate above 50, and osteopenia on x-rays” would be seen within a week, for example, while “another patient who’s had a [positive] ANA with no other symptoms, and maybe a family history, might be seen in 4-6 weeks,” said Dr. Wells, sharing his belief that “there is not a shortage of rheumatologists, [but a] shortage of using rheumatologists efficiently.”

Dr. Wells

AI for Improving Workflow

Current and future advances will enrich the intersection of AI and virtual medicine and improve outcomes and the rheumatologist-patient interaction, Dr. Wells said, pointing to research presented at the American College of Rheumatology (ACR) 2023 annual meeting on the use of computer vision technology for remotely assessing disease activity in rheumatoid arthritis (RA).

In the proof-of-concept “MeFisto” study, 28 patients with RA used an app that enabled computer vision inference of hand motion data. Upon recording, an algorithm tracked the mean degree change of joint angle on flexion and the mean time to maximal flexion for each joint.

The researchers found a strong correlation between flexion of the distal interphalangeal (DIP) joint and the Disease Activity Score in 28 joints, the Swollen Hand Joint Count, and the Tender Hand Joint Count. DIP flexion was found to be a significant predictor of low disease activity/remission and high disease activity, the researchers reported in their abstract.

“This blows you away — that a single camera on [one’s] smartphone can look at the manipulation of a hand … and that AI can tell me, there’s a chance this might be an inflammatory arthritis,” said Dr. Wells, noting that researchers are also developing ways to detect joint swelling in RA by AI.

AI can also be used for remote ultrasound scanning in RA, as evidenced by use of the ARTHUR system in Europe, he said. Developed by the Danish company ROPCA, the ARTHUR technology (Rheumatoid Arthritis Ultrasound Robot) interacts directly with the patient who has new joint pain or established RA to capture ultrasound images in grayscale and color flow of 11 joints per hand. AI analyzes the images and creates a report for the specialist.

“They’re trying to get a foothold in the US,” Dr. Wells said, sharing his prediction that similar technology will someday be seen not only in pharmacies but also — in support of equitable access — in locations such as grocery stores. “Again,” he said, “nothing will replace us. I’m taking all [such] information and saying, who needs to be seen in 7 days and who can wait.”
 

AI for Writing, for Improving Practice and Patient Care

To manage his “task overload,” Dr. Cush uses ChatGPT for jobs such as first drafts of articles and making PowerPoint slides. It must be used cautiously for medical writing, however, as inaccuracies and false data/fabricated information — some of which has been coined AI “hallucinations” — are not uncommon.

“It’s very good at manuscript drafts, at generating bibliographies … it can do systematic reviews, it can do network meta-analyses, and it can find trends and patterns that can very helpful when it comes to writing. But you have to know how it’s a tool, and how it can hurt you,” he said.

Researchers recently reported asking ChatGPT to write an editorial about “how AI may replace the rheumatologist in editorial writing,” Dr. Cush noted. ChatGPT was “very politically correct,” he quipped, because it wrote that AI is “a tool to help the rheumatologist, but not replace him.”

Publishers want to preserve human intelligence — critical thinking and the ability to interpret, for instance — and most of the top medical journals (those most often cited) have issued guidance on the use of generative AI. “One said AI can’t be attributed as an author because being an author carries with it accountability of the work, and AI can’t take responsibility,” Dr. Cush said. Journals also “are saying you can use AI but you have to be totally transparent about it … [how it’s used] has to be very well spelled out.”

In practice, chatbots can be used for summarizing medical records, drafting post-visit summaries, collecting patient feedback, reminding about vaccinations, and performing administrative functions. “It’s really limitless as to what chatbots can do,” Dr. Cush said. “The question is, [what is] really going to help you?”

Much of the research submitted for presentation at major rheumatology meetings over the years has had questionable real-world utility and value, he said. But in the future this will likely change. “Take the PsA [psoriatic arthritis] patient who hasn’t responded to methotrexate or apremilast [Otezla]. There are [so many] choices, and there really isn’t a clear one. Shouldn’t data guide us on whether an IL-23 is better than a JAK, or maybe a JAK preferred over a TNF for some reason?” Dr. Cush said. “That’s what we’re hoping will happen down the line.”

More realistic AI-guided clinical scenarios for now include the following: AI screens the chart of a 68-year-old with RA on methotrexate and etanercept who is following up, and retrieves pieces of history — an elevated C-reactive protein 3 months ago, for instance, and diverticulosis 5 years ago. “AI tells you, based on this, he may have active disease, and here are three medications covered by his insurance,” Dr. Wells said.

Or, in the case of a 58-year-old patient with RA who has scheduled a virtual follow-up visit after having been on methotrexate and hydroxychloroquine for 12 weeks, AI detects a low platelet count in her previsit labs and also sees that she received an MMR booster 5 weeks ago at a local CVS Minute Clinic. AI retrieves for the rheumatologist a review article about thrombocytopenic purpura after MMR vaccination.
 

AI for Drug Development, Clinical Trials

Dr. Cush is following with keen interest the integration of AI into the process of drug development, from drug discovery and biomarker evaluation to clinical trial efficiency and patient recruitment, as well as marketing. “A lot hasn’t been ‘rolled out’ or shown to us, but there’s a lot going on … everyone is investing,” he said. “The number one challenge is regulatory: How will the [Food and Drug Administration] handle AI-generated data sets or AI-generated or monitored trials?”

The FDA is working to ensure quality and utility of data and is rapidly “approving AI algorithms for use in medicine and healthcare,” he said.

AI’s ability to identify patients in populations can not only facilitate earlier diagnoses but can accelerate patient recruitment for clinical trials, Dr. Cush emphasized. He pointed to research presented at the ACR 2021 annual meeting in which a machine-learning algorithm was used with electronic health records in the United Kingdom to estimate the probability of a patient’s being diagnosed with axial spondyloarthritis (axSpA).

AI identified 89 best clinical predictors (out of 820 analyzed). When applying these predictors to the population, AI was able to differentiate patients with axSpA from healthy controls with a sensitivity of 75%, a specificity of 96%, and a positive predictive value of 81%. Such an application of AI “is ideal … It would make clinical trials more streamlined and productive,” he said.

The extent to which AI will lead to cost savings — in the pharmacology arena, for instance, or for Well’s medical group — is unknown, Dr. Cush and Dr. Wells said. And, of course, there are concerns about potential bias and abuse of AI. “The worry,” Dr. Cush said, “is, who’s watching?”

Dr. Wells disclosed that he has research support and has served as a member of advisory boards and/or speaker bureaus for 17 different pharmaceutical or medical technology companies. Dr. Cush disclosed relationships with AbbVie, Amgen, Bristol-Myers Squibb, Novartis, Sanofi, and UCB.

The rheumatologist of the future will see patients who have been assessed and triaged with artificial intelligence utilizing data from remote kiosk-placed ultrasound scanners and physician-directed algorithms. Practices will be broadly fueled by AI, which will screen charts, produce notes, handle prior authorizations and insurance issues, aid in earlier diagnoses, find patients for clinical trials, and maybe even suggest the next best therapy for individual patients.

Such is the future envisioned by Alvin F. Wells, MD, PhD, and John J. Cush, MD, who discussed the current and forthcoming reach of AI — and their own uses of it — at the 2024 Rheumatology Winter Clinical Symposium.

“We’re not at the stage where ChatGPT and AI can tell us what the next best therapy is, but we’re getting there,” said Dr. Cush, a rheumatologist based in Dallas and executive director of RheumNow.com. For now, he said, “AI affords us a truly big-time increase in efficiency. It helps you deal with your time constraints in managing information overload and task overload.”

Bruce Jancin/MDedge News

At a time when “PubMed doubles every 73 days ... and it’s getting harder and harder to stay abreast,” for example, new applications such as Scite, SciSpace, and Consensus can help curate, focus, and analyze the literature to match one’s own clinical interests. Such review tools are “just now getting into play and are evolving,” Dr. Cush said, noting that many but not all of them are based on ChatGPT, OpenAI’s chatbot that had a over 100 million users by January 2023 — just over a month after its version 3.5 was released.

For Dr. Wells, a rheumatologist and Midwest Region director in the department of rheumatology for the Advocate Health Medical Group in Franklin, Wisconsin, clinician-developed algorithms are helping his group assess patients — often remotely — and triage them to be seen fairly immediately by a rheumatologist versus in 4-6 weeks or in several months. “You can use AI to guide your access,” he said.

A patient “with a family history of RA, sed rate above 50, and osteopenia on x-rays” would be seen within a week, for example, while “another patient who’s had a [positive] ANA with no other symptoms, and maybe a family history, might be seen in 4-6 weeks,” said Dr. Wells, sharing his belief that “there is not a shortage of rheumatologists, [but a] shortage of using rheumatologists efficiently.”

Dr. Wells

AI for Improving Workflow

Current and future advances will enrich the intersection of AI and virtual medicine and improve outcomes and the rheumatologist-patient interaction, Dr. Wells said, pointing to research presented at the American College of Rheumatology (ACR) 2023 annual meeting on the use of computer vision technology for remotely assessing disease activity in rheumatoid arthritis (RA).

In the proof-of-concept “MeFisto” study, 28 patients with RA used an app that enabled computer vision inference of hand motion data. Upon recording, an algorithm tracked the mean degree change of joint angle on flexion and the mean time to maximal flexion for each joint.

The researchers found a strong correlation between flexion of the distal interphalangeal (DIP) joint and the Disease Activity Score in 28 joints, the Swollen Hand Joint Count, and the Tender Hand Joint Count. DIP flexion was found to be a significant predictor of low disease activity/remission and high disease activity, the researchers reported in their abstract.

“This blows you away — that a single camera on [one’s] smartphone can look at the manipulation of a hand … and that AI can tell me, there’s a chance this might be an inflammatory arthritis,” said Dr. Wells, noting that researchers are also developing ways to detect joint swelling in RA by AI.

AI can also be used for remote ultrasound scanning in RA, as evidenced by use of the ARTHUR system in Europe, he said. Developed by the Danish company ROPCA, the ARTHUR technology (Rheumatoid Arthritis Ultrasound Robot) interacts directly with the patient who has new joint pain or established RA to capture ultrasound images in grayscale and color flow of 11 joints per hand. AI analyzes the images and creates a report for the specialist.

“They’re trying to get a foothold in the US,” Dr. Wells said, sharing his prediction that similar technology will someday be seen not only in pharmacies but also — in support of equitable access — in locations such as grocery stores. “Again,” he said, “nothing will replace us. I’m taking all [such] information and saying, who needs to be seen in 7 days and who can wait.”
 

AI for Writing, for Improving Practice and Patient Care

To manage his “task overload,” Dr. Cush uses ChatGPT for jobs such as first drafts of articles and making PowerPoint slides. It must be used cautiously for medical writing, however, as inaccuracies and false data/fabricated information — some of which has been coined AI “hallucinations” — are not uncommon.

“It’s very good at manuscript drafts, at generating bibliographies … it can do systematic reviews, it can do network meta-analyses, and it can find trends and patterns that can very helpful when it comes to writing. But you have to know how it’s a tool, and how it can hurt you,” he said.

Researchers recently reported asking ChatGPT to write an editorial about “how AI may replace the rheumatologist in editorial writing,” Dr. Cush noted. ChatGPT was “very politically correct,” he quipped, because it wrote that AI is “a tool to help the rheumatologist, but not replace him.”

Publishers want to preserve human intelligence — critical thinking and the ability to interpret, for instance — and most of the top medical journals (those most often cited) have issued guidance on the use of generative AI. “One said AI can’t be attributed as an author because being an author carries with it accountability of the work, and AI can’t take responsibility,” Dr. Cush said. Journals also “are saying you can use AI but you have to be totally transparent about it … [how it’s used] has to be very well spelled out.”

In practice, chatbots can be used for summarizing medical records, drafting post-visit summaries, collecting patient feedback, reminding about vaccinations, and performing administrative functions. “It’s really limitless as to what chatbots can do,” Dr. Cush said. “The question is, [what is] really going to help you?”

Much of the research submitted for presentation at major rheumatology meetings over the years has had questionable real-world utility and value, he said. But in the future this will likely change. “Take the PsA [psoriatic arthritis] patient who hasn’t responded to methotrexate or apremilast [Otezla]. There are [so many] choices, and there really isn’t a clear one. Shouldn’t data guide us on whether an IL-23 is better than a JAK, or maybe a JAK preferred over a TNF for some reason?” Dr. Cush said. “That’s what we’re hoping will happen down the line.”

More realistic AI-guided clinical scenarios for now include the following: AI screens the chart of a 68-year-old with RA on methotrexate and etanercept who is following up, and retrieves pieces of history — an elevated C-reactive protein 3 months ago, for instance, and diverticulosis 5 years ago. “AI tells you, based on this, he may have active disease, and here are three medications covered by his insurance,” Dr. Wells said.

Or, in the case of a 58-year-old patient with RA who has scheduled a virtual follow-up visit after having been on methotrexate and hydroxychloroquine for 12 weeks, AI detects a low platelet count in her previsit labs and also sees that she received an MMR booster 5 weeks ago at a local CVS Minute Clinic. AI retrieves for the rheumatologist a review article about thrombocytopenic purpura after MMR vaccination.
 

AI for Drug Development, Clinical Trials

Dr. Cush is following with keen interest the integration of AI into the process of drug development, from drug discovery and biomarker evaluation to clinical trial efficiency and patient recruitment, as well as marketing. “A lot hasn’t been ‘rolled out’ or shown to us, but there’s a lot going on … everyone is investing,” he said. “The number one challenge is regulatory: How will the [Food and Drug Administration] handle AI-generated data sets or AI-generated or monitored trials?”

The FDA is working to ensure quality and utility of data and is rapidly “approving AI algorithms for use in medicine and healthcare,” he said.

AI’s ability to identify patients in populations can not only facilitate earlier diagnoses but can accelerate patient recruitment for clinical trials, Dr. Cush emphasized. He pointed to research presented at the ACR 2021 annual meeting in which a machine-learning algorithm was used with electronic health records in the United Kingdom to estimate the probability of a patient’s being diagnosed with axial spondyloarthritis (axSpA).

AI identified 89 best clinical predictors (out of 820 analyzed). When applying these predictors to the population, AI was able to differentiate patients with axSpA from healthy controls with a sensitivity of 75%, a specificity of 96%, and a positive predictive value of 81%. Such an application of AI “is ideal … It would make clinical trials more streamlined and productive,” he said.

The extent to which AI will lead to cost savings — in the pharmacology arena, for instance, or for Well’s medical group — is unknown, Dr. Cush and Dr. Wells said. And, of course, there are concerns about potential bias and abuse of AI. “The worry,” Dr. Cush said, “is, who’s watching?”

Dr. Wells disclosed that he has research support and has served as a member of advisory boards and/or speaker bureaus for 17 different pharmaceutical or medical technology companies. Dr. Cush disclosed relationships with AbbVie, Amgen, Bristol-Myers Squibb, Novartis, Sanofi, and UCB.

The rheumatologist of the future will see patients who have been assessed and triaged with artificial intelligence utilizing data from remote kiosk-placed ultrasound scanners and physician-directed algorithms. Practices will be broadly fueled by AI, which will screen charts, produce notes, handle prior authorizations and insurance issues, aid in earlier diagnoses, find patients for clinical trials, and maybe even suggest the next best therapy for individual patients.

Such is the future envisioned by Alvin F. Wells, MD, PhD, and John J. Cush, MD, who discussed the current and forthcoming reach of AI — and their own uses of it — at the 2024 Rheumatology Winter Clinical Symposium.

“We’re not at the stage where ChatGPT and AI can tell us what the next best therapy is, but we’re getting there,” said Dr. Cush, a rheumatologist based in Dallas and executive director of RheumNow.com. For now, he said, “AI affords us a truly big-time increase in efficiency. It helps you deal with your time constraints in managing information overload and task overload.”

Bruce Jancin/MDedge News

At a time when “PubMed doubles every 73 days ... and it’s getting harder and harder to stay abreast,” for example, new applications such as Scite, SciSpace, and Consensus can help curate, focus, and analyze the literature to match one’s own clinical interests. Such review tools are “just now getting into play and are evolving,” Dr. Cush said, noting that many but not all of them are based on ChatGPT, OpenAI’s chatbot that had a over 100 million users by January 2023 — just over a month after its version 3.5 was released.

For Dr. Wells, a rheumatologist and Midwest Region director in the department of rheumatology for the Advocate Health Medical Group in Franklin, Wisconsin, clinician-developed algorithms are helping his group assess patients — often remotely — and triage them to be seen fairly immediately by a rheumatologist versus in 4-6 weeks or in several months. “You can use AI to guide your access,” he said.

A patient “with a family history of RA, sed rate above 50, and osteopenia on x-rays” would be seen within a week, for example, while “another patient who’s had a [positive] ANA with no other symptoms, and maybe a family history, might be seen in 4-6 weeks,” said Dr. Wells, sharing his belief that “there is not a shortage of rheumatologists, [but a] shortage of using rheumatologists efficiently.”

Dr. Wells

AI for Improving Workflow

Current and future advances will enrich the intersection of AI and virtual medicine and improve outcomes and the rheumatologist-patient interaction, Dr. Wells said, pointing to research presented at the American College of Rheumatology (ACR) 2023 annual meeting on the use of computer vision technology for remotely assessing disease activity in rheumatoid arthritis (RA).

In the proof-of-concept “MeFisto” study, 28 patients with RA used an app that enabled computer vision inference of hand motion data. Upon recording, an algorithm tracked the mean degree change of joint angle on flexion and the mean time to maximal flexion for each joint.

The researchers found a strong correlation between flexion of the distal interphalangeal (DIP) joint and the Disease Activity Score in 28 joints, the Swollen Hand Joint Count, and the Tender Hand Joint Count. DIP flexion was found to be a significant predictor of low disease activity/remission and high disease activity, the researchers reported in their abstract.

“This blows you away — that a single camera on [one’s] smartphone can look at the manipulation of a hand … and that AI can tell me, there’s a chance this might be an inflammatory arthritis,” said Dr. Wells, noting that researchers are also developing ways to detect joint swelling in RA by AI.

AI can also be used for remote ultrasound scanning in RA, as evidenced by use of the ARTHUR system in Europe, he said. Developed by the Danish company ROPCA, the ARTHUR technology (Rheumatoid Arthritis Ultrasound Robot) interacts directly with the patient who has new joint pain or established RA to capture ultrasound images in grayscale and color flow of 11 joints per hand. AI analyzes the images and creates a report for the specialist.

“They’re trying to get a foothold in the US,” Dr. Wells said, sharing his prediction that similar technology will someday be seen not only in pharmacies but also — in support of equitable access — in locations such as grocery stores. “Again,” he said, “nothing will replace us. I’m taking all [such] information and saying, who needs to be seen in 7 days and who can wait.”
 

AI for Writing, for Improving Practice and Patient Care

To manage his “task overload,” Dr. Cush uses ChatGPT for jobs such as first drafts of articles and making PowerPoint slides. It must be used cautiously for medical writing, however, as inaccuracies and false data/fabricated information — some of which has been coined AI “hallucinations” — are not uncommon.

“It’s very good at manuscript drafts, at generating bibliographies … it can do systematic reviews, it can do network meta-analyses, and it can find trends and patterns that can very helpful when it comes to writing. But you have to know how it’s a tool, and how it can hurt you,” he said.

Researchers recently reported asking ChatGPT to write an editorial about “how AI may replace the rheumatologist in editorial writing,” Dr. Cush noted. ChatGPT was “very politically correct,” he quipped, because it wrote that AI is “a tool to help the rheumatologist, but not replace him.”

Publishers want to preserve human intelligence — critical thinking and the ability to interpret, for instance — and most of the top medical journals (those most often cited) have issued guidance on the use of generative AI. “One said AI can’t be attributed as an author because being an author carries with it accountability of the work, and AI can’t take responsibility,” Dr. Cush said. Journals also “are saying you can use AI but you have to be totally transparent about it … [how it’s used] has to be very well spelled out.”

In practice, chatbots can be used for summarizing medical records, drafting post-visit summaries, collecting patient feedback, reminding about vaccinations, and performing administrative functions. “It’s really limitless as to what chatbots can do,” Dr. Cush said. “The question is, [what is] really going to help you?”

Much of the research submitted for presentation at major rheumatology meetings over the years has had questionable real-world utility and value, he said. But in the future this will likely change. “Take the PsA [psoriatic arthritis] patient who hasn’t responded to methotrexate or apremilast [Otezla]. There are [so many] choices, and there really isn’t a clear one. Shouldn’t data guide us on whether an IL-23 is better than a JAK, or maybe a JAK preferred over a TNF for some reason?” Dr. Cush said. “That’s what we’re hoping will happen down the line.”

More realistic AI-guided clinical scenarios for now include the following: AI screens the chart of a 68-year-old with RA on methotrexate and etanercept who is following up, and retrieves pieces of history — an elevated C-reactive protein 3 months ago, for instance, and diverticulosis 5 years ago. “AI tells you, based on this, he may have active disease, and here are three medications covered by his insurance,” Dr. Wells said.

Or, in the case of a 58-year-old patient with RA who has scheduled a virtual follow-up visit after having been on methotrexate and hydroxychloroquine for 12 weeks, AI detects a low platelet count in her previsit labs and also sees that she received an MMR booster 5 weeks ago at a local CVS Minute Clinic. AI retrieves for the rheumatologist a review article about thrombocytopenic purpura after MMR vaccination.
 

AI for Drug Development, Clinical Trials

Dr. Cush is following with keen interest the integration of AI into the process of drug development, from drug discovery and biomarker evaluation to clinical trial efficiency and patient recruitment, as well as marketing. “A lot hasn’t been ‘rolled out’ or shown to us, but there’s a lot going on … everyone is investing,” he said. “The number one challenge is regulatory: How will the [Food and Drug Administration] handle AI-generated data sets or AI-generated or monitored trials?”

The FDA is working to ensure quality and utility of data and is rapidly “approving AI algorithms for use in medicine and healthcare,” he said.

AI’s ability to identify patients in populations can not only facilitate earlier diagnoses but can accelerate patient recruitment for clinical trials, Dr. Cush emphasized. He pointed to research presented at the ACR 2021 annual meeting in which a machine-learning algorithm was used with electronic health records in the United Kingdom to estimate the probability of a patient’s being diagnosed with axial spondyloarthritis (axSpA).

AI identified 89 best clinical predictors (out of 820 analyzed). When applying these predictors to the population, AI was able to differentiate patients with axSpA from healthy controls with a sensitivity of 75%, a specificity of 96%, and a positive predictive value of 81%. Such an application of AI “is ideal … It would make clinical trials more streamlined and productive,” he said.

The extent to which AI will lead to cost savings — in the pharmacology arena, for instance, or for Well’s medical group — is unknown, Dr. Cush and Dr. Wells said. And, of course, there are concerns about potential bias and abuse of AI. “The worry,” Dr. Cush said, “is, who’s watching?”

Dr. Wells disclosed that he has research support and has served as a member of advisory boards and/or speaker bureaus for 17 different pharmaceutical or medical technology companies. Dr. Cush disclosed relationships with AbbVie, Amgen, Bristol-Myers Squibb, Novartis, Sanofi, and UCB.

The Food and Drug Administration’s approval of leflunomide in September 1998 as a treatment for rheumatoid arthritis was sandwiched between the debuts of infliximab (Remicade and biosimilars) and etanercept (Enbrel) in August and November of that year, the latter of which was so exciting that “within 2 months you couldn’t get [it],” recalled Eric M. Ruderman, MD. And “like every middle child, [leflunomide] was underloved, underappreciated, and largely dismissed.”

Yet should it have been? Is it worth another look today?

Courtesy Michael Pollard

At the 2024 Rheumatology Winter Clinical Symposium, Dr. Ruderman reflected on some of the clinical trial data published after leflunomide’s approval that “got lost in the shuffle” of the rightful embrace of biologics in United States practice, and urged reconsideration of the loading strategy still advised in the drug’s labeling.

“I’m not telling you that you should be using [leflunomide] in place of biologics, instead of biologics, or before biologics … but it should be in your toolkit,” said Dr. Ruderman, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago. The drug “still has a role in RA, including in combination with methotrexate, and a potential role in other rheumatic diseases.”

“In our PsA clinic,” he noted, “we’ve actually not infrequently added leflunomide to some of the other agents we’ve been using.”
 

Key Findings Over the Years in RA

Leflunomide showed efficacy similar to that of sulfasalazine in a randomized trial published in 1999 that used primary endpoints of tender/swollen joints and physician and patient global scores. Then, against methotrexate, it proved just as efficacious in achieving at least 20% improvement in American College of Rheumatology composite response criteria (ACR20) over 52 weeks, and in meeting endpoints similar to those of the sulfasalazine trial, in two trials, one published in 1999 and another in 2000.

“So here were two big trials [comparing it with methotrexate] that suggested the drug was just as good as what had become our standard of care by that point,” Dr. Ruderman said.

Each of these three trials used a loading dose of 100 mg leflunomide for 3 days, followed by 20 mg daily. Sulfasalazine was initiated at 2 g and escalated over 4 weeks. Methotrexate was initiated in one of the trials at a dose of 7.5 mg, then increased to 15 mg in almost two-thirds of patients; in the other methotrexate trial the initial dose was 15 mg escalated over 3 months.

Side effects of leflunomide — GI issues, rash, alopecia (reversible), and elevated liver function tests — were similar across the trials, and represented “about the same toxicities as methotrexate,” he said.

Researchers then tested leflunomide as an add-on to methotrexate in patients who had inadequate response, which “was a little bit daunting since we were still concerned about the toxicity of methotrexate at this point,” Dr. Ruderman said. “The idea that we’d take another drug with similar toxicities and add it on to the methotrexate was a little scary.”

But it worked. Patients on a mean background dose of 16.5 mg methotrexate were randomized to placebo or to a 2-day leflunomide loading dose followed by 10 mg/day that could be escalated at 8 weeks to 20 mg if needed. At 6 months, 19.5% and 46.2%, respectively, met ACR20 (P < .001), and “interestingly,” he said, “adverse events were pretty similar” between combination therapy and methotrexate monotherapy.

“This was very much like all the studies we’ve seen over the years with new biologics — they were all added to background methotrexate,” he said. “And the truth is, the [46%] response seen when adding leflunomide to background methotrexate wasn’t very different from the 50% [ACR20] response you tend to see when you add a biologic.”

However, despite the study’s conclusion that combination therapy provided significant benefit to patients with inadequate response to methotrexate alone, “the drug got lost, because everyone was prescribing the biologics,” Dr. Ruderman said.

He said he found only one study comparing leflunomide with a biologic. In a notably small but well-designed study from Sri Lanka published in 2017, 40 patients with an inadequate response to methotrexate were randomized to low-dose rituximab (500 mg x 2) or 20 mg/day leflunomide (no loading dose). At week 24, ACR20 was nearly identical (85% vs 84%), with a similar rate of adverse events.

The researchers pointed out “that there’s a potential cost benefit in developing countries where biologics aren’t as accessible,” he said, agreeing that “the big opportunity for a drug like leflunomide is outside the US, where you don’t have access to the drugs we take advantage of all the time.”

A meeting participant from Canada pointed out that rheumatologists there are “mandated to use it for PsA in combination with methotrexate before we can get a biologic, and for RA we can use it with Plaquenil [hydroxychloroquine] and methotrexate before we get a biologic, so we’re using it all the time.”

Asked about efficacy, the physician said the combination with methotrexate is “absolutely” efficacious. “It works really well” he said. “The problem is, you really have to watch the white cell count and liver function … and the half-life is long.”

Indeed, Dr. Ruderman said during his talk, the plasma half-life of teriflunomide, its active metabolite, is 15.5 days, which is challenging when adverse events occur. “And it’s a terrible drug in young women thinking about pregnancy because it’s teratogenic and stays around,” he said.

Leflunomide, which, notably, was “developed specifically for RA from the get-go” and not borrowed from another specialty, works by blocking de novo pyrimidine synthesis, Dr. Ruderman said. T-cell activation requires the upregulation of pyrimidine production (salvage pathways are insufficient); the “drug prevents that” by inhibiting an enzyme that catalyzes conversion of dihydroorotate to orotate, which, in turn, is converted to pyrimidine ribonucleotides, he explained.

Other potential mechanisms of action have been proposed — mainly, inhibition of tumor necrosis factor signaling and inhibition of kinase activity, including the JAK/STAT pathway — but “there’s not great data for any of them,” he said.
 

Loading vs Not Loading, and Its Role in PsA and Other Diseases

“We stopped loading years ago because at 100 mg for 3 days in a row, everyone has GI issues,” Dr. Ruderman said. “It may have made sense from a pharmacokinetic standpoint because [based on the long half-life] you could get to a higher drug level quicker, but not a practical standpoint, because patients would stop the drug — they couldn’t take it.” The first study to examine the necessity of loading leflunomide in a “prospective, careful way” was published in 2013. It randomized 120 patients to 100 mg or 20 mg for 3 days, followed by a 3-month open-label period of 20 mg, and found no clinical benefit with loading but more diarrhea and elevated liver enzymes.

“It tells us something about how we need to think about half-lives,” he said. “Maybe [loading is] not necessary because the biological effects are different than the drug levels.”

In the PsA space, in 2004, researchers reported a double-blind randomized trial in which 190 patients with active PsA and cutaneous psoriasis with at least 3% body surface area involvement were randomized to receive leflunomide (a loading dose followed by 20 mg/day) or placebo for 24 weeks. Almost 60% of leflunomide-treated patients, compared with 30% of placebo-treated patients, were classified as responders by the Psoriatic Arthritis Response criteria (P < .0001), “which is a soft endpoint” but was utilized at the time, Dr. Ruderman said. The researchers noted improvements in ACR20 and skin responses as well, and toxicity was similar to that reported in the RA studies.

However, approval was never sought, and the drug was infrequently prescribed, “because etanercept came out for this disease, and then adalimumab … and then the world changed,” he said.

More recently, a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA tested leflunomide plus methotrexate vs methotrexate monotherapy and was published in The Lancet Rheumatology. After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1 [standard deviation (SD), 1.4] vs 3.7 [SD, 1.3]; treatment difference, -0.6; 90% CI, -1.0 to -0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than that of the monotherapy group (34%; P = .019). Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group.

In an interview after the meeting, Dr. Ruderman explained that in his practice, about 15 years ago, leflunomide was sometimes prescribed as an alternative to a biologic change for patients whose skin disease improved significantly with ustekinumab (Stelara) but who “suddenly had more joint symptoms that they didn’t have before.”

And “we’ve found ourselves a bit recently with the same sort of story, where patients are prescribed IL-23 inhibitors like Skyrizi [risankizumab] and Tremfya [guselkumab] and their skin does really well but now they’re having more joint symptoms than previously,” he said. “Our choices are to switch to a whole different biologic, or to think about adding something as an adjunct — and maybe leflunomide is a reasonable option.”

In the last 5 years, Dr. Ruderman noted, randomized trial data has been published on leflunomide in lupus nephritis induction, and in lupus nephritis maintenance, as well as in IgG4-related disease.

Dr. Ruderman disclosed consulting and/or drug safety monitoring board work for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Lilly, Merck, Novartis, NS Pharma, and UCB.

The Food and Drug Administration’s approval of leflunomide in September 1998 as a treatment for rheumatoid arthritis was sandwiched between the debuts of infliximab (Remicade and biosimilars) and etanercept (Enbrel) in August and November of that year, the latter of which was so exciting that “within 2 months you couldn’t get [it],” recalled Eric M. Ruderman, MD. And “like every middle child, [leflunomide] was underloved, underappreciated, and largely dismissed.”

Yet should it have been? Is it worth another look today?

Courtesy Michael Pollard

At the 2024 Rheumatology Winter Clinical Symposium, Dr. Ruderman reflected on some of the clinical trial data published after leflunomide’s approval that “got lost in the shuffle” of the rightful embrace of biologics in United States practice, and urged reconsideration of the loading strategy still advised in the drug’s labeling.

“I’m not telling you that you should be using [leflunomide] in place of biologics, instead of biologics, or before biologics … but it should be in your toolkit,” said Dr. Ruderman, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago. The drug “still has a role in RA, including in combination with methotrexate, and a potential role in other rheumatic diseases.”

“In our PsA clinic,” he noted, “we’ve actually not infrequently added leflunomide to some of the other agents we’ve been using.”
 

Key Findings Over the Years in RA

Leflunomide showed efficacy similar to that of sulfasalazine in a randomized trial published in 1999 that used primary endpoints of tender/swollen joints and physician and patient global scores. Then, against methotrexate, it proved just as efficacious in achieving at least 20% improvement in American College of Rheumatology composite response criteria (ACR20) over 52 weeks, and in meeting endpoints similar to those of the sulfasalazine trial, in two trials, one published in 1999 and another in 2000.

“So here were two big trials [comparing it with methotrexate] that suggested the drug was just as good as what had become our standard of care by that point,” Dr. Ruderman said.

Each of these three trials used a loading dose of 100 mg leflunomide for 3 days, followed by 20 mg daily. Sulfasalazine was initiated at 2 g and escalated over 4 weeks. Methotrexate was initiated in one of the trials at a dose of 7.5 mg, then increased to 15 mg in almost two-thirds of patients; in the other methotrexate trial the initial dose was 15 mg escalated over 3 months.

Side effects of leflunomide — GI issues, rash, alopecia (reversible), and elevated liver function tests — were similar across the trials, and represented “about the same toxicities as methotrexate,” he said.

Researchers then tested leflunomide as an add-on to methotrexate in patients who had inadequate response, which “was a little bit daunting since we were still concerned about the toxicity of methotrexate at this point,” Dr. Ruderman said. “The idea that we’d take another drug with similar toxicities and add it on to the methotrexate was a little scary.”

But it worked. Patients on a mean background dose of 16.5 mg methotrexate were randomized to placebo or to a 2-day leflunomide loading dose followed by 10 mg/day that could be escalated at 8 weeks to 20 mg if needed. At 6 months, 19.5% and 46.2%, respectively, met ACR20 (P < .001), and “interestingly,” he said, “adverse events were pretty similar” between combination therapy and methotrexate monotherapy.

“This was very much like all the studies we’ve seen over the years with new biologics — they were all added to background methotrexate,” he said. “And the truth is, the [46%] response seen when adding leflunomide to background methotrexate wasn’t very different from the 50% [ACR20] response you tend to see when you add a biologic.”

However, despite the study’s conclusion that combination therapy provided significant benefit to patients with inadequate response to methotrexate alone, “the drug got lost, because everyone was prescribing the biologics,” Dr. Ruderman said.

He said he found only one study comparing leflunomide with a biologic. In a notably small but well-designed study from Sri Lanka published in 2017, 40 patients with an inadequate response to methotrexate were randomized to low-dose rituximab (500 mg x 2) or 20 mg/day leflunomide (no loading dose). At week 24, ACR20 was nearly identical (85% vs 84%), with a similar rate of adverse events.

The researchers pointed out “that there’s a potential cost benefit in developing countries where biologics aren’t as accessible,” he said, agreeing that “the big opportunity for a drug like leflunomide is outside the US, where you don’t have access to the drugs we take advantage of all the time.”

A meeting participant from Canada pointed out that rheumatologists there are “mandated to use it for PsA in combination with methotrexate before we can get a biologic, and for RA we can use it with Plaquenil [hydroxychloroquine] and methotrexate before we get a biologic, so we’re using it all the time.”

Asked about efficacy, the physician said the combination with methotrexate is “absolutely” efficacious. “It works really well” he said. “The problem is, you really have to watch the white cell count and liver function … and the half-life is long.”

Indeed, Dr. Ruderman said during his talk, the plasma half-life of teriflunomide, its active metabolite, is 15.5 days, which is challenging when adverse events occur. “And it’s a terrible drug in young women thinking about pregnancy because it’s teratogenic and stays around,” he said.

Leflunomide, which, notably, was “developed specifically for RA from the get-go” and not borrowed from another specialty, works by blocking de novo pyrimidine synthesis, Dr. Ruderman said. T-cell activation requires the upregulation of pyrimidine production (salvage pathways are insufficient); the “drug prevents that” by inhibiting an enzyme that catalyzes conversion of dihydroorotate to orotate, which, in turn, is converted to pyrimidine ribonucleotides, he explained.

Other potential mechanisms of action have been proposed — mainly, inhibition of tumor necrosis factor signaling and inhibition of kinase activity, including the JAK/STAT pathway — but “there’s not great data for any of them,” he said.
 

Loading vs Not Loading, and Its Role in PsA and Other Diseases

“We stopped loading years ago because at 100 mg for 3 days in a row, everyone has GI issues,” Dr. Ruderman said. “It may have made sense from a pharmacokinetic standpoint because [based on the long half-life] you could get to a higher drug level quicker, but not a practical standpoint, because patients would stop the drug — they couldn’t take it.” The first study to examine the necessity of loading leflunomide in a “prospective, careful way” was published in 2013. It randomized 120 patients to 100 mg or 20 mg for 3 days, followed by a 3-month open-label period of 20 mg, and found no clinical benefit with loading but more diarrhea and elevated liver enzymes.

“It tells us something about how we need to think about half-lives,” he said. “Maybe [loading is] not necessary because the biological effects are different than the drug levels.”

In the PsA space, in 2004, researchers reported a double-blind randomized trial in which 190 patients with active PsA and cutaneous psoriasis with at least 3% body surface area involvement were randomized to receive leflunomide (a loading dose followed by 20 mg/day) or placebo for 24 weeks. Almost 60% of leflunomide-treated patients, compared with 30% of placebo-treated patients, were classified as responders by the Psoriatic Arthritis Response criteria (P < .0001), “which is a soft endpoint” but was utilized at the time, Dr. Ruderman said. The researchers noted improvements in ACR20 and skin responses as well, and toxicity was similar to that reported in the RA studies.

However, approval was never sought, and the drug was infrequently prescribed, “because etanercept came out for this disease, and then adalimumab … and then the world changed,” he said.

More recently, a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA tested leflunomide plus methotrexate vs methotrexate monotherapy and was published in The Lancet Rheumatology. After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1 [standard deviation (SD), 1.4] vs 3.7 [SD, 1.3]; treatment difference, -0.6; 90% CI, -1.0 to -0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than that of the monotherapy group (34%; P = .019). Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group.

In an interview after the meeting, Dr. Ruderman explained that in his practice, about 15 years ago, leflunomide was sometimes prescribed as an alternative to a biologic change for patients whose skin disease improved significantly with ustekinumab (Stelara) but who “suddenly had more joint symptoms that they didn’t have before.”

And “we’ve found ourselves a bit recently with the same sort of story, where patients are prescribed IL-23 inhibitors like Skyrizi [risankizumab] and Tremfya [guselkumab] and their skin does really well but now they’re having more joint symptoms than previously,” he said. “Our choices are to switch to a whole different biologic, or to think about adding something as an adjunct — and maybe leflunomide is a reasonable option.”

In the last 5 years, Dr. Ruderman noted, randomized trial data has been published on leflunomide in lupus nephritis induction, and in lupus nephritis maintenance, as well as in IgG4-related disease.

Dr. Ruderman disclosed consulting and/or drug safety monitoring board work for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Lilly, Merck, Novartis, NS Pharma, and UCB.

The Food and Drug Administration’s approval of leflunomide in September 1998 as a treatment for rheumatoid arthritis was sandwiched between the debuts of infliximab (Remicade and biosimilars) and etanercept (Enbrel) in August and November of that year, the latter of which was so exciting that “within 2 months you couldn’t get [it],” recalled Eric M. Ruderman, MD. And “like every middle child, [leflunomide] was underloved, underappreciated, and largely dismissed.”

Yet should it have been? Is it worth another look today?

Courtesy Michael Pollard

At the 2024 Rheumatology Winter Clinical Symposium, Dr. Ruderman reflected on some of the clinical trial data published after leflunomide’s approval that “got lost in the shuffle” of the rightful embrace of biologics in United States practice, and urged reconsideration of the loading strategy still advised in the drug’s labeling.

“I’m not telling you that you should be using [leflunomide] in place of biologics, instead of biologics, or before biologics … but it should be in your toolkit,” said Dr. Ruderman, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago. The drug “still has a role in RA, including in combination with methotrexate, and a potential role in other rheumatic diseases.”

“In our PsA clinic,” he noted, “we’ve actually not infrequently added leflunomide to some of the other agents we’ve been using.”
 

Key Findings Over the Years in RA

Leflunomide showed efficacy similar to that of sulfasalazine in a randomized trial published in 1999 that used primary endpoints of tender/swollen joints and physician and patient global scores. Then, against methotrexate, it proved just as efficacious in achieving at least 20% improvement in American College of Rheumatology composite response criteria (ACR20) over 52 weeks, and in meeting endpoints similar to those of the sulfasalazine trial, in two trials, one published in 1999 and another in 2000.

“So here were two big trials [comparing it with methotrexate] that suggested the drug was just as good as what had become our standard of care by that point,” Dr. Ruderman said.

Each of these three trials used a loading dose of 100 mg leflunomide for 3 days, followed by 20 mg daily. Sulfasalazine was initiated at 2 g and escalated over 4 weeks. Methotrexate was initiated in one of the trials at a dose of 7.5 mg, then increased to 15 mg in almost two-thirds of patients; in the other methotrexate trial the initial dose was 15 mg escalated over 3 months.

Side effects of leflunomide — GI issues, rash, alopecia (reversible), and elevated liver function tests — were similar across the trials, and represented “about the same toxicities as methotrexate,” he said.

Researchers then tested leflunomide as an add-on to methotrexate in patients who had inadequate response, which “was a little bit daunting since we were still concerned about the toxicity of methotrexate at this point,” Dr. Ruderman said. “The idea that we’d take another drug with similar toxicities and add it on to the methotrexate was a little scary.”

But it worked. Patients on a mean background dose of 16.5 mg methotrexate were randomized to placebo or to a 2-day leflunomide loading dose followed by 10 mg/day that could be escalated at 8 weeks to 20 mg if needed. At 6 months, 19.5% and 46.2%, respectively, met ACR20 (P < .001), and “interestingly,” he said, “adverse events were pretty similar” between combination therapy and methotrexate monotherapy.

“This was very much like all the studies we’ve seen over the years with new biologics — they were all added to background methotrexate,” he said. “And the truth is, the [46%] response seen when adding leflunomide to background methotrexate wasn’t very different from the 50% [ACR20] response you tend to see when you add a biologic.”

However, despite the study’s conclusion that combination therapy provided significant benefit to patients with inadequate response to methotrexate alone, “the drug got lost, because everyone was prescribing the biologics,” Dr. Ruderman said.

He said he found only one study comparing leflunomide with a biologic. In a notably small but well-designed study from Sri Lanka published in 2017, 40 patients with an inadequate response to methotrexate were randomized to low-dose rituximab (500 mg x 2) or 20 mg/day leflunomide (no loading dose). At week 24, ACR20 was nearly identical (85% vs 84%), with a similar rate of adverse events.

The researchers pointed out “that there’s a potential cost benefit in developing countries where biologics aren’t as accessible,” he said, agreeing that “the big opportunity for a drug like leflunomide is outside the US, where you don’t have access to the drugs we take advantage of all the time.”

A meeting participant from Canada pointed out that rheumatologists there are “mandated to use it for PsA in combination with methotrexate before we can get a biologic, and for RA we can use it with Plaquenil [hydroxychloroquine] and methotrexate before we get a biologic, so we’re using it all the time.”

Asked about efficacy, the physician said the combination with methotrexate is “absolutely” efficacious. “It works really well” he said. “The problem is, you really have to watch the white cell count and liver function … and the half-life is long.”

Indeed, Dr. Ruderman said during his talk, the plasma half-life of teriflunomide, its active metabolite, is 15.5 days, which is challenging when adverse events occur. “And it’s a terrible drug in young women thinking about pregnancy because it’s teratogenic and stays around,” he said.

Leflunomide, which, notably, was “developed specifically for RA from the get-go” and not borrowed from another specialty, works by blocking de novo pyrimidine synthesis, Dr. Ruderman said. T-cell activation requires the upregulation of pyrimidine production (salvage pathways are insufficient); the “drug prevents that” by inhibiting an enzyme that catalyzes conversion of dihydroorotate to orotate, which, in turn, is converted to pyrimidine ribonucleotides, he explained.

Other potential mechanisms of action have been proposed — mainly, inhibition of tumor necrosis factor signaling and inhibition of kinase activity, including the JAK/STAT pathway — but “there’s not great data for any of them,” he said.
 

Loading vs Not Loading, and Its Role in PsA and Other Diseases

“We stopped loading years ago because at 100 mg for 3 days in a row, everyone has GI issues,” Dr. Ruderman said. “It may have made sense from a pharmacokinetic standpoint because [based on the long half-life] you could get to a higher drug level quicker, but not a practical standpoint, because patients would stop the drug — they couldn’t take it.” The first study to examine the necessity of loading leflunomide in a “prospective, careful way” was published in 2013. It randomized 120 patients to 100 mg or 20 mg for 3 days, followed by a 3-month open-label period of 20 mg, and found no clinical benefit with loading but more diarrhea and elevated liver enzymes.

“It tells us something about how we need to think about half-lives,” he said. “Maybe [loading is] not necessary because the biological effects are different than the drug levels.”

In the PsA space, in 2004, researchers reported a double-blind randomized trial in which 190 patients with active PsA and cutaneous psoriasis with at least 3% body surface area involvement were randomized to receive leflunomide (a loading dose followed by 20 mg/day) or placebo for 24 weeks. Almost 60% of leflunomide-treated patients, compared with 30% of placebo-treated patients, were classified as responders by the Psoriatic Arthritis Response criteria (P < .0001), “which is a soft endpoint” but was utilized at the time, Dr. Ruderman said. The researchers noted improvements in ACR20 and skin responses as well, and toxicity was similar to that reported in the RA studies.

However, approval was never sought, and the drug was infrequently prescribed, “because etanercept came out for this disease, and then adalimumab … and then the world changed,” he said.

More recently, a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA tested leflunomide plus methotrexate vs methotrexate monotherapy and was published in The Lancet Rheumatology. After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1 [standard deviation (SD), 1.4] vs 3.7 [SD, 1.3]; treatment difference, -0.6; 90% CI, -1.0 to -0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than that of the monotherapy group (34%; P = .019). Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group.

In an interview after the meeting, Dr. Ruderman explained that in his practice, about 15 years ago, leflunomide was sometimes prescribed as an alternative to a biologic change for patients whose skin disease improved significantly with ustekinumab (Stelara) but who “suddenly had more joint symptoms that they didn’t have before.”

And “we’ve found ourselves a bit recently with the same sort of story, where patients are prescribed IL-23 inhibitors like Skyrizi [risankizumab] and Tremfya [guselkumab] and their skin does really well but now they’re having more joint symptoms than previously,” he said. “Our choices are to switch to a whole different biologic, or to think about adding something as an adjunct — and maybe leflunomide is a reasonable option.”

In the last 5 years, Dr. Ruderman noted, randomized trial data has been published on leflunomide in lupus nephritis induction, and in lupus nephritis maintenance, as well as in IgG4-related disease.

Dr. Ruderman disclosed consulting and/or drug safety monitoring board work for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Lilly, Merck, Novartis, NS Pharma, and UCB.