RU2268719C2 - Method for preventing osseous-cartilaginous destruction in case of rheumatoid arthritis - Google Patents

Abstract

FIELD: medicine, rheumatology.

SUBSTANCE: the innovation deals with therapy with metothrexate at the dosage of 7.5 mg/wk in combination with small dosages of glucocorticosteroids, up to 10 mg/d against prednisolone. Metothrexate should be once introduced at the quantity of 7.5-20 mg/wk, glucocorticosteroids - once at 3 a.m. Therapy course lasts for bout 6 mo, not less followed by decreasing the dosage of glucocorticosteroids for 6 mo up to their complete refusal at keeping maintenance therapy with metothrexate. The innovation enables to achieve maximal increase of antidestructive action at any terms of disease due to preventing the development of new articular erosions and keeping the width of articular fissura at the most physiological scheme of glucocorticosteroids' intake.

EFFECT: higher efficiency of prophylaxis.

4 cl, 12 dwg, 4 ex, 3 tbl

Description

The present invention relates to medicine, namely to rheumatology, and is used for the prevention of bone-cartilage destruction in rheumatoid arthritis (RA).

Modern drug therapy of RA includes the simultaneous use of drugs of two different classes - fast-acting anti-inflammatory drugs (steroidal or non-steroidal) and slow-acting (basic) drugs that have a deeper and more stable therapeutic effect on RA.

A known method of combination therapy in the treatment of RA using anti-inflammatory drugs, including glucocorticoids (GCS), and immunomodulators, which is used as oxydevitis (see RF patent No. 2038082, application 24.06.92, A 61 K 31/59).

There is a method of combination therapy in the treatment of RA using prospidine and methotrexate (MT), which have anti-inflammatory and immunomodulatory effects (see RF patent No. 2299329, claimed 19.09.2001, A 61 K 31/495).

A known method of combination therapy in the treatment of RA with gold drugs, in particular auranofin and methotrexate (see Clinical Medicine, 1990, No. 1, p.119-124).

Gold preparations have a rather large list of contraindications, while the circle of patients able to tolerate these drugs is limited (more than 30% of patients cannot be tolerated).

The mentioned sources provide data on the effect of combination therapy on the clinical and laboratory parameters of patients with RA and do not provide radiological parameters characterizing bone-cartilage destruction in the joints. The latter is a criterion for the effectiveness of basic therapy, as well as a factor determining the functional status and quality of life. In addition, information is not given on the results of long-term follow-up of patients. Apparently, in the described methods, the introduction of anti-inflammatory and immunomodulatory agents consists mainly in alleviating the symptoms of the disease and is not aimed at preventing bone-cartilage destruction.

Rheumatoid arthritis is an autoimmune disease. Like any autoimmune self-sustaining process, RA is a chronic progressive disease, accompanied by inflammatory reactions and gradually increasing destruction of soft tissues, cartilage and bones. Since RA is a long-term disease, and not a disease with a pronounced “beginning” and “end”, prevention of bone-cartilage destruction is important so that the pathological process can be slowed down or suppressed. It is very important that prevention be started at an early stage of the disease, before significant damage to the bone and joint has occurred. In the initial stage of RA, there are no joint deformities, no osteopenia, since in the early phase of RA, autoimmune pathogenetic mechanisms have not yet fully formed and there is no pannus, the morphological basis of joint destruction. Therefore, the active start of prevention at the very early stages of RA is justified by the desire to quickly and stably suppress the active immune-inflammatory process and thereby prevent subsequent irreversible destruction of the joints.

A known method for the prevention of bone-cartilage destruction in RA, including basic therapy with methotrexate (MT) in combination with low doses of glucocorticosteroids (GCS), up to 10 mg / day for prednisone, is aimed at preventing or slowing down bone-cartilage destruction (see Scientific and practical Rheumatology, 2000, No. 1, pp. 29-31). If the anti-inflammatory and immunomodulatory properties of GCS have been known and actively used for over 50 years, then the anti-destructive properties were unexpected.

This source reports on the possibility of the anti-destructive effect of low doses of corticosteroids, in particular prednisone, up to 10 mg / day on the background of basic therapy with methotrexate, but there is no treatment regimen aimed at preventing bone-cartilage destruction in the joints, at slowing down or suppressing the process. The mentioned method is taken as a prototype.

The problem to which the present invention is directed, is the development of a method for the prevention of bone-cartilage destruction in RA, aimed at preventing, slowing down or reverse development of the destruction process.

The problem is solved in that in the known method for the prevention of bone-cartilage destruction in RA, including basic therapy with methotrexate in combination with low doses of corticosteroids, up to 10 mg / day for prednisone, according to the invention, MT is administered in an amount of 7.5-20 mg / once a week, and GCS - at 3 a.m. once, the course of treatment is carried out for at least 6 months with a gradual reduction in the dose of GCS for 6 months, until it is completely canceled, while maintaining a maintenance dose of MT.

Betamethasone, or methylprednisolone, or cortisone, or triamcinolone, or dexamethasone can be used as GCS, but it is preferable to use prednisolone as the most easily tolerated (at least in rheumatology) GCS, which gives the most stable and pronounced therapeutic effect.

It is preferable for women to administer prednisolone 5-10 mg / day, depending on weight, and for men - 10 mg / day, since the effectiveness of GCS in the latter is somewhat lower. The course of treatment is advisable to be carried out within 12 months, since during the indicated period in most patients a therapeutic effect is achieved.

To eliminate side effects - nausea and other dyspeptic phenomena, it is advisable to administer folic acid 1 mg / day once, except for the day of taking methotrexate.

From the literature it is known that patients who give a minimal response to corticosteroids and MT separately, given the given doses, were sensitive to their combination (see Ya.A. Sigidin, G.V. Lukina, Basic (pathogenetic) therapy of rheumatoid arthritis - M ., 2000, p. 128; J. Kremer and J. Lee A long-term prospective study of the use of methotrexate in rheumatoid arthritis: update after a mean fifty-three months. Arthritis Rheum. 1988; 31: 577-584) . The authors of the claimed invention also showed that MT alone does not have a prophylactic effect on suppressing or slowing down bone-cartilage destruction (see Example 5).

Methotrexate belongs to the class of antimetabolites, that is, substances that are chemically close to the body’s natural metabolites and therefore compete with it for participation in biochemical processes, thereby leading to inhibition of cellular and humoral immune reactions in small doses due to the inhibitory effect on the development of lymphocytes in the synthesis phase . It belongs to the category of so-called phase-specific drugs, since it has the most pronounced immunomodulating effect in a specific phase of the cell cycle, namely in the synthesis phase. The ability of corticosteroids to affect bone-cartilage destruction in RA can be due to either a direct effect on the destruction factors or regulatory mechanisms of their implementation, or an indirect effect on these factors through an immunomodulating and anti-inflammatory effect. GCS have a direct effect on humoral factors, the macrophage system of migration of leukocytes into the area of inflammation. Since macrophages play a key role in both immune responses, presenting antigen to lymphoid cells, and chronic inflammation, corticosteroids can exert a simultaneous inhibitory effect on both pathological processes. Thus, the combined use of MT and GCS leads to qualitative synergism due to the effect on various lines of immunocompetent cells (macrophage, lymphoid), on their interaction and on the inflammatory process itself, that is, on the main pathogenetic factors of RA.

MT in the amount of 7.5-20 mg / week is administered depending on the previous effect. Administration at a dose of less than 7.5 mg / week is ineffective, and at a dose of more than 20 mg / week, the likelihood of toxic effects increases sharply. The use of GCS at 3 a.m. provides a more pronounced effect on the duration of morning stiffness, joint pain, Lansby and Richie indices, morning concentration of interleukin-6 in blood serum than the traditional intake of low doses of GCS in the morning. Reception of corticosteroids during the specified period of time is the most physiological and acts in accordance with the endogenous rhythm of the production of corticosteroids. It is essential that the given scheme for the prevention of bone-cartilage destruction should be carried out for at least 6 months. It is during this period of time that the complex administration of MT and GCS at the doses indicated above, and at the same time, the time of taking GCS at 3 a.m., has a clear anti-destructive effect and clinical-laboratory and radiological remission is achieved in a sufficient proportion of patients. Less than 6 months is not enough for a clear anti-destructive effect. Reducing the dose of corticosteroids for 6 months is the best time to ensure the gradual and prevention of withdrawal syndrome of the above drugs. Preservation of maintenance therapy of MT provides a long-term remission, up to two or more years.

The therapeutic effect of this method was shown in 74 patients with reliable, according to the criteria of the American College of Rheumatology, rheumatoid arthritis. Depending on the type of therapy, all examined patients were divided into 2 groups.

The main group (38 people) included patients receiving MT at a dose of 5-10 mg / week (on average 7.8 mg / week) in combination with GCS (prednisone) at a dose of 2.5-10 mg / day (average 6.25 mg / day), prescribed at 3 a.m.

The control group (36 people) consisted of patients taking only MT at a dose of 5-10 mg / week (an average of 7.8 mg / week), with 31 patients taking the drug before the start of the observation. The average duration of MT intake at the beginning of the study was 2.9 years, the average dose was 9.1 mg / week.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) was allowed in both groups.

Table 1 shows the demographic and clinical characteristics of the patients included in the study.

Table 1.
Demographic and clinical characteristics of patients included in the study Characteristic The main group (n = 38) Control Group (n = 36) R Age 47.82 ± 10.9 52.22 ± 10.3 0,078 Disease duration 64.58 ± 57.8 74.61 ± 54.2 0.44 Rheumatoid factor seropositivity 32 (84%) 28 (78%) 0.14 Activity (degree) one 2 5 9 0.20 3 21 eighteen (χ2 = 7.0) 12 9 X-ray stage I 8 5 0.20 II eighteen 17 (χ2 = 6.0) III 12 fourteen Functional failure I fourteen fifteen 0.16 II 24 21 (χ2 = 2.0) Flow fast slow 3/35 1/35 0.16 progressive (χ2 = 2.0)

Compared groups of patients are comparable in demographic and clinical characteristics. The groups are homogeneous in most clinical and laboratory parameters at the beginning of therapy.

The effectiveness of the therapy was evaluated after a year in patients receiving appropriate treatment during this time according to the given scheme. Clinical, laboratory, and X-ray indices characterizing the activity and progression of RA were evaluated.

When analyzing the rate of increase of x-ray progression in the two groups, significant differences were found (table 2).

Table 2.
The average difference in x-ray indices in the main and control groups after 12 months of observation (M ± m). X-ray parameters The main group (n = 38) Control Group (n = 36) p Larsen Index 2.82 ± 0.97 6.67 ± 5.71 0.04 Erosion rate 0.53 ± 0.06 2.11 ± 1.34 0.003 The degree of narrowing of the joint space in points 2.55 ± 1.49 4.47 ± 2.75 0.08

In patients taking MT and low doses of corticosteroids, after a year of observation, the degree of articular destruction estimated by the Larsen indices and the number of erosions was significantly lower than in the control group. The dynamics of the degree of narrowing of the joint gap, reflecting the destruction of cartilage, also turned out to be less in patients of the main group compared with patients in the control group. These results indicate that the addition of low doses of corticosteroids to MT gives a more pronounced effect on the slowdown of radiological progression compared with MT monotherapy for at least 12 months.

It was noted that in the main group there is a high percentage of patients with a decrease in the Larsen index corresponding to regression of bone-cartilage destruction (11% compared with 3% of the control group). The lack of dynamics of Larsen's count, indicating the stabilization of the process, was also observed in a larger number of patients of the main group (about 2 times) than the control. At the same time, an increase in Larsen's score prevailed in patients receiving MT monotherapy (83% compared with 58% of the main group).

Our data indicate the presence of "radiological remission" in 42% of patients (16 people) from the main and 17% of patients (6 people) from the control group.

Similar results were obtained by analyzing the dynamics of other radiological parameters (total number of erosions, narrowing of the joint space). Thus, a decrease in the number of erosions was observed in a larger number of patients of the main group compared with the control group (13% compared with 6%, respectively). The effect of low doses of corticosteroids on narrowing the width of the joint space can most likely be described as inhibitory (in 42% of patients of the main group, the width of the joint space after a year of therapy was unchanged compared to 14% of the control group).

An increase in articular destruction after a year of observation was observed in most patients in both groups, however, patients with worsening were almost 2 times less in the group with combined therapy compared with patients receiving MT monotherapy.

Thus, in both compared groups there were patients in whom an increase in bone-cartilage destruction was observed, but there were also patients in whom it did not occur or even underwent reverse development. In the group receiving GCS and MT, a stop or decrease in such indicators of bone-cartilage destruction as the Larsen index, the number of erosions, and the degree of narrowing of the joint gap occurred in a significantly larger number of patients.

In 23 patients, we followed the dynamics of radiological progression after 2 years (in 17 patients from the main group and in 6 from the control group). Patients continued to take the same therapy (table 3).

Table 3.
Dynamics of X-ray indices in the main and control groups after 12 and 24 months of observation (M ± σ). X-ray parameters Study start After 12 months of observation After 24 months of observation The main group (n = 17) Control group (n = 6) The main group (n = 17) Control group (n = 6) The main group (n = 17) Control group (n = 6) Larsen Index 73.2 ± 26.5 72.4 ± 31.9 76.0 ± 27.9 78.3 ± 19.6 78.5 ± 20.1 83.9 ± 17.4 Erosion rate 9.0 ± 9.4 8.7 ± 8.5 9.8 ± 7.4 11.0 ± 1 ± 9.1 10.2 ± 8.8 13.25 ± 8.49 The degree of narrowing of the joint space in points 40.8 ± 33.8 39.4 ± 32.4 42.1 ± 32.5 42.2 ± 1 ± 28.2 44.3 ± 26.7 45.1 ± 30.1

With comparable (p> 0.5) initial values of the indicators of articular destruction (Larsen index, the number of erosions and the degree of narrowing of the joint space), it was found that in the main and control groups there was an increase in bone-cartilage destruction after 12 and 24 months of observation. However, the rate of its increase in patients receiving combination therapy with MT and GCS is slower than in patients undergoing MT monotherapy. This is more noticeable in the Larsen index and in the erosion count, where this difference is statistically significant (p <0.05). The dynamics of an increase in the narrowing of the joint space in the main and control groups after 12 and 24 months is stable and comparable.

It has been shown that with long-term combined administration of MT and low doses of MTs during the year, GCS is inhibited, and in some cases, articular destruction in RA regresses. This effect persisted for at least 2 years. The effect on signs of inflammation and functional impairment in combination therapy with MT and GCS was also more pronounced compared with MT monotherapy. Therefore, the treatment regimen used is proposed as a method for the prevention of bone-cartilage destruction of joints in rheumatoid arthritis.

Clinical example 1. The development of remission of RA in the treatment of low doses of corticosteroids and MT.

Patient X., 46 years old, was admitted to the hospital with a diagnosis of RA, polyarthritis, seronegative, activity II, stage II, functional impairment II. The disease is 16 months old. Prior to admission to the ward, only symptomatic NSAIDs were administered. By the beginning of the observation - pronounced articular syndrome (number of painful joints 17, number of inflamed joints 5, Ritchie index 40, pain intensity on a visual analogue scale of 8 cm), ESR - 37 mm / h, circulating immune complexes - 176 p.u., index DAS3 activity = 5.153, anemia with a decrease in hemoglobin to 107 g / l. On radiographs of the hands and feet - periarticular osteoporosis, narrowing of the joint spaces, erosive arthritis. The total number of erosions is 3, the Larsen index is 53 points. Basic therapy of MT was started at a dose of 7.5 mg / week once in combination with prednisolone at a dose of 5 mg / day at 3 a.m. After 6 months of therapy, a significant effect was noted in the form of a decrease in the joint syndrome (number of painful joints 8, number of inflamed joints 1, Ritchie index 13, pain intensity on a visual analogue scale of 4 cm) and laboratory activity (ESR -28 mm / h, circulating immune complexes 95 pu, DAS3 activity index = 3.337), the hemoglobin level increased to 116 g / l, the degree of functional insufficiency - 0. During this period, it was possible to reduce the dose of prednisone from 5 to 2.5 mg / day without the development of exacerbation, dose MT - no change. The patient took folic acid at a dose of 1 mg / day once, except for the day of receiving MT. After 12 months of therapy, a clinical remission of the disease was achieved (there were no pain at rest and when moving in the joints, morning stiffness, ESR was 15 mm / h, DAS3 activity index = 1.118). By this time, the Larsen index was 53 points, and the total erosion score was 3. This allowed the GCS to be completely canceled. The total duration of a decrease in the dose of KS until complete cancellation was 6 months. The effect of therapy persists for 2 years. Treatment tolerance is good. The patient does not need to take NSAIDs during the observation period.

Below are the radiographs of this patient before and after the end of the study (photos 1, 2 - radiographs of the hands, photos 3, 4 - radiographs of the feet).

In the presented pictures, there is no radiological progression, both from the side of small joints of the hands and feet during the year. There is a stabilization of the destructive process in the joints.

Clinical example 2. Slowing of the pace of radiological progression in combination therapy of MT and low doses of corticosteroids

Patient S., 38 years old, was admitted to the hospital with a diagnosis of RA, polyarthritis, seropositive, with systemic manifestations (fever, rheumatoid nodules), activity III, stage III, functional impairment II. Prescription RA 3 years. Before admission to the clinic, MT therapy at a dose of 7.5 mg / week and NSAIDs was performed during the year. At the beginning of the observation, pronounced articular syndrome (the number of painful joints 16, the number of inflamed joints 6, Ritchie index 30, ESR 56 mm / h, rheumatoid factor - 1: 1280, activity index DAS3 = 5.103). On radiographs of the hands and feet - periarticular osteoporosis, narrowing of the joint spaces, erosive arthritis. The Larsen index is 80 points, the total number of erosions is 6, the degree of narrowing of the joint spaces in the hands and distal parts of the feet is 23 points. Prednisone was added to the therapy at a dose of 5 mg / day at 3 a.m. The patient took folic acid at a dose of 1 mg / day once, except for the day of receiving MT. After a month of treatment, the fever was stopped, the laboratory activity of the disease (ESR 38 mm / h) decreased. By 18 months from the start of combination therapy, a good clinical effect was noted (the number of painful joints 6, the number of inflamed joints 0, Ritchie index 10, ESR 15 mm / h, rheumatoid factor 1:80, DAS3 = 2.825). In addition, healing and a decrease in the size of two erosions were noted, the severity of racemose enlightenment in the small joints of the hands decreased, which led to an improvement in radiological parameters (Larsen index 75 points, total erosion score 4, the degree of narrowing of the joint spaces 23 points).

As can be seen, the addition of small doses of corticosteroids to the basic therapy of MT after 18 months made it possible to reduce the severity of the articular syndrome, disease activity, estimated by the presence of systemic manifestations, laboratory parameters and the DAS3 activity index, and inhibition of radiological progression in the joints.

Below are the radiographs of the patient before and after the end of the study:

photo 5, 6 - healing of erosion of the scaphoid of the left wrist;

photo 7, 8 - a decrease in the severity of racemose enlightenment in the bones of the wrist on the right.

Clinical example 3. Slowing of the progression rate of erosive arthritis in patients with RA can be observed with a long period of the disease on the background of combined therapy of MT and small doses of corticosteroids

Patient 3., 47 years old, observed in the clinic with a diagnosis of RA, seronegative, activity I, stage III, functional insufficiency I. Prescription RA - 11 years. Within three years from the onset of the disease, the patient received NSAIDs, then 8 years - combined MT therapy with 10 mg / week inside and prednisone 5 mg / day. The treatment regimen for MT + GCS was left for the duration of the study. Reception of prednisolone is postponed to 3 a.m. The patient also took folic acid at a dose of 1 mg / day once, except for the day of taking MT. The disease proceeds with minimal laboratory and clinical activity. At the time of observation, the number of painful joints 5, the number of inflamed joints 1, Ritchie index 9, ESR 25 mm / h, the rheumatoid factor is negative, DAS3 = 2,972. On radiographs of the hands and feet - periarticular osteoporosis, narrowing of the joint spaces, erosive arthritis. Larsen index 91, total erosion score 12, the degree of narrowing of the joint spaces in the hands and distal parts of the feet 32 points. After 2 years of observation, the number of painful joints 6, the number of inflamed joints 0, Ritchie index 9, ESR 27 mm / h, rheumatoid factor is negative, DAS3 = 2,933. Larsen index 91 points, the total erosion score 13, the degree of narrowing of the joint spaces in the hands and distal parts of the feet 32 points. Thus, in a patient with an RA duration of more than 10 years, against the background of MT therapy and low doses of corticosteroids, minimal radiological progression of the disease is observed (there was only one erosion in the absence of dynamics from the Larsen index and narrowing of the joint gap).

The given example shows that a slowdown in the progression of erosive arthritis in patients with RA can be observed with a long period of the disease against the background of combined therapy of MT and small doses of corticosteroids.

Below are the radiographs of this patient before and after the end of the study (photo 9-12). There is the appearance of small erosion in the head region of the first metacarpal bone on the left. In the remaining joints of the hands and distal parts of the feet, radiological progression is absent.

Clinical example No. 4. X-ray progression on the background of methotrexate monotherapy.

Patient T., 48 years old, was admitted to the hospital with a diagnosis of RA, polyarthritis, seropositive, activity II, stage II, functional impairment II. The disease is 12 months old. Prior to admission to the ward, only symptomatic NSAIDs were administered. By the beginning of the observation, pronounced articular syndrome (morning stiffness 2 hours, number of painful joints 20, number of inflamed joints 8, Ritchie index 44, pain intensity on a visual analogue scale of 8 cm), ESR 38 mm / h, CEC - 204 p.u. , DAS3 activity index = 5.253, hemoglobin 110 g / L. On radiographs of the hands and feet - periarticular osteoporosis, narrowing of the joint spaces, erosive arthritis. The total number of erosions is 3, the Larsen index is 53 points. Basic therapy with methotrexate at a dose of 7.5 mg / week in tablets was started. After 6 months of treatment, a certain effect was noted in the form of a decrease in articular syndrome (morning stiffness 40 minutes, number of painful joints 12, number of sore joints 4, Ritchie index 20, pain intensity according to YOUR 5 cm) and laboratory activity (ESR 30 mm / h, CEC - 124 p.u., activity index DAS3 = 4,122), the hemoglobin level increased to 120 g / l, the degree of functional insufficiency I. After 12 months of therapy, the condition worsened again. Morning stiffness 2.5 hours, pain at rest and when moving in the joints, synovitis of the small joints of the hands, a rheumatoid nodule appeared over the proximal interphalangeal joint of the fourth finger of the right hand, functional insufficiency II. ESR was 44 mm / h, CEC 220 p.u., DAS3 activity index = 5.823. Hemoglobin 106 g / l. By this time, the Larsen index was 64 points, and the total erosion score was 7. Thus, treatment with methotrexate for 12 months gave a temporary incomplete clinical and laboratory effect, which was replaced by deterioration, and the progression of bone-cartilage destruction in the joints was revealed radiologically.

It can be seen from the examples that the proposed method for the prevention of bone-cartilage destruction in RA ensures the suspension, deceleration, or reverse development of destruction both in the early stages and in the long term of the disease.

Claims (5)

1. A method for the prevention of bone-cartilage destruction in rheumatoid arthritis, including therapy with methotrexate at a dose of 7.5 mg / week in combination with low doses of glucocorticosteroids, up to 10 mg / day for prednisone, characterized in that methotrexate is administered in an amount of 7.5- 20 mg / week once, glucocorticosteroids - once at 3 a.m. once, the course of treatment is carried out for at least 6 months, followed by a reduction in the dose of glucocorticosteroids for 6 months, until they are completely canceled, while maintaining maintenance therapy with methotrexate. 2. The method according to claim 1, characterized in that betamethasone, or cortisone, or prednisolone, or triamcinolone, or dexamethasone are used as glucocorticosteroids. 3. The method according to claims 1 or 2, characterized in that prednisolone is essentially used as glucocorticosteroids. 4. The method according to claim 1, characterized in that the course of treatment is essentially carried out for 12 months. 5. The method according to claim 1, characterized in that the folic acid 1 mg / day is additionally administered, except for the day the methotrexate is taken.

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