<<
>>

Chapter 2. MATERIALS And METHODS.

Dissertational work is executed on the basis of UDKB GBOU VPO the First MGMU of I.M.Setchenov (the director of clinic - the Deserved doctor of Russia, d.m.n., professor N.A.Geppe) during the period with 2012 for 2014.

Work has included the analysis of retrospective data and prospektivnoe opened nerandomizirovannoe clinical research into which 102 patients with juvenilnym an idiopathic arthritis at the age from 3 till 18 years have entered, (are surveyed 108 clinical cases of application GIBP). A diagnosis code on МКБ-10: М08.2, М08.3, М08.4. Appointment GIBP was spent after ascertaining of an inefficiency of standard antirheumatic therapy by criteria of the American board of rheumatologists (the American College of Rheumatologists) for pediatric patients - ACR pedi.

All patients depending on spent therapy have been parted on 3 groups:

1. Group of the patients who are on therapy infliksimabom - 30 children;

2. Group of the patients who are on therapy etanertseptom - 48 children;

3. Group of the patients who are on therapy abatatseptom - 30 children;

In turn, each group has been parted on two subgroups, depending on a variant juvenilnogo an idiopathic arthritis:

1. A subgroup with system variant JUIA.

2. A subgroup with articulate variant JUIA.

The diagnosis was established on the basis of criteria of the International league of rheumatological associations (1997г.):

1. System variant JUIA was defined in the presence of an arthritis accompanied or with a previous fever within 2 weeks in a combination to two or more signs: transient, flying erythematic rashes, a serositis, a generalised lymphadenopathy, a hepatomegalia and-or a splenomegaly.

2. Articulate variant JUIA:

• the Polyarthritis, seronegative across the Russian Federation, was defined at a lesion of five or more joints within 6 months of disease, the Russian Federation - the negative.

• the Polyarthritis, seropositive across the Russian Federation, was defined at a lesion of five and more joints within the first 6 months of disease, in the presence of the positive Russian Federation in two tests throughout 3 months.

• Oligoartrit it was defined in the presence of an arthritis of 1-4 joints within the first 6 months of disease:

Criteria of including in research:

• children from 3 till 18 years of both floors with established diagnosis JUIA with a various degree of activity of disease and prevalence of inflammatory process,

• reception by patients as basic therapy one of GIBP (infliksimab, etanertsept, abatatsept).

Criteria of an exception of research:

• presence of the contraindications limiting application GIBP and-or essentially worsening quality of a life of patients,

• impossibility to receive the ordered treatment (including refusal of parents of carrying out of the prescribed therapy).

For verification of the diagnosis and therapy selection to all children complex clinico-laboratory and tool inspection was spent:

1. The analysis of data of the anamnesis:

• age and clinical implications at the moment of the beginning and disease;

• duration of disease at the moment of research;

• time from the beginning of illness prior to the beginning of treatment;

• the basic implications of illness at the moment of a manifestation;

• a variant, duration, efficiency and safety of the spent

2.

3.

4.

Therapies.

Survey data:

The standard clinical survey of the patient;

Estimation of an articulate syndrome;

Estimation of extraarticular implications JUIA.

Laboratory methods of research:

The general clinical and biochemical analyses of blood with definition of indicators of inflammatory activity (on the basis of laboratory of clinical centre GBOU VPO the First MGMU of I.M.Setchenov and laboratory UDKB);

Immunologic blood analysis: definition of level of the rhematoid factor (Russian Federation), immunoglobulins A, M, G, antinukliarnogo the factor (ANF), S-jet fiber (SRB) (on the basis of interclinical immunologic laboratory GBOU VPO the First MGMU of I.M.Setchenov);

immunogeneticheskoe a blood analysis: definition HLA of 1 and 2 classes gistosovmestimosti (on the basis of interclinical immunologic laboratory GBOU VPO the First MGMU of I.M.Setchenov).

Tool methods of inspection:

• the X-ray inspection of organs of a thorax,

X-ray inspection of joints, magnitno-resonant tomography of joints (were spent on the basis of unit of radial diagnostics UDKB GBOU VPO the First MGMU of I.M.Setchenov);

• for an exception tubinfitsirovanija before appointment long immunosupressivnoj therapy and the control of safety of spent treatment, if necessary provodilal a multispiral computer tomography of organs of a thorax (on the basis of unit of radial diagnostics UKB №2 GBOU VPO the First MGMU it. I.M.

Setchenov);

• the Electrocardiography (on the basis of unit of functional diagnostics UDKB GBOU VPO the First MGMU of I.M.Setchenov);

• Ultrasonic research (ultrasonic) of organs of an abdominal cavity, kidneys, joints, echocardiographic research (ECHO-KG) (on the basis of unit of ultrasonic diagnostics UDKB GBOU VPO the First MGMU of I.M.Setchenov).

5. Mantoux test and-or Diaskin-test statement.

6. Consultation of the phthisiatrician.

For an estimation of efficiency of spent therapy "pediatric" criteria of the American board of rheumatologists (ACR pedi) were used. Criteria include 6 indicators:

1. Number of joints with activity signs (from 75 joints);

2. Number of joints with function restriction (from 75 joints);

3. Value of an ESR and-or SRB;

4. The general estimation of activity of illness, according to the doctor (the Visually-analogue scale - YOURS);

5. An estimation of the general state of health of the child (activity of illness), according to the patient or his parent (the Visually-analogue scale - YOURS);

6. An estimation of functional ability by means of the Questionnaire according to the general state of health for pediatric patients (Childhood Health Assesment Quesionnare - CHAQ).

Signs of activity of a joint concern: an exudation, rising of a local body temperature over a joint, morbidity presence at a palpation of a joint and / or at movement. The general estimation was spent by the doctor of activity of illness with the help YOUR 100-mm, where “0” - absence of activity of illness, and “100” - the extremely bad state of health of the child. The estimation was spent by the patient or his parent of the general state of health also with the help YOURS, where “0” - very good condition of the child, and “100” - very bad state of health of the child (a drawing 2.1).

Drawing 2.1. A visual analogue scale.

Functional insufficiency (TNFS) it was spent by means of questionnaire CHAQ consisting of two sections: an estimation of the functional status and level of discomfort (pain) at the patient. By means of an index functionality of the patient on 8 sections (30 questions) was estimated: “ Clothing and care of self "," lifting "," meal "," walking "," hygiene "," possibility to get something "," compression "," possibility of performance of additional functions ”. The estimation was made in 3 directions: difficulties at performance of daily actions, necessity of use of extras and-or the help of other persons. The questionnaire was filled independently with children is more senior 8 years or parents of children is more younger 8 years. On each question there are 4 variants of answers (without difficulties, moderate difficulties, serious difficulties, cannot execute). At impossibility to answer on the brought attention to the question there is an answer variant“ it is impossible to estimate ”. The minimum value of an index of functional insufficiency -“0”, maximum -“3”. At use of the additional help of other persons or adaptations the minimum account of points for this functional area makes“2”. To the best functional ability of the patient there corresponds the least value of an index. The discomfort is defined by pain measurement on YOURS. Dempster and co-workers. Have allocated 4 variants (category) of functional disturbances according to value CHAQ:

• absence of TNFS (average value CHAQ 0),

• minimum TNFS (mild) (sredn. znach. CHAQ 0,13),

• moderated TNFS (moderate) (average value CHAQ 1,75),

• serious TNFS (severe) (CHAQ> 1,5).

Minimum clinically important improvement has made reduction of value CHAQ on 0,13, and the minimum deterioration - augmentation of an average level on 0,75.

The functional class (FK) was estimated by criteria SHtejnbrokkera:

• FK I - functional ability of joints is kept,

• FK II - restriction of functional ability of joints without restriction of ability to self-service.

• FK III - restriction of functional ability of the joints, accompanied by restriction of ability to self-service.

• FK IV - the child independently is not capable to serve itself, requires assistance.

The disease degree of activity was defined on ESR and concentration SRB indicators:

• 0 degree - the ESR to 12 mm/ch, SRB is not defined (to 0,8 mg/dl)

• I degree - an ESR of 13 20 mm/ch, SRB slabopolozhitelnyj (+), (0,8-1,9 mg/dl)

• II degree - an ESR of 21-39 mm/ch, SRB positive (++), (2,0-2,9 mg/dl)

• SHstepen - an ESR of 40 mm/ch and more, SRB sharply positive (+++, ++++), (more than 3 mg/dl).

Radiological stages of activity of disease - stages of anatomic changes (on SHtejnbrokkeru):

• I stage - an epiphyseal osteoporosis,

• II stage - an epiphyseal osteoporosis, razvoloknenie a cartilage, narrowing of an articulate cleft, individual erosions

• III stage - a cartilage and bone destruction, formation of osteoarticular erosions, subluxations in joints

• IV stage - criteria of III stage + a fibrous or osteal ankylosis.

Achievement at least 50 % (ACR pedi 50) improvements by criteria of the American board was considered as the basic criterion of efficiency of treatment
Rheumatologists. Under 50 % by improvement improvement in comparison with an initial condition a minimum on 50 % not less than on 3 of 6 indicators with deterioration more than 30 % no more than 1 of 6 indicators was understood. ACR pedi 70 answer - improvement on 70 % not less than on 3 from 6 criteria with deterioration more than 30 % no more than by 1 criterion, accordingly. Similar calculations were used for other answers on ACR pedi. At achievement ACR pedi 30 effect was estimated as satisfactory, ACR pedi 50 - as good, ACR pedi 70 - as excellent, ACR pedi 90, 100 - medicamental clinico-laboratory remission and-or the status of inactive illness.

Criteria of remission of disease:

• Absence of joints with an active arthritis

• Absence of system implications of disease: fevers, eruptions, a serositis, a hepatomegalia, a splenomegaly, a generalised lymphadenopathy

• Normal indicators of an ESR, SRB

• Absence of an active uveitis

• Absence of activity of illness on YOURS.

The status of inactive illness was established, if the condition of the patient satisfied to all listed criteria within 6 months; medicamental clinico-laboratory remission - after 6 months of inactive illness against medicinal therapy.

Also, the estimation of efficiency of therapy GIBP was spent by means of criterion LUNDEX, which considers as dynamics of activity of disease (ACR pedi), and adherence to pharmacotherapy. Index LUNDEX was defined as product of a share of the patients continuing therapy after 6, 12, 18 and 24 months of treatment GIBP (adherence to therapy), on a share of patients with the answer to therapy by criteria ACR 30/50/70/80/90/100 after 6, 12 and 18 monthly courses of treatment GIBP. Adherence to therapy has been defined as the relation of number continuing treatment GIBP after 6, 12, 18 and 24 months of therapy, to quantity of the patients who have begun treatment.

The safety and shipping GIBP estimation was spent to clinical signs of intolerance (a nausea, a headache, vomiting, abdominal pains, augmentation of the sizes of a liver etc.); on datas of laboratory (changes in the clinical analysis of blood, the clinical analysis of urine, the biochemical analysis of blood).

The information on preparations:

Since 2005, in the Russian Federation the first has been registered GIBP - infliksimab. During the period with 2005 for 2009 in territory of the Russian Federation there were no others GIBP. Because infliksimab has not been resolved for application for children with JUIA, before preparation appointment, the permission of local ethical committee has been received. The decision on appointment infliksimaba was accepted by a consultation, with participation of the principal of hospital, the child and-or parents signed the voluntary informed consent. To children corresponding preparation for the beginning of biological therapy was spent. The preparation was prescribed to children with the most serious current JUIA, with the long experience of disease, torpid to all standard antirheumatic preparations both as monotherapy, and in combinations. Children have mainly got to group with system variant JUIA (with extraarticular and articulate implications of disease), is more rare with entezitnym variant JUIA and articulate, polyarticulary.

Infliksimab it was applied intravenously driply, originally from calculation of mass of a body of 3-5 mg/kg under the scheme 0,2,6 and further each 8 weeks. At insufficient efficiency of therapy the dose infliksimaba in some cases has been raised to 8-10 mg/kg. Before the first infusions parenteral introduction of Methylprednisolonum in a dose 125мг on introduction, for the purpose of preventive maintenance of allergic reactions was spent.

Etanertsept has been registered for treatment of children with JUIA in the Russian Federation with 2009г. The preparation was prescribed to children with serious current JUIA, torpid to standarnoj antirheumatic therapy and-or infliksimabu, at development of a secondary inefficiency infliksimaba. Into group etanertsepta have mainly entered
Children with sistemym variant JUIA (with extraarticular and articulate implications of disease), with a serious current of articulate, polyarticulary variant JUIA. Etanertsept it was applied subcutaneously from calculation of 0,4 mg/kg on introduction 2 times a week with an interval of 72-96 hours, but no more than 25 mg on introduction.

Abatatsept it is registered in the Russian Federation since 2008. During research abatatsept it was prescribed to children mainly with second degree of activity JUIA: with a system variant without extraarticular implications, with an articulate variant, a polyarthritis “on adult type” with oligo - and a polyarticulary variant with a rhematoid uveitis. Abatatsept it was applied intravenously driply from calculation of mass of a body of 10 mg/kg on introduction under the scheme: 0 week (the first introduction of a preparation - initsiatsija), further repeated introductions in 2, 4 weeks from the first introduction (first three introductions with an interval in 2 weeks) and further each subsequent introduction of 1 times every 4 week. Duration of infusion made 30 minutes.

After the therapy beginning clinical both laboratory shipping and efficiency GIBP was estimated. Further patients of all groups were repeatedly hospitalised every 3-6 months in GBOU VPO UDKB the First MGMU of I.M.Setchenov in a planned order for dynamic observation and correction of spent therapy. At occurrence of exacerbations JUIA or the serious undesirable phenomena, and also at a sharp aggravation of symptoms for the obscure reasons, patients were hospitalised in GBOU VPO UDKB the First MGMU of I.M.Setchenov vneplanovo. At absence of the patient on planned hospitalisation in the put terms contact to his parents and-or the attending physician on a residence by phone or by e-mail was carried out. For some patients the dynamic estimation of activity of disease against therapy GIBP was carried out on the basis of archival case histories.

According to references feature of therapy infliksimabom, is the prompt reply developing right after of the first infusions by a preparation. As, to all children receiving infliksimab, the next infusions were spent in the conditions of children's rheumatological unit, that
Gave the chance to a thicket to estimate efficiency of therapy. In this connection, in the course of studying of features of therapy infliksimabom, it has been decided to estimate efficiency and safety of a preparation in 3, 6, 9, 12 and 18 months from initsiatsii at children with system variant JUIA and in 3, 6, 9, 12, 18 and 24 months - with articulate. To children, with the system variant JUIA receiving Etanertsept or Abatatsept, the efficiency and safety estimation was spent in 6, 12 and 18 months from initsiatsii, with an articulate variant - in 6, 12, 18 and 24 months.

Statistical data processing was spent with use of programs Biostat and Microsoft Excel 2010. Quantitative variables were represented in the form of average value yo a standard deviation, medians - М5 (Me), qualitative - in the form of number of observations and a share from the general number of patients (in percentage %). For the purpose of comparison of efficiency and safety of preparations Hi-square Pirsona, and Fisher's exact criterion were used criterion.

The evident graphic representation of the received results by means of schedules and charts was spent.

<< | >>
Scientific source Loskutova Olga Jurevna. Efficiency and safety of genno-engineering biological preparations (infliksimab, etanertsept, abatatsept) at children with various variants juvenilnogo an idiopathic arthritis. The DISSERTATION on competition of a scientific degree of the candidate of medical sciences. Moscow - 2014. 2014

Other medical related information Chapter 2. MATERIALS And METHODS.:

  1. Chapter 2 Materials and research methods
  2. CHAPTER 2. THE CHARACTERISTIC OF OBSERVABLE TEENAGERS, VOLUME AND RESEARCH METHODS
  3. Chapter 2 MATERIALS And RESEARCH METHODS
  4. Chapter 7. The PROGRAM CONCEPT CHRONIC HEPATITISES At CHILDREN And TEENAGERS
  5. CHAPTER 2. MATERIALS AND RESEARCH METHODS
  6. CHAPTER 5. RESULTS OF STUDYING OF MICROORGANISMS ON THE STRUCTURAL, GENETICALLY DETERMINED FAT ACIDS IN OBJECT OF RESEARCH BY MEANS OF THE METHOD OF THE GAS CHROMATOGRAPHY OF MASS SPECTROMETRY
  7. CHAPTER 2 MATERIALS AND METHODS OF RESEARCHES
  8. Chapter 2 Base, the program, a research technique
  9. CHAPTER 2. MATERIALS AND RESEARCH METHODS
  10. Chapter 2 the MATERIAL And RESEARCH METHODS
  11. CHAPTER 2. MATERIALS AND RESEARCH METHODS
  12. INTRODUCTION
  13. Chapter 2 MATERIALS And RESEARCH METHODS
  14. Chapter 2. MATERIALS And METHODS.
  15. CHAPTER 2 MATERIALS AND RESEARCH METHODS, VOLUME OF OBSERVATIONS
  16. Chapter 2 MATERIALS And RESEARCH METHODS
  17. CHAPTER 2. MATERIALS AND RESEARCH METHODS
  18. Chapter 2 the MATERIAL And RESEARCH METHODS