Does the JAK inhibitor baricitinib raise the bar on treating lupus?

By Warren R. Heymann, MD
Aug. 20, 2018

Undeniably, the JAK inhibitors have been at the forefront of advances in immunologically-based diseases, including alopecia areata, vitiligo, psoriasis, rheumatoid arthritis, atopic dermatitis, graft-versus-host disease, and other disorders. The literature on these drugs has proliferated since last discussed on DI&I (“I Don’t Know JAK — But I Will! Ruxolitinib Improving Chilblain Lupus Erythematosus”, May 31, 2016).

In their systematic review of JAK (Janus kinase) inhibitors in dermatology, Shreberk-Hassidim note that the target of these drugs is the JAK/STAT (signal transducer and activator of transcription) pathway belonging to the group of cytoplasmic tyrosine kinases, which is pivotal for the downstream signaling of inflammatory cytokines and growth factors. “After activation, they phosphorylate STAT transcription factors, resulting in the transportation of STAT factors to the nucleus, affecting expression of specific genes. There are 4 known types of JAKs: JAK1, JAK2, JAK3 and TYK2, expressed mainly in hematopoietic cells.” Tofacitinib (Xeljans) targets JAK1/3; Ruxolitinib (Jakafi) JAK1/2; and Baricitinib (Olumiant) JAK1/2. (1)
 
This commentary focuses on baricitinib, which was approved by the FDA for the treatment of moderate-to-severe rheumatoid arthritis on June 1, 2018. All prescribers must be aware of the black box warnings for the drug, including serious infections (including tuberculosis), malignancies (lymphoma and others), and thrombosis (potentially fatal).

Guttman-Yassky et al evaluated the efficacy and safety of baricitinib in patients with moderate-to-severe atopic dermatitis (AD). They performed a phase 2, randomized, double-blind, placebo-controlled study, on 124 patients with moderate-to-severe AD, who applied topical corticosteroids (TCS) for 4 weeks before randomization, to once daily placebo, baricitinib 2 mg, or baricitinib 4 mg for 16 weeks. Use of TCS was permitted during the study. Primary outcome was the proportion of patients achieving ≥50% reduction in the Eczema Area and Severity Index (EASI-50) compared to placebo. Significantly, more baricitinib 4-mg patients achieved EASI-50 compared to placebo (61% vs. 37%; P=0.027) at 16 weeks. The proportion of baricitinib 2- and 4-mg patients achieving EASI-50 compared to placebo was significant as early as week 4. Baricitinib also improved pruritus and sleep loss. Treatment-emergent adverse events were reported in 24 (49%) placebo, 17 (46%) baricitinib 2-mg, and 27 (71%) baricitinib 4-mg patients (the most common being headache, nasopharyngitis, and increase creatine phosphokinase). The main limitation of the study was not using baricitinib as monotherapy. The authors concluded that baricitinib used with TCS reduces inflammation and pruritus in patients with moderate-to-severe atopic dermatitis (AD), although further studies are warranted.(2)
 
In other studies, baricitinib was administered to a 17 year-old man with alopecia areata and the autoinflammatory CANDLE (Chronic Atypical Neutrophil Dermatosis with Lipodystrophy) syndrome. Although prominent interferon signatures characterize both diseases, they are considered genetically distinct. His alopecia areata completely resolved within a few months of continual treatment with baricitinib (interestingly, there was no mention about a response to the CANDLE syndrome). (3) In mice, baricitinib has been demonstrated to dually inhibit the interferon gamma receptor and IL-6 receptor, allowing for reversal of graft-versus-host disease while enhancing graft-versus-leukemia effects. (4)
 
Wallace et al hypothesized that baricitinib might have a therapeutic benefit in patients with systemic lupus erythematosus (SLE). They performed a double-blind, multicenter, randomized, placebo-controlled, 24-week phase 2 study in patients 18 years or older, with a diagnosis of SLE, and active disease involving skin or joints. They randomly assigned patients (1:1:1) to receive once-daily baricitinib 2 mg, baricitinib 4 mg, or placebo for 24 weeks. The primary endpoint was the proportion of patients achieving resolution of arthritis or rash at week 24, as defined by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K). A total of 314 patients were randomly assigned to receive placebo (n=105), baricitinib 2 mg (n=105), or baricitinib 4 mg (n=104). At week 24, resolution of SLEDAI-2K arthritis or rash was achieved by 70 (67%) of 104 patients receiving baricitinib 4 mg (odds ratio [OR] vs. placebo 1·8, and 61 (58%) of 105 patients receiving baricitinib 2 mg (OR 1·3). Adverse events were reported in 68 (65%) patients in the placebo group, 75 (71%) patients in the baricitinib 2 mg group, and 76 (73%) patients in the baricitinib 4 mg group. Serious adverse events were reported in ten (10%) patients receiving baricitinib 4 mg, 11 (10%) receiving baricitinib 2 mg, and five (5%) receiving placebo; no deaths were reported. Serious infections were reported in six (6%) patients with baricitinib 4 mg, two (2%) with baricitinib 2 mg, and one (1%) with placebo. The authors concluded that a baricitinib 4 mg dose, but not the 2 mg dose, significantly improved the signs and symptoms of active SLE in patients who were not adequately controlled despite standard of care therapy (NSAIDS, corticosteroids, antimalarials), with a safety profile consistent with previous studies of baricitinib. They recommend future phase 3 trials of JAK1/2 inhibition with baricitinib as a new potential oral therapy for systemic lupus erythematosus. (5).
 
As noted in the editorial accompanying Wallace et al, the difference in primary outcome was mostly based on a greater reduction in mean tender joint count in the baricitinib 4 mg group. Indeed the CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) showed a greater reduction at week 24 in the placebo group than the 4 mg baricitinib group. (6)

Many key kinases are implicated in the pathogenesis of SLE are dependent on JAKs for intracellular signaling (5). Although dermatologists may be discouraged by the lack of cutaneous improvement of lupus to baricitinib, further research elucidating the intricacies of these pathways, will likely bring novel JAK inhibitors to the cutting edge of dermatological therapy.

Point to remember: The JAK inhibitor baricitinib, approved for rheumatoid arthritis, appears to be more valuable for the arthritic aspects of lupus rather than cutaneous disease. Further research about JAK inhibitors and lupus is warranted.

1. Shreberk-Hassidim R, et al. Janus kinase inhibitors in dermatology. J Am Acad Dermatol 2017; 76: 745-53.
2. Guttman-Yassky E, et al. Baricitinib in adult patients with moderate-to-severe atopic dermatitis; A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J Am Acad Dermatol 2018 Feb 1 [Epub ahead of print].
3. Jabbari A, et al. Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib. EBioMedicine 2015; 26: 2: 351-5.
4. Choi J, et al. Baricitinib-induced blockade if interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia 2018 April 2 [Epub ahead of print].
5. Wallace D, et al. Baricitinib for systemic lupus erythematosus: A double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2018; 392: 222-31.
6. Mucke J, Schneider M. Baricitinib for systemic lupus erythematosus. Lancet 2018; 392; 190-2.

*I have no financial conflict of interest regarding baricitinib or Eli Lilly and Company.

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