Efficacy and safety of baricitinib in treatment of systemic lupus erythematosus: a systematic review and meta-analysis
BMC Rheumatology volume 7, Article number: 40 (2023)
SLE is an autoimmune disease marked by broad immunological dysregulation and multi-system inflammation. Baricitinib is one of the novel treatments for SLE. We conducted this meta-analysis to evaluate its safety and effectiveness in treating SLE.
We looked for all published randomized controlled trials in PubMed, Scopus, Web of Science, and Cochrane and included all RCTs comparing baricitinib and placebo in the treatment of SLE. Review Manager 5.4 program was used for data analysis.
Three trials with a total of 1849 individuals were included. Participants in the baricitinib group were significantly more likely to attain SRI-4 response than those in the placebo group [RR = 1.11, 95% CI (1.02, 1.21), P = 0.01]. Additionally, baricitinib performed better than the placebo in terms of reduction of ≥ 4 points from baseline in SLEDAI-2 K score [RR = 1.13, 95% CI (1.04, 1.22), P = 0.004]. In terms of SLEDAI-2 K remission of arthritis or rash, baricitinib was also superior to placebo [RR = 1.08, 95% CI (1.00, 1.17), P = 0.04]. Treatment-emergent adverse events did not differ significantly [RR = 1.01, 95% CI (0.97, 1.05), P = 0.61].
Baricitinib is potentially safe and effective in the treatment of SLE. It has successfully met the study’s primary endpoint and some secondary endpoints highlighting its potential to improve the outcomes of SLE. Despite achieving an SRI-4 response, glucocorticoids sparing and some other secondary outcomes weren’t reached by baricitinib.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects numerous body organs and systems . It is caused by the interplay between genetic, immunological, and environmental factors and presents with a wide range of symptoms like joint pain, skin rash, and multi-organ damage .
SLE has no known cause or treatment; nevertheless, there are several ways to manage the condition and slow its progression. These drugs include a combination of NSAIDs, anti-malarial drugs, corticosteroids, and immunosuppressive agents . However, these medications are linked to substantial adverse events, and many patients suffer from disease relapse and symptom flare-ups .
The development of new treatments for SLE has been challenging, with few advancements in the past six decades. Only two new treatments approved in the last 60 years targeting B cells and type 1 interferon highlighting the unmet need for the development of new SLE therapies [5, 6].
The pathogenesis of SLE is complex, involving various immune mechanisms and factors underlying the disease activity. Different patients and clinical presentations exhibit variations in the dominance of these mechanisms. Consequently, the existing limited range of therapeutic targets does not cater to all patients. Extensive research has implicated a range of cytokines, including interferons, B-cell activating factors, various interleukins, and TNF in the development of SLE [7,8,9]. Many of these cytokines rely on Janus kinases (JAKs) for intracellular signaling [1, 10, 11].
Janus kinase inhibitors, a group of drugs approved by the US Food and Drug Administration, have shown an effective role in treating many inflammatory and autoimmune diseases, such as rheumatoid arthritis and psoriasis [3, 12]. They work by blocking the pathways of several cytokines, including interleukin (IL)-6 and interferon and interferon (IFN)-γ, which are involved in the pathogenesis of SLE [11, 13].
Baricitinib, one of Janus kinase inhibitors, has emerged as a potential therapeutic option for the treatment of a wide scale of autoimmune conditions including SLE [14,15,16,17]. A number of clinical trials have been carried out to assess the safety and efficacy of baricitinib in the treatment of SLE [15,16,17]. However, the results of these trials were conflicting, Morand et al. reported potential effectiveness of baricitinib 4 mg in treatment of SLE which was supported by Wallace et al. On the other hand, Petri et al. reported failure of baricitinib to meet the primary end point of the study. Therefore, it is still uncertain if baricitinib is effective for SLE treatment.
We carried out this comprehensive systematic review to compare the safety and effectiveness of baricitinib versus placebo in the treatment of SLE. Moreover, we conducted a meta-analysis of available data to estimate the effect of baricitinib on disease activity, flare-ups, and adverse events.
Methods and materials
Literature search and screening
We performed a systematic search on PubMed, Scopus, Web of Science, and Cochrane till March 2023. Entry terms were as follows: (“Systemic Lupus Erythematosus,” “Lupus Erythematosus Disseminatus,” “Libman-Sacks Disease,” “Disease, Libman-Sacks,” “Libman Sacks Disease,” “baricitinib,” “Olumiant,” “baricitinib phosphate,” “baricitinib phosphate salt.”
In order to find pertinent publications for our systematic review, we carried out a four-step screening procedure. In the initial phase, we collected all retrieved articles and eliminated duplicates using Endnote 20 software. Next, the articles’ titles and abstracts were inspected to rule out studies that weren’t relevant. In the third step, we examined the complete texts of the remaining articles to determine whether they qualified for the review. Finally, we looked over the reference lists of the articles that were included to identify any potentially relevant publications that were missed in the initial search. The screening process was conducted independently by two researchers using the SR Accelerator tool, and any disagreements were resolved by a third researcher .
We restricted our analysis to baricitinib versus placebo comparisons in randomized clinical trials for the treatment of SLE. Observational studies, case studies, conference abstracts, and in vitro and animal experiments were all disregarded.
Risk of bias assessment
We used the Cochrane risk of bias assessment tool (ROB2) to evaluate the quality of the included articles . ROB2 compromises six domains: the randomized process, deviations from intended interventions, missing outcome data, measurement of outcome, choice of reported findings, and overall risk of bias.
Using a predetermined data extraction sheet, two different researchers independently extracted the data from the included studies, and any inconsistencies were resolved by a third researcher.
Study ID, study design, NCT, site, length of treatment, inclusion criteria, exclusion criteria, and conclusion were included in the summary data. Age, time since onset of SLE, concomitant medications, baseline Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2 K) score, (SLEDAI-2 K) score organ system involvement, Physician’s Global Assessment of Disease Activity (PGA), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score, tender joint counts (TJC), swollen joint counts (SJC), Systemic Lupus International Collaborating Clinics/ American College of Rheumatology (SLICC/ACR) Damage Index score was among the baseline characteristics.
Efficacy outcomes included Systemic Lupus Erythematosus Responder Index-4 (SRI-4) as the primary outcome, reduction of 4 points or more from baseline in Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2 K) score, SLEDAI-2 K remission of arthritis or rash, no new British Isles Lupus Assessment Group (BILAG) A and no more than one new (BILAG) B disease activity score, no worsening in Physician Global Assessment (PGA), glucocorticoid sparing, lupus low disease activity state (LLDAS). while safety outcomes included Treatment-emergent adverse events (TEAEs) Discontinuation from study treatment because of an adverse event, infections, serious infections, Opportunistic infections, hepatic disorders, and serious adverse effects.
In order to compare the baricitinib group with the placebo group, we used Review Manager version 5.4. To determine the differences in safety and efficacy between baricitinib 2 mg and baricitinib 4 mg, we performed subgroup analysis based on dose. For dichotomous data, the Mantel-Haenszel technique was used to display the risk ratio (RR) and 95% confidence intervals (CI); for continuous data, the inverse variance method was used to display the mean difference (MD) and 95% CI. When P < 0.05, there were significant differences. To assess the degree of heterogeneity, we conducted Chi-Square and I2 tests. When the I2 > 50% and the P-value of the Chi-square < 0.1, there was significant heterogeneity. If the data were heterogeneous, we would apply a leave-one-out sensitivity analysis or a random effect model. A fixed effect model was utilized in the other cases.
Using Comprehensive meta-analysis (CMA) software, we conducted meta regression analysis to determine if the dose of baricitinib, age of patients, sample size of the study and time since onset of SLE have influenced the primary outcome (SRI-4).
After removing duplicates with the systematic review accelerator tool , the search turned up a total of 267 citations out of 376 citations. Additionally, two writers looked at the title and abstract of 267 citations and concluded that 16 of them could move on to the full-text screening stage. Finally, three of the 16 citations were included in this meta-analysis [15,16,17]. All discrepancies were resolved by the third author. PRISMA flow diagram is shown in. (Fig. 1)
In our study, there were 1849 participants, with a mean age of 43.1 years, a mean SLEDAI-2 K score of 9.7, and a prevalence of glucocorticoid use of 77.3%. 621 (33.6%) received 2 mg of baricitinib, 614 (33.2%) received 4 mg of baricitinib, and 614 (33.2%) received a placebo. The summary and baseline characteristics of the included studies are displayed in (Table 1) and (Table 2).
Risk of bias results
Participants in the baricitinib group were significantly more likely to obtain an SRI-4 response than those in the placebo group [RR = 1.13, 95% CI (1.04, 1.22), P = 0.004]. Moreover, baricitinib 4 mg significantly outperformed placebo in the sub-group analysis [RR = 1.18, 95% CI (1.06, 1.32), P = 0.003]. (Fig. 3)
Reduction of ≥ 4 points from baseline in SLEDAI-2 K score
Participants in the baricitinib group were significantly more likely to obtain a reduction of ≥ 4 points from baseline in SLEDAI-2 K score than those in the placebo group [RR = 1.13, 95% CI (1.04, 1.22), P = 0.004]. Moreover, baricitinib 4 mg significantly outperformed the placebo in the sub-group analysis [RR = 1.18, 95% CI (1.06, 1.32), P = 0.003]. (Fig. 4)
SLEDAI-2 K remission of arthritis or rash
Participants in the baricitinib group were significantly more likely to obtain SLEDAI-2 K remission of arthritis or rash than those in the placebo group [RR = 1.08, 95% CI (1.00, 1.17), P = 0.04]. Moreover, baricitinib 4 mg significantly outperformed placebo in the sub-group analysis [RR = 1.14, 95% CI (1.03, 1.27), P = 0.01]. (Fig. 5)
No new BILAG A and no more than one new BILAG B disease activity score
In terms of BILAG, there was no significant difference between the baricitinib group and the placebo group [RR = 1.03, 95% CI (0.98, 1.07), P = 0.25]. Similarly, there was no significant difference between baricitinib 4 mg and placebo in the sub-group analysis [RR = 1.03, 95% CI (0.97, 1.10), P = 0.32]. The data, however, were heterogeneous [P = 0.11, I2 = 56%]. I took out Petri et al.  to address this heterogeneity. The outcome was altered and baricitinib 4 mg was significantly better than the placebo [RR = 1.09, 95% CI (1.01, 1.19), P = 0.03]. (Fig. 6A&B)
No worsening by PGA
In terms of PGA, there was no significant difference between the baricitinib group and the placebo group [RR = 1.03, 95% CI (0.98, 1.07), P = 0.25]. (Fig. 7)
The glucocorticoid-sparing outcome was reported in two studies [16, 17]. There was no significant difference between the baricitinib group and the placebo group [RR = 1.02, 95% CI (0.84, 1.24), P = 0.86]. (Figure S2)
In terms of LLDAS, there was no significant difference between the baricitinib group and the placebo group [RR = 1.12, 95% CI (0.98, 1.27), P = 0.1]. (Figure S3)
Participants with ≥ 1 severe flare
In terms of participants with ≥ 1 severe flare, there was no significant difference between the baricitinib group and the placebo group [RR = 0.88, 95% CI (0.70, 1.09), P = 0.24]. (Figure S4)
SLEDAI-2 K “score”
The baricitinib group achieved a lower SLEDAI-2 K score than the placebo group, indicating a significant difference between the two groups [MD = -0.44, 95% CI (-0.72, -0.15), P = 0.003]. Moreover, baricitinib 4 mg significantly outperformed the placebo in the sub-group analysis [MD = -0.67, 95% CI (-1.08, -0.26), P = 0.001]. (Figure S5)
The baricitinib group and the placebo group did not differ significantly in terms of TEAEs [RR = 1.01, 95% CI (0.97, 1.05), P = 0.61]. Moreover, there was no significant difference between the baricitinib group and the placebo group in terms of mild, moderate, or severe TEAEs. (Fig. 8)
Serious adverse events
Participants in the baricitinib group were significantly more likely to obtain serious AEs than those in the placebo group [RR = 1.49, 95% CI (1.16, 1.92), P = 0.002]. (Figure S6)
Discontinuation from study because of an adverse event
Regarding Discontinuation from study treatment because of an AE, there was no significant difference between the baricitinib group and the placebo group [RR = 1.19, 95% CI (0.92, 1.54), P = 0.19]. (Figure S7)
Infections and serious Infections
The baricitinib group and the placebo group did not differ significantly in terms of infections [RR = 1.03, 95% CI (0.95, 1.12), P = 0.46]. However, participants in the baricitinib group were significantly more likely to obtain serious infections than those in the placebo group [RR = 2.07, 95% CI (1.28, 3.34), P = 0.003]. (Figures S8 and S9)
Participants in the baricitinib group were significantly more likely to obtain opportunistic infection than those in the placebo group [RR = 1.47, 95% CI (1.02, 2.11), P = 0.04]. (Figure S10)
The baricitinib group and the placebo group did not differ significantly in terms of hepatic disorders. (Figure S11)
Random effect meta-regression was applied for dose of baricitinib, age, sample size of the study and time since onset of SLE regarding SRI-4. There was no significant association between SRI-4 outcome and age of patients [OR = 0.0104, 95% CI (-0.2488, 0.2697), P = 0.937, figure S12], sample size [OR = -0.0005, 95% CI (-0.0024, 0.0014), P = 0.6093, figure S13], dose of baricitinib [OR = 0.0371, 95% CI (-0.2238, 0.2979), P = 0.7805, figure S14], or time since onset of SLE[OR = 0.1441, 95% CI (-0.1594, 0.4476), P = 0.352, figure S15].
Baricitinib has emerged as a potential therapeutic option for the treatment of wide scale autoimmune conditions including SLE due to its ability to modulate multiple cytokines involved in the pathogenesis of the disease . Recent clinical trials have evaluated the safety and efficacy of baricitinib in SLE [15,16,17]. Herrin, we performed a meta-analysis utilizing data from these trials. Based on the literature search, we believe that our study is the first meta-analysis to evaluate the safety and efficacy of baricitinib in the treatment of SLE.
In terms of efficacy, the overall analysis demonstrated that baricitinib achieved the primary endpoint of a higher proportion of patients reaching an SRI-4 response compared with placebo. Our results were in line with the results of phase three RCT reported by Morand et al. . In contrast, Petri et al. reported no significant SRI-4 response in baricitinib group compared with placebo . The profile of patients, including organ involvement, in both trials was almost similar suggesting that patient clinical and immunological characteristics were not a major factor. Furthermore, the results of meta-regression analysis demonstrated no significant effect of age of patients, sample size, baricitinib dose, or time since onset on the primary outcome (SRI-4).
Furthermore, baricitinib demonstrated superiority over placebo in terms of BILAG A or B disease activity score. Additionally, it outperformed placebo in SLEDAI-2 K score of 4 points or more from baseline as well as a decrease in rash or arthritis based on the SLEDAI-2 K score. This adds a potential impact on reducing specific disease symptoms and activity. Our observations on these outcomes align with the results obtained from preclinical models. Preclinical studies conducted on (MRL/lpr) mice and in vitro using immortalized primary podocytes and B cells isolated from C57BL/6 mice have demonstrated significant reductions in disease activity with baricitinib .
In terms of safety, Baricitinib appeared to be a well-tolerated drug for SLE. However, it is noteworthy that baricitinib had a higher incidence of serious adverse events and infections. This was similar to the results of pooled analysis on the safety of baricitinib in the treatment of SLE retorted by Dörner T et al. .
The results of our study should be interpreted cautiously because we were limited by the small number of clinical trials included. Only three randomized clinical trials were identified, which may have resulted in inaccurate precision of the results. Further research on the effectiveness of the baricitinib drug on patients with SLE is recommended. Moreover, long-term studies are also needed to assess the safety and efficacy of the drug over extended periods. Additionally, investigating the potential benefits of combining baricitinib with other treatments for SLE could provide valuable insights into the optimal management of this complex disease.
There is now sufficient clinical evidence to support Baricitinib’s safety and efficacy in the treatment of SLE. This study’s primary aim and some secondary endpoints were significantly reached by baricitinib. While glucocorticoids sparing and some other of the secondary outcomes didn’t reach statistical significance, the overall analysis demonstrates a promising efficacy of baricitinib in the management of SLE.
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
British Isles Lupus Assessment Group
Lupus low disease activity state
Physician Global Assessment
Risk of Bias Assessment tool
Systemic Lupus Erythematosus Disease Activity Index-2000)
Systemic Lupus Erythematosus Responder Index-4
Treatment-Emergent Adverse Events
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Allam, A.R., Alhateem, M.S. & Mahmoud, A.M. Efficacy and safety of baricitinib in treatment of systemic lupus erythematosus: a systematic review and meta-analysis. BMC Rheumatol 7, 40 (2023). https://doi.org/10.1186/s41927-023-00363-6