RU2844704C1 - Method of treating refractory ulcerative colitis - Google Patents

Abstract

FIELD: medical science.

SUBSTANCE: invention refers to medicine, namely to gastroenterology. A combination therapy with the anti-TNF preparations Infliximab 5 mg/kg of body weight every 8 weeks is administered intravenously drop-by-drop, and the targeted immunosuppressive agent Tofacitinib 5 mg a day and daily orally for a year.

EFFECT: method enables providing remission of ulcerative colitis, arresting abdominal and intestinal syndromes, thereby reducing a risk of developing infectious complications ensured by using the preparations in lower supporting dosages.

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Description

The invention relates to medicine, namely to gastroenterology, and can be used in the treatment of refractory forms of ulcerative colitis.

A method for treating patients with inflammatory bowel diseases in severe cases of inflammatory bowel diseases is known, including systemic glucocorticosteroids (GCS) - prednisolone at a dose of 2 mg / kg with an assessment of the therapeutic effect after 2-4 weeks, followed by a decrease in the GCS dose by 5 mg every 5-7 days until complete cancellation while continuing therapy with immunosuppressants. The total duration of GCS therapy should not exceed 12 weeks. Simultaneously with GCS, it is recommended to prescribe the immunosuppressants azathioprine (2-2.5 mg / kg) or methotrexate (25 mg / week subcutaneously or intramuscularly 1 time per week). [1 - Knyazev O.V. Principles of diagnosis and treatment of Crohn's disease: a tutorial / 1 - O.V. Knyazev, A.I. Parfenov. - M. 6 VITA_PRESS. 2021. 128 p.].

This method is accepted as an analogue.

A method for treating inflammatory bowel diseases refractory to standard therapy using biological therapy drugs and small molecules is known [2 - Parfenov A.I., Kagramanova A.V., Knyazev O.V. Systemic manifestations of inflammatory bowel diseases // Therapeutic archive. 2020. No. 2. URL: https://cyberleninka.ru/article/n/sistemnye-proyavleniya-vospalitelnyh-zabolevaniy-kishechnika-1 (date accessed: 04/18/2022)]. This method is taken as a prototype. However, this method is not effective enough in the treatment of refractory inflammatory bowel diseases, with ineffectiveness to the 1st line of biological therapy.

The goal is to increase the effectiveness of therapy for refractory forms of ulcerative colitis.

The technical result is achieved by using combined therapy with anti-TNF drugs infliximab at a dose of 5 mg/kg of body weight every 8 weeks intravenously by drip for a year and the targeted immunosuppressant tofacitinib 5 mg per day for 1 year to treat ulcerative colitis.

The method is carried out as follows.

Ulcerative colitis (UC) is a progressive immune-inflammatory disease that requires regular monitoring of inflammatory activity and an interdisciplinary approach involving doctors of many specialties (gastroenterologist, proctologists, rheumatologists, phthisiologists, dermatologists, ophthalmologists).

The use of two or more treatments to achieve a synergistic effect in patients with refractory forms of UC has been a focus of attention for many years. This approach, known as combination therapy, has been proposed for a variety of drugs, most commonly biologics and immunosuppressants.

Although the mainstay of biological therapy for UC has traditionally focused on anti-TNF agents, the development of new multi-target biologics such as vedolizumab and ustekinumab has introduced the possibility of using combination biologic therapy.

The efficacy and safety of combination therapy with a biological agent and an immunosuppressant have not been sufficiently studied; recently, the use of dual biological therapy in patients with refractory disease has become increasingly important due to the loss of patient response to standard therapy. The treatment algorithm proposes combination biological therapy for 2 categories of patients with UC: patients with well-controlled luminal IBD and uncontrolled extraintestinal symptoms (indications such as arthritis or psoriasis) and patients with refractory, uncontrolled IBD.

The role of combination therapy, which includes an anti-TNFalpha agent and a new biologic agent, is an area of great interest. The first study demonstrating the safety of biologic therapy was published in 2007 (Sands BE, Kozarek R, Spainhour J, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab. Inflamm Bowel Dis. 2007; 13(1): 2-11). However, since then there have been no clear recommendations regarding whether biologics can or should be used in combination or which patients would benefit most from such therapy.

Upon admission with a diagnosis of ulcerative colitis, the activity of the disease is assessed in patients based on the results of clinical and instrumental examination. During colonoscopy, the activity of ulcerative colitis is assessed in accordance with endoscopic scales of inflammation activity.

Blood tests evaluate the level of ESR, C-reactive protein and the level of fecal calprotectin, and if the level of fecal calprotectin increases to more than 80 μg/g, C-reactive protein to more than 10 mg/l and ESR to more than 20 mm/h, the presence of inflammatory bowel disease is assessed.

During an endoscopic examination of the intestine - colonoscopy - the activity of ulcerative colitis is assessed according to Schroreder.

When collecting anamnesis, the effectiveness of biological therapy and immunosuppressants is taken into account. When deciding on the use of combination therapy with anti-TNFalpha drugs (infliximab at a dose of 5 mg / kg of body weight every 8 weeks intravenously by drip for 1 year) and targeted immunosuppressants (tofacitinib 5 mg per day daily orally for 1 year). In the declared technical solution, the combination of drugs is lower than the usually used doses of drugs, which are respectively: infliximab 10 mg per kg every 8 weeks intravenously by drip, tofacitinib 20 mg per day).

In the claimed method, when prescribing combination therapy, doses of drugs were used in smaller maintenance doses, which contributed to a favorable safety profile and a reduction in the risks of developing infectious diseases.

The method is confirmed by the following examples.

Example 1

Patient K., 24 years old, with a history of ulcerative colitis, total lesion since 2013. Took 5-ASA drugs with positive dynamics. An outpatient examination was conducted in 2018, an exacerbation of ulcerative colitis was diagnosed. Azathioprine 100 mg per day was added to the therapy, 6 months later, during the examination, ulcerative colitis remained active. Biological therapy with infliximab at a dose of 10 mg / kg intravenously by drip according to the administration scheme was prescribed, during the therapy, slight positive clinical dynamics were noted. In 2021, during the next examination, according to colonoscopy data, ulcerative colitis, moderate activity, 3 Schroreder points. In blood tests, ESR is 57 mm / h, CRP is 43 mg / l, the fecal calprotectin level is 1710 mcg / g.

Given the low efficacy of monotherapy with the anti-TNFalpha drug, combination therapy with the anti-TNFalpha drug infliximab at a dose of 5 mg/kg every 8 weeks intravenously by drip for 1 year and the targeted immunosuppressant tofacitinib 5 mg per day orally for 1 year was prescribed.

A follow-up examination was performed in 2022. Colonoscopy revealed ulcerative colitis, remission, 1 Schroreder point. Fecal calprotectin 130 mcg/g.

After the combination therapy is prescribed, the patient is hospitalized in the department for a follow-up examination 12 months later. The patient's abdominal and intestinal syndromes have been relieved. According to colonoscopy data, remission of ulcerative colitis is noted. The patient continues combination therapy.

Example 2

Patient T., 34 years old, with a history of ulcerative colitis since 2010. He took monotherapy with infliximab at a dose of 10 mg / kg according to the administration scheme, clinical and instrumental remission was achieved. In 2021, he was an inpatient in the intestinal pathology department. During the examination: Diagnostic colonoscopy: The colonoscope was inserted into the cecum. There is no haustration in the examined sections. The vascular pattern is blurred. The mucosa of the colon is diffusely edematous, hyperemic, granular, contact vulnerable. Endoscopic signs of UC of the colon, severe activity 4 Schroreder points.

Due to the insufficient effectiveness of the first line of biological therapy, the patient was prescribed combined biological therapy according to the scheme: infliximab at a dose of 5 mg/kg of body weight every 8 weeks intravenously by drip and tofacitinib 5 mg per day orally. The drugs are prescribed for 1 year.

After 12 months, the patient was hospitalized in the department for a control examination. The patient's abdominal and pain syndromes were relieved. According to colonoscopy data, UC is in remission.

Example 3

Patient T., 60 years old, with a history of UC since 2013, has been observed in the IBD Treatment Department of the Moscow Clinical Research Center since 2015. History of taking infliximab at a dose of 10 mg/kg - without effect. Disease activity was monitored annually: colonoscopy, blood tests. Colonoscopy: Anal sphincter tone is preserved. The colonoscope is inserted into the cecum. In the examined sections of the colon, the tone of the colon is normal. Haustration and vascular pattern in the cecum, ascending, sigmoid colon are absent. The mucosa of the cecum and ascending colon is diffusely edematous, hyperemic, granular, vulnerable to contact, transverse colon: mucous membrane is pink, shiny, descending colon, sigmoid colon are hyperemic, granular, vulnerable to contact. Conclusion: endoscopic signs of high activity UC, 4 Schroreder points.

Given the high activity of UC, the ineffectiveness of monotherapy with the anti-TNFalpha drug infliximab at a dose of 10 mg/kg of body weight in the anamnesis, combination therapy was started with the anti-TNFalpha drug infliximab at a dose of 5 mg/kg of body weight every 8 weeks intravenously by drip for |1 year and the targeted immunosuppressant tofacitinib 5 mg per day for 1 year. Against the background of combination therapy, clinical and instrumental remission is achieved.

Due to the resistant course of IBD, the ineffectiveness of monotherapy with biological or immunosuppressive therapy, as well as combined immunoinflammatory pathology, patients were prescribed combined biological therapy.

After 12 months, patients are admitted to the department for a follow-up examination.

The patients' abdominal and pain syndromes have been relieved. According to colonoscopy data, remission of ulcerative colitis is noted. The patient continues therapy with combined biological therapy and immunosuppressants.

Due to the resistant course of IBD, the ineffectiveness of biological and immunosuppressive therapy, patients with UC are prescribed a combination therapy according to the scheme. In this case, the doses of the drugs used in combination therapy are reduced, which allows avoiding the side effects of the drugs.

According to the claimed method, combined therapy was performed on 64 patients with refractory forms of UC. One year after the start of treatment, all patients were brought into clinical and instrumental remission, which confirms the achievement of the invention.

Sources of information

1. Knyazev O.V. Principles of diagnosis and treatment of Crohn's disease: a tutorial / O.V. Knyazev, A.I. Parfenov. - M. 6 VITA_PRESS. 2021. 128 p.

2. Parfenov A.I., Kagramanova A.V., Knyazev O.V. Systemic manifestations of inflammatory bowel diseases // Therapeutic archive. 2020. No. 2. URL: https://cyberleninka.ru/article/n/sistemnye-proyavleniya-vospalitelnyh-zabolevaniy-kishechnika-1 (date of access: 04/18/2022).

Claims (1)

A method for treating refractory forms of ulcerative colitis, including biological therapy, characterized in that for the treatment of ulcerative colitis, combined therapy is used with anti-TNFalpha drugs infliximab at a dose of 5 mg/kg of body weight every 8 weeks intravenously by drip for 1 year and the targeted immunosuppressant tofaciticib 5 mg per day for 1 year.