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Systemic lupus erythematosus: Baricitinib may be potential therapy, and clinical benefit of ustekinumab

EULAR 2018

Baricitinib may be potential therapy for systemic lupus erythematosus patients

Recent data has shown that once-daily oral baricitinib 4 mg for patients with SLE who receive standard background therapy is associated with significant clinical improvements on skin and joint manifestations compared to placebo.

The results of a phase 2 study over 24 weeks showed a promising benefit/risk profile. Baricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2. This agent has been approved for the treatment of RA in over 40 countries in the European Union, the United States and Japan and has prompted research in other fields such as SLE. Wallace et al. reported the results from a 24-week global, Phase 2, double-blind, placebo-controlled study of baricitinib in patients with SLE who received standard therapy.

A total of 314 patients with positive antinuclear antibodies or anti-double stranded DNA, clinical Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) ≥4, arthritis or rash were randomised 1:1:1 to placebo (n=105) or baricitinib (2 or 4 mg, n=105 and n=104, respectively) once daily.

The primary endpoint of the study was resolution of SLEDAI-2K for arthritis or rash at week 24. Of this population, 79% of patients on placebo, 82% on baricitinib 2 mg and 83% on baricitinib 4 mg completed 24 weeks of treatment. At week 24, a significantly greater proportion of patients who received baricitinib 4 mg achieved resolution of SLEDAI-2K arthritis or rash compared to placebo (67% vs 53%, p<0.05) and Systemic Lupus Erythematosus Responder Index 4 (SRI-4) response (64% vs 48%, p<0.05). At week 24, the proportion of patients achieving flare reduction (SELENA-SLEDAI Flare Index [SFI]), Lupus Low Disease Activity State (LLDAS), and TJC change from baseline were also significantly improved for baricitinib 4 mg compared to placebo. Researchers did not observe statistically significant differences between baricitinib 2 mg and placebo in any of the above endpoints. The occurrence of AEs leading to treatment discontinuation and serious AEs was higher for both baricitinib dose groups compared to placebo with both around 10% for baricitinib. No deaths, malignancies, major adverse cardiovascular events, cases of tuberculosis, or serious herpes zoster infections were reported, while there was one serious AE (deep vein thrombosis) reported in a Korean patient with known risk factors (positive anticardiolipin antibodies) in the baricitinib 4 mg group.

It was concluded that the safety and tolerability profile of baricitinib remained satisfactory as no new events occurred. Wallace et al. concluded that these interesting findings support further study of baricitinib 4 mg as a potential therapy for patients with SLE.[11]

Clinical benefit of ustekinumab for patients with systemic lupus erythematosus

Treatment with ustekinumab provides clinical benefits in patients with SLE; safety was as expected based on earlier extensive experience with the agent in psoriasis, PsA and CD. Based on these results, ustekinumab – targeting IL-12 and -23 – may have the potential to offer a new treatment option for patients with SLE.

The study reported by van Vollenhoven et al. evaluated ustekinumab – a monoclonal antibody which blocks the shared p40 subunit of the cytokines IL-12 and IL-23 in patients with active SLE in a Phase 2, placebo-controlled study in 102 patients. They were randomised (3:2) to receive ustekinumab ~6 mg/kg or placebo at week 0, followed by ustekinumab s.c. 90 mg or placebo injections every 8 weeks beginning at week 8, and both added to standard care. Primary endpoint was the proportion of patients achieving SRI-4 response at week 24. Secondary endpoints were change from baseline in SLEDAI-2K, PhGA and the British Isles Lupus Assessment Group (BILAG)-based Composed Lupus Assessment (BICLA) response. Additional pre-specified endpoint analyses included no BILAG worsening (which was defined as no new BILAG A and ≤1 new BILAG B domain) and BILAG flare (≥1 new BILAG A or ≥2 new BILAG B domain score).

The results show that ustekinumab exhibited a statistically significant improvement in SRI-4 response at week 24 compared to placebo (60% vs 31%, p=0.0046). Patients on ustekinumab had greater median change from baseline SLEDAI-2K and PhGA vs placebo (-4.4 vs -3.8 and -2.17 vs -1.93, respectively).

No difference was observed in BICLA response at week 24. However, in the ustekinumab group vs placebo, more patients had no BILAG worsening (48.3% vs 26.25, p=0.028) and the risk of a new BILAG flare was significantly lower (HR 0.11; 95% CI 0.01-0.94; p=0.0078). Moreover, ustekinumab demonstrated improvement in musculoskeletal and mucocutaneous disease features vs placebo, with the mean change from baseline in active joint count at week 24 of -4.5 for ustekinumab and -2.8 for placebo (median value -4.0 and -3.0, respectively) (see Figure).[12]

Figure: Change from baseline in active joint count at week 24 [12]

EULAR 2018: Table 5 Change from

Low C3 and elevated anti-double stranded DNA autoantibody levels, which are markers of increased disease activity, improved in ustekinumab patients over time when compared to placebo. CRP levels and antinuclear antibody titres were stable over time in both treatment groups. With regard to AEs through week 24, 78% of patients on ustekinumab vs 67% of placebo patients had ≥1 AE; 8.3% and9.5% respectively, had ≥1 serious AE. No deaths occurred during the study and it was concluded that the overall safety profile was comparable between ustekinumab and placebo.[12]

  1. Wallace DJ, et al. Abstract OP0019. EULAR 2018.

  2. van Vollenhoven R, et al. Abstract FRI0303. EULAR 2018.

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