CN118787745A - Application of pan-JAK inhibitors in the treatment of familial benign chronic pemphigus - Google Patents

Abstract

The present invention discloses the use of a pan-JAK inhibitor in the treatment of familial benign chronic pemphigus. The present invention shows that the use of a pan-JAK inhibitor can effectively treat familial benign chronic pemphigus, and at a lower dose, it has a shorter healing time than the JAK1 inhibitor upadacitinib disclosed in the prior art, that is, it has a fast onset of action and significant efficacy, and has significant progress, which is a more effective solution for treating familial benign chronic pemphigus.

Description

Application of pan-JAK inhibitors in the treatment of familial benign chronic pemphigus

Technical Field

The present invention relates to the field of biomedicine technology, and more specifically, to the application of a pan-JAK inhibitor in the treatment of familial benign chronic pemphigus.

Background Art

Familial benign chronic pemphigus, also known as Hailey-Hailey disease, is a genetically inherited skin disease, specifically an autosomal dominant inherited skin disease. The pathogenic gene is located at 3q21-22 and is associated with multiple mutations in the ATP2C1 gene encoding the calcium pump protein. The ATP2C1 gene plays an important role in maintaining the calcium ion concentration of the Golgi apparatus. Mutations in the ATP2C1 gene lead to adhesion disorders between keratinocytes. External stimuli such as friction, cold, and ultraviolet radiation eventually cause the skin surface spinous layer to loosen and fissures to form. Its clinical characteristics are repeated appearance of erythema, blisters, erosions, keratotic papules, etc. in the neck, axilla, groin, and perianal areas, often accompanied by secondary infections. In clinical practice, glucocorticoids are often used systemically or topically to treat the disease. On the one hand, the efficacy is often poor, resulting in repeated attacks of rashes, which seriously affects the quality of life of patients; on the other hand, glucocorticoids have serious side effects, and long-term use also affects the health of patients. Therefore, a more effective treatment for familial benign chronic pemphigus is urgently needed.

The JAK family of molecules is a key kinase and central node of the cell signaling pathway in the body. JAK (Januskinase) is an important non-receptor tyrosine kinase family, including four subtypes: JAK1, JAK2, JAK3, and TYK2. The upstream is the membrane surface receptor of various cytokines, and the downstream is the signal transducer and activator of transcription (STAT). The main pathway of its signaling pathway is: after the extracellular cytokines bind to the receptor, the JAK coupled to the receptor is activated. After the activated JAK further enhances the kinase activity through the autophosphorylation of tyrosine residues, it phosphorylates the downstream STAT. The activated STAT forms a dimer and enters the cell nucleus to regulate the transcription process of the corresponding gene. JAK-STAT is one of the core intracellular signaling pathways, which is widely involved in physiological processes such as cell proliferation, differentiation, and apoptosis, and plays an important role in immune regulation.

JAK is closely related to many diseases, especially the JAK1 subtype, which is the common core of many pathways. Due to its wide range of cellular functions, the dysregulation of the JAK-STAT signaling pathway is related to many diseases. Different JAK family members tend to control different STATs. After every 2-3 JAK molecules combine to form an aggregate, they are jointly responsible for a pathway and produce specific biological effects. Among them, JAK1 is closely related to inflammation, cancer, immunity and other diseases, JAK2 is closely related to diseases of the blood system, and JAK3 is related to a variety of autoimmune diseases. Among the JAK family members, JAK1 is the only subtype that can form heterodimers with all three JAKs. JAK1 dysfunction can lead to severe inflammation, autoimmune diseases, etc. Therefore, JAK1 has received particular attention in recent years. The spectrum of pathway-related diseases is wide, and the potential of drug targets is sufficient. The related discoveries of the JAK-STAT pathway not only provide insights into various autoimmune diseases, inflammatory diseases, blood diseases and tumors, but also suggest the broad prospects of JAK as a drug target. Its specific mechanisms include: ① In autoimmune diseases, JAK inhibitors can mediate immunosuppression and inhibit the increase of serum proinflammatory factors; ② In diseases induced by JAK mutations (such as myeloproliferative cancer), JAK inhibitors can exert therapeutic effects by inhibiting JAK mutants.

Currently, many JAK drugs have been approved worldwide, which can be divided into two categories: pan-JAK inhibitors and specific JAK1 inhibitors. With its excellent therapeutic potential, JAK1 has become a hot target for new drug development. According to the selectivity of the drug against the target, it can be divided into two categories: the first-generation pan-JAK inhibitors with lower selectivity and wider binding spectrum, which not only bind to JAK1 but also bind to homologous targets such as JAK2, JAK3 or TYK2, including ruxolitinib, tofacitinib, baricitinib, peftinib, etc.; and the second-generation inhibitors with higher selectivity and specific binding to JAK1, including upadacitinib, abrocitinib, etc.

Murphy L et al. (2023) disclosed that the JAK1 inhibitor upadacitinib can be successfully used to treat bullous pemphigoid. Patients took 15 mg of upadacitinib daily for treatment. After 12 weeks of treatment, all active areas had healed, leaving only some post-inflammatory erythema (Murphy L, Ch'en P, Song EJ. Refractory Hailey-Hailey disease cleared with upadacitinib. JAAD Case Rep. 2023 Sep 27; 41: 64-67. doi: 10.1016/j.jdcr.2023.09.011. PMID: 37869368; PMCID: PMC10587664.). However, its treatment cycle is long and the dosage is large, so a more effective treatment for familial benign chronic pemphigus is urgently needed. There is currently no report on the use of pan-JAK inhibitors to treat familial benign chronic pemphigus.

Summary of the invention

The purpose of the present invention is to overcome the above-mentioned defects and deficiencies in the prior art and provide the use of a pan-JAK inhibitor in the preparation of a drug for treating familial benign chronic pemphigus.

The above-mentioned object of the present invention is achieved through the following technical solutions:

The team of the present invention recently admitted a middle-aged male patient with recurrent erythema, papules and erosions in the perianal area, vulva and axilla for 2 years. His daughter had a history of painful papules in the axilla, and biopsy suggested familial benign chronic pemphigus. His uncle had a similar medical history, but no skin pathology examination was performed. The patient's perianal skin pathology showed extensive loosening of the spinous layer. The patient's peripheral blood exon whole gene sequencing confirmed that there was a mutation in the 19th exon of the familial benign chronic pemphigus pathogenic gene ATP2C1. The PCR of the ATP2C1 gene in the peripheral blood of his daughter showed that there was the same mutation in the 19th exon of the ATP2C1 gene. Through skin pathology examination, gene sequencing and family history, the patient can be diagnosed with proliferative familial benign chronic pemphigus. The patient has been using hormone therapy for a long time, but the disease is not well controlled, the skin lesions often recur, and the side effects are obvious, which seriously affects the patient's quality of life. The patient was tried to use a pan-JAK inhibitor (JAK1/2 inhibitor) to treat familial benign chronic pemphigus. After screening for hepatitis B virus, hepatitis C virus, tuberculosis infection, etc., the patient was given a treatment regimen of 2 mg/day of oral baricitinib. After one week of treatment, the patient's symptoms were observed to be significantly improved. The original proliferative papules around the anus had subsided, the original testicular erythema erosion had subsided and healed, and the original axillary erythema erosion had also subsided and healed. That is, the use of a pan-JAK inhibitor (JAK1/2 inhibitor) can effectively treat familial benign chronic pemphigus, and it has a shorter healing time than the JAK1 inhibitor upadacitinib disclosed in the prior art at a lower dose, which is a significant improvement and a more effective treatment for familial benign chronic pemphigus.

Therefore, the present invention claims the use of a pan-JAK inhibitor in the preparation of a drug for treating familial benign chronic pemphigus. The pan-JAK inhibitor is a non-selective JAK inhibitor that can simultaneously target two or more JAKs targets and block multiple related signal pathways.

Furthermore, the pan-JAK inhibitor is a JAK1/2 inhibitor.

Preferably, the JAK1/2 inhibitor is Ruxolitinib or Baricitinib.

More preferably, the JAK1/2 inhibitor is baricitinib.

Furthermore, the dosage of baricitinib is 1.5 to 3 mg/day.

Preferably, the dosage of baricitinib is 2 mg/day.

Furthermore, the medicine is an oral preparation.

Furthermore, the medicine also includes pharmaceutically acceptable excipients.

Compared with the prior art, the present invention has the following beneficial effects:

The present invention shows that pan-JAK inhibitors can more effectively treat familial benign chronic pemphigus, and significant clinical efficacy can be seen after one week of medication. The use of pan-JAK inhibitors to treat familial benign chronic pemphigus has a shorter healing time than the JAK1 inhibitor upadacitinib disclosed in the prior art at a lower dose, that is, it has a fast onset of action and significant efficacy, which is a significant improvement and is a more effective treatment for familial benign chronic pemphigus.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a comparison of patient symptoms before and one week after using the pan-JAK inhibitor.

DETAILED DESCRIPTION

The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

Baricitinib (LY-3009104, INCB-028050) CAS number: 1187594-09-7.

Example 1 Clinical treatment example

The inventor's team recently treated a middle-aged male patient with recurrent erythema, papules, and erosions in the perianal area, vulva, and axilla for 2 years. His daughter had a history of painful papules in the axilla, and a biopsy suggested familial benign chronic pemphigus. His uncle had a similar medical history, but no skin pathology examination was performed. The patient's perianal skin pathology showed extensive loosening of the spinous layer. The patient's peripheral blood exon whole gene sequencing confirmed that there was a mutation in exon 19 on the familial benign chronic pemphigus pathogenic gene ATP2C1. The PCR of the ATP2C1 gene in the peripheral blood of his daughter showed the same mutation in exon 19 on the ATP2C1 gene. Through skin pathology examination, gene sequencing and family history, the patient can be diagnosed with proliferative familial benign chronic pemphigus. The patient has been using hormone treatment for a long time, but the disease is not well controlled, the skin lesions often recur, and the side effects are obvious, which seriously affects the patient's quality of life. Pan-JAK inhibitors (JAK1/2 inhibitors) were tried to treat the patient with familial benign chronic pemphigus. After screening for hepatitis B virus, hepatitis C virus, tuberculosis infection, etc., the patient was given a treatment regimen of 2 mg 1/day of oral baricitinib. After one week of treatment, the patient's symptoms were significantly improved. The results are shown in Figure 1, showing that the original proliferative papules around the anus have subsided, the original testicular erythema erosions have subsided and healed, and the original axillary erythema erosions have also subsided and healed. This shows that pan-JAK inhibitors (JAK1/2 inhibitors) can effectively treat familial benign chronic pemphigus, and at a lower dose, they have a shorter healing time than upadacitinib, which is a significant improvement and a more effective treatment for familial benign chronic pemphigus.

Claims (8)

1. Application of pan-JAK inhibitors in the preparation of drugs for the treatment of familial benign chronic pemphigus. 2. The use according to claim 1, characterized in that the pan-JAK inhibitor is a JAK1/2 inhibitor. 3. The use according to claim 2, characterized in that the JAK1/2 inhibitor is ruxolitinib or baricitinib. 4. The use according to claim 3, characterized in that the JAK1/2 inhibitor is baricitinib. 5. The use according to claim 4, characterized in that the dosage of baricitinib is 1.5 to 3 mg/day. 6. The use according to claim 5, characterized in that the dosage of baricitinib is 2 mg/day. 7. The use according to any one of claims 1 to 6, characterized in that the drug is an oral preparation. 8. The use according to any one of claims 1 to 6, characterized in that the drug further comprises a pharmaceutically acceptable excipient.