Can JAK inhibitors used in RA have a place in the SLE field?

*Only for medical professionals to read and refer to so many new developments, I have learned and learned! Systemic lupus erythematosus (SLE) is still a disease with high unmet clinical needs.
The field has been progressing slowly for decades, clinical trials have failed frequently, and new and reliable treatments are still lacking.
We urgently need a reliable and effective treatment
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On August 29, 2021, the 2021 Asia-Pacific Alliance for Rheumatology (APLAR) Annual Meeting was held in Kyoto, Japan.
Professor Eric Morand, Director of Rheumatology at Monash University from Australia, brought us the topic of "JAK inhibitoor in SLE" , Shared the latest progress in the application of JAK inhibitors in SLE
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Unmet needs in SLE treatment: Why do we need new treatments? The figure below is from a long-term health-related quality of life (HRQoL) study of SLE patients who have been treated with belimumab for 6 consecutive years
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Studies have shown that in the 6-year follow-up treatment, the use of belyumumab + standard therapy resulted in meaningful improvements in all dimensions of HRQoL in SLE patients
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However, the purpose of inserting this figure is not to illustrate the efficacy of belyumumab, but to illustrate the gap between the quality of life of SLE patients and age-sex-matched normal people: significant gaps can be seen in the eight dimensions of HRQoL (yellow and The distance of the blue part), even after the treatment is improved (orange/green/purple part), there is still a significant gap
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The current status of treatment of SLE patients is largely unsatisfied
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Figure 1: Compared with age- and gender-matched normal people, the HRQoL scores of patients with active SLE are very low.
Note: The blue part represents the HRQoL of SLE patients, and the yellow part represents the HRQoL of people with the same gender and age.

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The purple/green/orange part represents the HRQoL of 1 year, 3 years, and 6 years treated with belyumumab
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The octagon represents 8 SF-36 domains (physical function, physical role, physical pain, general health, vitality, emotional role and social function, mental health)
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The unmet needs of SLE patients are also reflected in the inevitable accumulation of organ damage in SLE patients
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In a large international SLE cohort study (SLICC), we observed that the organ damage of SLE patients increased steadily over time: SDI scores were all 1 or above in the subgroup during the 6 years of follow-up, 51.
1% of the patients At least one organ damage occurs.
Over time, the possibility of further organ damage is greater, the risk of death is also higher, and the impact on body function is more significant
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Figure 2: Inevitable accumulation of organ damage in SLE patients.
The following are two concurrent studies on the mortality of rheumatoid arthritis (RA) and SLE in the last 20 years
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Based on the general population and the RA patient cohort study (Figure 3, left panel), compared with the general population, the survival rate of RA patients has improved to a greater extent in the past 10 years
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Another study based on the general population and SLE patients during the same period showed that the mortality rate of SLE patients has not decreased in recent years-the mortality rate is still more than twice that of the general population
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This indicates that the critical need for drug therapy and management strategies for SLE and its complications has not yet been met
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Figure 3: The mortality rate of RA has decreased significantly, and the mortality rate of SLE is still more than twice that of the general population.
The role of JAK-STAT pathway in the onset of SLE In the past 60 years, only a few drugs have been approved for the treatment of SLE
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Belyumumab was approved abroad as an intravenous preparation in 2011 and was approved as a subcutaneous injection in 2017
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However, due to the heterogeneity of the disease, current treatments have not yet met the needs of all patients
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Therefore, there is still a huge demand for new therapies for SLE
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Why has the development of new drugs for the treatment of SLE been so difficult over the years? This is related to the SLE clinical trial endpoints-there is still a lack of satisfactory clinical trial endpoints
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In the clinical trials of a series of new drugs for the treatment of SLE and its complications announced in 2018, only one positive result met the primary trial endpoint
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The reasons for trial failure may be related to factors such as poor trial design, lack of reliable endpoints, and heterogeneity of the study population
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At present, the treatment response outcome indicators used in SLE clinical trials have evolved from the use of SLEDAI and BILAG to the use of comprehensive effect indicators, such as the SLE Responder Index (SRI) and the BILAG-based Comprehensive Lupus Evaluation Index (BICLA)
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Even so, these measurement methods still have shortcomings, and the best clinical trial endpoint for SLE is still a problem worth solving
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The heterogeneity and complexity of SLE is also one of the important reasons why the development of new drugs for the treatment of SLE has been difficult over the years
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The heterogeneity of patients makes clinical trials to determine the efficacy of new treatments full of variability
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Studying the origin of transcriptional characteristics and disease heterogeneity of SLE patients may help solve the problem of high heterogeneity of patient populations faced by research
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A study used single-cell RNA-seq technology to analyze 33 children with SLE with varying disease activity (cSLE) and 11 matched controls with approximately 276,000 peripheral blood mononuclear cells (PBMC)
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The results of the study showed that the difference between the cSLE group and the healthy control group was the increase in the expression of cellular interferon-stimulating genes (ISG)
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The amplification of ISG and/or lupus-related single gene subgroups is a characteristic manifestation of patients with higher lupus activity
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The analysis of about 82,000 individual peripheral blood PBMCs in adult SLE patients also yielded similar results-the expression of ISG and/or lupus-related single gene subgroups in patients with high SLE activity was amplified
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Figure 4: The amplification of ISG and/or lupus-related single gene subgroups and the pathogenesis of SLE-related multiple cytokines play an important role in the development of SLE, which is the basis for the complexity of the pathogenesis of SLE, as shown in the figure below
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However, the abnormal activation of the above-mentioned complex cytokine receptor pathways may all play a role by directly or indirectly activating the downstream signal cascade pathway JAK-STATS
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So, if blocking one signal pathway target is always ineffective, why not try to block multiple immune targets? The blocking of multiple immune targets by JAK inhibitors may be the direction for the development of new therapies for SLE
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Figure 5: Directly or indirectly activate the downstream signal cascade JAK-STATS to play a role.
Note: Neutrophils and apoptotic cells are at the top of the pathogenesis cascade of SLE and are the key partners for the expression of type I interferon (IFN).
Body
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Neutrophils are key inflammatory participants in organ damage; these cells also release citrullinated peptides and nucleic acid antigens through the release of NETs
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A variety of cells produce type I interferons, but plasmacytoid dendritic cells produce the highest levels of these cytokines
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Apoptotic fragments can also activate the expression of inflammatory cytokines
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Both T cells and B cells participate in self-reactions, and eventually B cells produce autoantibodies
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At the same time, IL-17 produced by T cells is also involved in the organ infiltration of neutrophils
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A study found that there are active expressions of type I interferon markers, CLE, and typical cytokines (CXCL10, MxA) and JAK2 (p-JAK2) in the skin pathology of patients with frostbite-like lupus
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After treatment with the JAK inhibitor ruxolitinib (JAK1 inhibitor), a significant reduction in the expression of CLE typical cytokines (CXCL10, CXCL9, MxA) can be observed
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Therefore, JAK1 inhibitors may become promising drugs for the treatment of patients with cutaneous lupus and related autoimmune skin diseases
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Figure 6: Histological manifestations of active skin lesions in patients with frostbite lupus Note: Tissue (H&E) staining, type I interferon marker MxA immunostaining, pro-inflammatory cytokine CXCL10 immunostaining and JAK2 (p-JAK2) immunostaining
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The active expression of type I interferon markers, CLE typical cytokines (CXCL10, MxA) and JAK2 (p-JAK2) can be observed
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Earlier studies have shown that the expression of STAT1 in the mouse lupus nephritis model is significantly increased, suggesting that the STAT1 signaling pathway may play an important role in the pathogenesis of renal inflammation
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It is suggested that targeting the JAK-STAT pathway may provide a potential treatment method for LN
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Figure 7: The expression of STAT1 in the murine lupus nephritis model is significantly increased.
The results of clinical trials of JAK inhibitors in the treatment of SLE.
Multi-center preclinical studies can overcome single-center bias, but at the cost of increased variability and reduced therapeutic effects
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A multi-center/double-blind preclinical animal trial randomly divided mice with lupus nephritis into two groups, and were treated with JAK1/2 inhibitor Baricitinib or placebo for 4 weeks
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Baritinib had no significant effect on proteinuria, histological markers of chronic inflammatory activity, and glomerular filtration rate in LN model mice, but it significantly improved plasma autoantibody levels and lymph node lesions
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It is predicted that in SLE patients with heterogeneity, the effect of baritinib in the treatment of human LN may also face variables
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In addition, in a double-blind, multi-center, randomized, placebo-controlled phase II clinical trial using baritinib for the treatment of human SLE, the investigators classified the patients as baritinib according to (1:1:1) 2 mg qd, baritinib 4 mg qd and placebo group were treated for 24 weeks.
The primary endpoint was the remission ratio of SLEDAI-2000 and systemic lupus erythematosus responder index (SRI) at week 24
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In the 24th week, 70 patients (67%) in the Baritinib 4 mg qd patient group achieved remission of SLEDAI-2K or SRI-4
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61 patients (58%) in the Baritinib 2 mg qd patient group achieved remission of SLEDAI-2K or SRI-4
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Baritinib can significantly improve the symptoms and signs of patients with active SLE, and has good safety.
It is expected to become a new potential oral therapy for SLE
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Figure 8: SLE patients in the baritinib treatment group responded well.
During the same period, Thomas Dörner and others selected 274 patients from this phase II clinical trial, collected whole blood for RNA isolation analysis, and used ultra-sensitive quantitative analysis to determine serum Cytokines
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The gene expression profile showed that the expression of STAT1, STAT2 and multiple IFN genes increased at baseline in SLE patients
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After treatment with baritinib, the mRNA expression of genes related to the pathogenesis of SLE was significantly reduced, including STAT1 target genes, STAT2 target genes, STAT4 target genes, and multiple IFN response genes
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In the baseline period, serum cytokines IFN-α, IFN-γ, interleukin (IL)-12p40 and IL-6 were significantly higher than those in the healthy control group
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After 12 to 24 weeks of baritinib treatment, serum IL-12p40 and IL-6 cytokine levels were significantly reduced
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In general, baritinib induces changes in the expression of STAT1/STAT2 target genes, and these changes are related to treatment response
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The JAK/STAT pathway may play a central role in the treatment of SLE with baritinib
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Figure 9: The expression of genes related to the onset of SLE is increased in SLE patients, and decreased after treatment with Baritinib.
A 30-year-old man with frostbite erythema (localized dark red edema plaques with distal finger ulcers) ) SLE patients have been regularly treated with azathioprine, hydroxychloroquine, glucocorticoids, mycophenolate mofetil, dapsone, aspirin, pentoxifylline and other drugs for more than 12 months-system symptoms and Raynaud’s phenomenon have However, the frostbite-like lupus rash has not improved
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After stopping phenylsulfone and mycophenolate mofetil, the patient changed to tofacitib 5 mg bid for 8 weeks, and her frostbite symptoms improved significantly
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Figure 10: Tofacitinib in the treatment of refractory frostbite lupus erythematosus rash, the rash improved significantly after 8 weeks of treatment.
Another study reported a 29-year-old SLE patient with refractory severe diffuse non-scarring alopecia for 10 years , After treatment with tofacitinib, the hair regenerates obviously
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This helps to expand the field of JAK inhibitors in the treatment of SLE, such as severe hair loss
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Figure 11: Tofacitinib treatment of long-term refractory diffuse non-scarring alopecia caused by SLE has been improved.
In addition to safety and tolerability, the effect of the drug on the cardiovascular and cerebrovascular risks of SLE patients was also explored
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In this study, 30 subjects were randomly divided into tofacitinib group (5mg bid) and placebo group (2:1)
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The results show that tofacitinib is safe and well tolerated in the treatment of SLE
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At the same time, tofacitinib improved the parameters related to early atherosclerosis in SLE-low-density lipoprotein cholesterol level decreased, arterial stiffness and endothelium-dependent vasodilator factor improved, and the patient's type I interferon gene expression There has also been a decline
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Summary: In general, there is still a heavy burden of disease in SLE, and there is an urgent need for powerful new therapies
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The pathogenesis of SLE involves the activation of multiple immune pathways.
JAK-STAT, as a downstream signaling cascade pathway, may be expected to solve the problem of complex immune pathway activation
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In the clinical exploration of JAK inhibitors in the treatment of SLE, promising case reports appeared.
JAK inhibitors in the treatment of SLE also obtained positive phase II clinical trial results, which partially confirmed the above inferences
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Although part of the heterogeneous SLE patient population, the effect of JAK inhibitors in the treatment of SLE may also face variables, the new era of JAK inhibitors in the treatment of SLE is still worthy of our expectation
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Experts comment that SLE, as one of the most classic connective tissue diseases, is often referred to as the "jewel" in the crown.
Various systems from "hair" to "heel" can be affected, with different clinical phenotypes and organ involvement.
Differences and rapid onset are different.
Therefore, the evaluation of the clinical condition, the selection of treatment plans, and the long-term maintenance of the condition after remission all require the clinician's profound basic skills and the ability to control the disease
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The complex heterogeneity of the disease increases the difficulty of disease assessment, and also limits the progress and success rate of the development and design of new drugs and the implementation of clinical trials, so that in recent years, various new treatment methods have emerged one after another.
New drugs, especially SLE new drugs that can get positive results in large-scale RCT studies, can be approved for marketing
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In recent years, JAK inhibitors have emerged in the treatment of RA, and the role of JAK-STAT pathway in various rheumatic immune diseases has also been widely concerned
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This article focuses on the role of the JAK-STAT pathway in the pathogenesis of SLE, proposes that this pathway may be a potential direction for the treatment of SLE, and summarizes the successful cases of JAK inhibitors in the treatment of alopecia and chilblain-like rash in SLE patients in recent years.
Interpretation The results of the recent phase II clinical trials related to the treatment of SLE with JAK inhibitors are also analyzed, and the possible problems in the initial treatment attempts are also analyzed
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We hope that in future work, we can report more relevant basic research results, more high-quality clinical trial data, and face up to and solve a series of possible problems, and further demonstrate the treatment of SLE with JAK inhibitors from both positive and negative aspects.
Its effectiveness and safety provide a strong basis for clinical practice
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We will wait and see
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 Expert profile: Associate Professor Wang Li, Associate Professor, Department of Rheumatology and Immunology, Peking Union Medical College Hospital, Master's degree supervisor, Doctor of Medicine, and Associate Chief Physician Member and Secretary of the Youth Committee of the Chinese Medical Association Rheumatology Branch, Deputy Chairman of the Youth Committee of the Chinese Medical Association Rheumatology Branch, Chinese Medical Association Liver Diseases References for members of the Society of Autoimmune Liver Diseases Group: [1] Strand V, Berry P, Lin X et al Arthritis Care Res.
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