Smoking reduces the efficacy of belimumab in mucocutaneous lupus

Parodis, Ioannis; Gomez, Alvaro; Frodlund, Martina; Jönsen, Andreas; Zickert, Agneta; Sjöwall, Christopher; Bengtsson, Anders; Gunnarsson, Iva

doi:10.1080/14712598.2018.1494719

Cited by 29 publications

(33 citation statements)

References 44 publications

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“…One previous paper has also shown the potential advantages of specific musculoskeletal outcome measures in patients treated with belimumab [36]. The CLASI and joint counts have also revealed nuances of response in individual organ domains in patient subgroups after belimumab therapy [37].…”

Section: Discussionmentioning

confidence: 99%

Responsiveness of clinical and ultrasound outcome measures in musculoskeletal systemic lupus erythematosus

et al. 2019

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Objective To assess the responsiveness of clinical outcome measures in musculoskeletal SLE compared with US. Methods A prospective pilot study was conducted in consecutive SLE patients with inflammatory musculoskeletal symptoms. Clinical assessments including SLEDAI, BILAG, 28 tender and swollen joint counts, physician and patient visual analogue scales (VAS), and US were performed at 0, 2 and 4 weeks following 120 mg i.m. methylprednisolone acetate. Responsiveness was analysed using changes and effect sizes using Cohen’s criteria. Results Twenty patients were recruited. Fifteen out of 20 had clinical swelling at baseline. All clinical and US parameters were significantly improved at week 4 (all P ⩽ 0.01). Musculoskeletal-BILAG score improved in 16/20. Musculoskeletal-SLEDAI improved in 7/20. SLE responder index 4 criteria were assessed in 19 patients with SLEDAI ⩾4 at baseline and were met in 9/19 at 4 weeks. Effect sizes at 4 weeks were large (>0.5) for US, physician VAS and BILAG, and medium (>0.3) for joint counts and SLEDAI. Large effect sizes for improvement in US grey-scale and power Doppler were observed in both SLE responder index 4 responders (r = −0.51 and −0.56, respectively) and non-responders (r = −0.62 and −0.59, respectively) at 4 weeks. Conclusion This is the first study to measure the responsiveness of clinical outcome measures in musculoskeletal SLE against an objective inflammation measure. BILAG and physician VAS were the most responsive clinical instruments. US was highly responsive in musculoskeletal SLE, while SLEDAI and joint counts appeared suboptimal for detection of improvement. These results suggest that clinical trials based on the SLEDAI and SLE responder index 4 may underestimate the efficacy of therapy in SLE.

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Section: Discussionmentioning

confidence: 99%

Responsiveness of clinical and ultrasound outcome measures in musculoskeletal systemic lupus erythematosus

et al. 2019

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“…The effects of belimumab on serum levels of anti-double stranded (ds)DNA antibodies and BAFF, as well as the homologous to BAFF plasma cell survival factor a proliferation-inducing ligand (APRIL), have been demonstrated in previous studies [2][3][4]. Furthermore, predictors of response and non-response to belimumab treatment have been implicated; high disease activity and anti-dsDNA positivity at baseline have been associated with increased probability of good response, whereas established organ damage, especially in the cardiovascular and neuropsychiatric domains, has been shown to reduce belimumab efficacy [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 94%

Autoantibody and Cytokine Profiles during Treatment with Belimumab in Patients with Systemic Lupus Erythematosus

Parodis

Åkerström

Sjöwall

et al. 2020

IJMS

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We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-α2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5–54.9 pg/mL) versus baseline (28.4; 20.9–100.3 pg/mL; p = 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9–16.1 pg/mL) decreased from month 6 (0.5; 0.5–6.3 pg/mL; p = 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8–29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6–9.1 pg/mL; p = 0.003). Levels of anti-dsDNA (p < 0.001), anti-Smith antigen (Sm) (p = 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) (p < 0.001), anti-Sm-U1RNP complex (p = 0.028), and anti-ribosomal P (p = 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20–5.29; p = 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-α2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome.

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“…Two response thresholds were initially selected to screen factors for each analysis. These included standard thresholds, representing relative decreases in CLASI-A (≥50%) or CLASI-D (≥20%) within the range of outcomes considered in prior studies,8 14–16 19 and stringent thresholds, representing larger relative decreases in CLASI-A (≥75%) or CLASI-D (≥40%) score.…”

Section: Methodsmentioning

confidence: 99%

“…Prior studies have found four-point or 20% decrease in CLASI-A score on a 70-point scale to be indicative of noticeable clinical improvement 13. Despite the possibility that such modest changes may be less meaningful for patients with more severe involvement or may fail to distinguish treatment response from expected clinical variability, similar thresholds have been used to classify activity improvement in interventional and observational studies 8 14. Other endpoints used include larger relative changes in CLASI-A scores (eg, 50% improvement in CLASI-A),15 16 analogous to the Psoriasis Area Severity Index (PASI) percentage change endpoints common in psoriasis studies (eg, PASI50) 17.…”

Section: Introductionmentioning

confidence: 99%

Robust measurement of clinical improvement in patients with cutaneous lupus erythematosus

2020

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Objective The severity and disease course of cutaneous lupus erythematosus (CLE) are highly variable. Consequently, outcome measures for CLE clinical improvement are heterogeneous, complicating treatment decisions and therapeutic development. This study characterises CLE outcome measures and identifies the influence of clinical improvement thresholds on strengths of associations with patient demographic and clinical factors.Methods In this pilot cohort study, multivariable models identified factors associated with CLE activity and skin damage improvement, defined as relative decreases in Cutaneous Lupus Activity and Severity Index (CLASI) activity (CLASI-A) and damage (CLASI-D) scores, over ranges of response thresholds. Results 66 patients with 119 visit-pairs were included in the CLASI-A analysis. 74 patients with 177 visit-pairs were included in the CLASI-D analysis. Factors associated with CLE activity and damage improvement depended on the response threshold. Some associations were stronger at more stringent thresholds, including subacute CLE predominance with increased likelihood of CLASI-A improvement (R 2 =0.73; 50% reduction: OR 1.724 (95% CI 0.537 to 5.536); 75%: 5.67 (95% CI 1.56 to 20.5)) and African-American race with decreased likelihood of CLASI-D improvement (R 2 =0.80; 20%: 0.40 (95% CI 0.17 to 0.93); 40%: 0.25 (95% CI 0.08 to 0.82)). Other associations were stable across multiple thresholds, including older age of CLE development with increased likelihood of CLASI-A improvement (R 2 =0.25; 50%: 1.05 (95% CI 1.01 to 1.09]; 75%: 1.05 (95% CI 1.00 to 1.10)) and higher initial disease activity with decreased likelihood of CLASI-D improvement (R 2 =0.55; 20%: 0.91 (95% CI 0.84 to 0.98); 40%: 0.88 (95% CI 0.79 to 0.97)). Conclusions Examining a range of CLASI threshold outcomes can comprehensively characterise changes in disease course in patients with CLE. Insufficiently stringent thresholds may fail to distinguish meaningful clinical change from natural fluctuation in disease activity.

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Smoking reduces the efficacy of belimumab in mucocutaneous lupus

Abstract: We observed a negative impact of smoking on the efficacy of belimumab in mucocutaneous SLE. In contrast, no impact of smoking on belimumab efficacy was seen in patients with articular manifestations.

Cited by 29 publications

References 44 publications

Responsiveness of clinical and ultrasound outcome measures in musculoskeletal systemic lupus erythematosus

Responsiveness of clinical and ultrasound outcome measures in musculoskeletal systemic lupus erythematosus

Autoantibody and Cytokine Profiles during Treatment with Belimumab in Patients with Systemic Lupus Erythematosus

Robust measurement of clinical improvement in patients with cutaneous lupus erythematosus

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