RU2460072C1 - Method for prediction of clinical course of endocrine ophthalmopathy in patients with graves disease by detecting anti-thyroid peroxidase antibodies - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: prediction of the clinical course of endocrine ophthalmopathy in the patients suffering Graves disease is ensured by detecting a pre-radio-iodine-therapy anti-thyroid peroxidase antibody in blood serum. The presence of the antibodies enables predicting a manifested and prolonged inflammatory process and maintaining a level of activity of the clinical course of endocrine ophthalmopathy.

EFFECT: using said method enables predicting the clinical course of endocrine ophthalmopathy in the patients with Graves disease, and prescribing well-timed and adequate treatment of the patients suffering said pathology.

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Description

The present invention relates to ophthalmology and is intended to predict the clinical course of endocrine ophthalmopathy in patients with Graves disease.

Endocrine ophthalmopathy (EOP) is an autoimmune disease of the orbit associated with an autoimmune pathology of the thyroid gland (thyroid gland), in particular, with Graves' disease (BG). The literature is actively debating the question of what is the main antigen (AH), which triggers an autoimmune reaction in orbit. According to one hypothesis, thyroid and orbit tissues have the same AH, and autoimmune reactions in the thyroid gland, accompanied by the production of antibodies (AT) to receptor and thyroid AH, can cross-react with orbit tissue, triggering autoimmune inflammation there [see, for example, Bahn Rebecca S. Pathogenesis of Graves ophthalmopathy: the role of orbital thyroid-stimulating hormone receptor expression Current Opinion in Endocrinology & Diabetes: - 2003 - Vol.10 - Issue 5 - p.353-356]. A thyrotropic hormone receptor (rTTG) is recognized as one of the candidates for the role of an AG target. AT to rTTG is found in almost 100% of patients with EOP and BG [Goh SY, S.C. No, LLSeah, KSFong, D. N.C. Khoo Thyroid autoantibody profiles in ophthalmic dominant and thyroid dominant Graves' disease differ and suggest ophthalmopathy is a multiantigenic disease. Clinical Endocrinology. - 2004 - Vol.60 - No. 5 - p. 600-607].

According to domestic authors, clinical and subclinical forms of image intensifier are found in almost 90% of patients with GB [Brovkina A.F. Endocrine ophthalmopathy. Publishing house "Geotar-Med." - Moscow. - 2004]. The subclinical form is understood to mean the expansion of the transverse dimensions of extraocular muscles (EOM) according to instrumental methods of visualizing the orbit in the absence of obvious clinical symptoms. A severe course with the threat of loss of vision develops in about 5% of cases. Untimely and unskilled treatment leads to a decrease in visual function and disability of the patient.

When choosing a method of treating BG, the state of the organ of vision is not always taken into account. It has been established that certain types of treatment, for example, radioiodine therapy (RTI) of the thyroid gland, can lead to the progression of an EOP. To determine the degree of risk of developing highly active and severe forms of EOP at the planning stage (RIT) and timely prescribe treatment aimed at the prevention of complications seems to be an urgent task for both the optometrist and the endocrinologist. This is the purpose of forecasting.

A known method for predicting the course of diffuse toxic goiter (DTZ) and endocrine ophthalmopathy (Gerasimov G.A. et al. Role of antibodies to the thyroid stimulating receptor hormone in the diagnosis and prognosis of diffuse toxic goiter and endocrine ophthalmopathy // Problems of Endocrinology, 2001. - N 4 - S.38-40). It was found that the degree of EOP positively correlates with the level of antibodies to the TSH receptor. According to the authors of the study, the total assessment of the levels of AT to the TSH receptor and AT to TG most correctly reflects the severity of the image intensifier in DTZ. The conclusions they reached were as follows:

1. In patients with newly diagnosed DTZ, the degree of EOP depends on the level of antibodies to the TSH receptor.

2. A high level of antibodies to TG is a favorable sign in relation to the severity of the image intensifier in DTZ.

3. A joint quantitative determination of antibodies to the TSH receptor and thyroglobulin is preferable for characterizing the image intensifier in DTZ, since it allows one to take into account the multidirectional effect of these antibodies on the degree of manifestation of the image intensifier.

The disadvantages of this method are incorrect techniques (methods) for assessing the main characteristics of the disease. The degree of image intensifier was evaluated according to the classification of V.G. Baranova, which casts doubt on the correctness of the work itself and conclusions from it. Currently, activity and severity are recognized as the key characteristics of the image intensifier tube. They are evaluated in accordance with EUGOGO international guidelines.

The closest analogue of the invention is a method for predicting the clinical course of EOP in patients with Graves' disease (BG) based on determining the level of AT to the TSH receptor [Ditkovskaya L.V., Skorodok Yu.L. Diagnostic clinical and prognostic value of antibodies to thyroid stimulating hormone receptor in diffuse toxic goiter. // Russian Pediatric Journal, 2007. - N 1. - C.8-11]. High levels of autoantibodies correlated with the severity of thyrotoxicosis: in patients with severe thyrotoxicosis, high levels of AT to rTTG were observed.

However, the use of thyreostatics in the treatment of BG can be accompanied by an inversion of the AT titer to rTTG (when a seropositive patient from an AT carrier to rTTG becomes a seronegative patient) and then the use of this forecasting method becomes impossible.

The task of the invention is the creation of an adequate method for predicting EOP in Graves disease.

The technical result of the invention is to objectify and improve the accuracy of predicting the clinical course of endocrine ophthalmopathy (EOP) in patients with Graves' disease (BG), which allows a timely and adequate course of drug treatment.

The technical result is achieved by determining in the blood serum antibodies to thyroperoxidase before radioiodine therapy.

It is known that the AT spectrum in autoimmune thyroid pathology is not limited to only AT to rTTG. From 50 to 70% of patients with BG have AT to thyroglobulins (TG), which do not fix complement and do not have cytotoxic activity. It is believed that the definition of AT for TG and TPO in case of BG and EOP has no diagnostic, prognostic, and, therefore, practical value.

In our studies, we studied the possibility of predicting the clinical course of EOP in patients with Graves disease based on the determination of the presence of antibodies to thyroid peroxidase (AT to TPO) in the blood serum, moreover, prior to radioiodine therapy.

The course of the image intensifier was observed in 38 patients (76 orbits) with BG, who received drug treatment for 1 year, and then were sent to treatment with radioactive 131 iodine (RTI). Monitoring was carried out for two years: in the 1st year of observation, the inspection was carried out every 3 months, and then 3, 6, and 12 months after RIT.

Graves' disease was diagnosed on the basis of a clinical symptom complex, ultrasound (US) diagnostics, and laboratory findings. The severity and degree of compensation of thyrotoxicosis was determined.

The levels of thyroid-stimulating hormone of the pituitary gland (TSH), free thyroxine (CBT4), and free triiodothyronine (CBT3) were determined. The enhanced luminescence method and the Vitros automatic analyzer (Johnson and Johnson) were used. The normal limits for the basal TSH level were: 0.25-3.5 mU / l, svT4 9.0-20.0 pmol / l, svtz 4.26-8.1 pmol / l.

The level of AT to TPO was determined using an ARCHITECT analyzer (Abbott, USA, by immunochemiluminescent analysis).

A thyroid thyroid study was carried out on a Hewlett Packard Image Point HX scanner with a variable frequency 7.5-10 MHz sensor. We used the standard set of programs for surface tissues, as well as the Doppler scanning mode.

The image intensifier was verified in accordance with international diagnostic standards (EUGOGO protocol). The standard included: collection of complaints, anamnestic data, clinical and instrumental assessment of 42 parameters of the organ of vision initially and in dynamics at each visit (visometry with maximum correction of ametropia; tonometry, biomicroscopy, ophthalmoscopy in conditions of maximum mydriasis, exophthalmometry, etc.). Oculomotor disturbances were detected by analyzing the mobility of the eyeball in 9 directions, including convergence. The position of the eye in orbit, the width of the palpebral fissures, and lagophthalmos (in mm) were evaluated. The presence of diplopia was evaluated on a Gorman scale [Graves orbitopathy. - Ed W. M. Wiersinga, G.J. Kahaly. - KARGER. - Basel - 2007 - P.260].

The main characteristics of the image intensifier were determined: severity and activity. EOP activity was evaluated according to the CAS clinical activity scale. CAS≥3 indicated the active stage of the image intensifier tube. The severity of EOP was assessed by the NOSPECS classification, highlighting the mild, moderate and severe degree of the disease [Graves orbitopathy. - Ed W. M. Wiersinga, G.J. Kahaly. - KARGER. - Basel - 2007 - P.260].

EOPs were assigned a severe gradation if there was: optical neuropathy (OH), regardless of the degree of exophthalmos and / or violation of the structural integrity of the cornea (erosion, ulcer), as well as erosion or ulcer of the cornea, regardless of the magnitude of exophthalmos and OH. Moderate severity - if there was one or more of the following symptoms: moderate changes in the soft tissues of the orbit on MSCT, exophthalmometry 21-23 mm, the presence of unstable or constant diplopia, but the absence of optical neuropathy. Mild severity - if there was one or more of the following symptoms: a slight change in the soft tissues of the orbit on MSCT, exophthalmometry data not more than 20 mm, complete absence of diplopia or intermittent diplopia.

For verification of subclinical forms and visualization of orbital tissues, volume dynamic multispiral computed tomography (MSCT) was used. MSCT of the orbits was performed on a Siemens Emotion 16 apparatus. Each orbit was evaluated in 3 projections: axial, coronal, sagittal.

Since the eyes of the same patient had different degrees of severity of the clinical symptoms of the image intensifier tube, the study results were processed separately for each eye (CAS, NOSPECS) and each orbit (MSCT). The control group of MSCT was 10 patients (20 eyes and orbits), of a similar age range (26-67 years, 3 men and 7 women) without symptoms of EIT and thyroid pathology.

Computer statistical analysis of the results of this study was carried out using the SAS application package of statistical programs (Statistical Analysis System, SAS Institute Inc., USA) using standard variational statistics algorithms, including correlation analysis and contingency table analysis, as well as various types of intergroup comparison of the distributions of the studied indicators .

In the course of the studies, it was found that the detection rate in the blood serum of patients with HD and clinical manifestations of EOP antibodies to TPO was 56% (41 patients). According to the results of immunochemiluminescent analysis of AT to TPO, all patients were divided into 2 groups. Group I consisted of patients in whom there was no AT to TPO in the blood (AT-negative individuals). Group II was represented by patients in whom AT to TPO (AT-positive individuals) were determined in the blood.

To study the role of circulating serum AT to TPO, patients of both groups were compared by the main clinical characteristics of the image intensifier (severity and activity). The correctness of the comparison was checked statistically. The analyzed groups were quite comparable in the number of included patients; they were approximately equally distributed by gender and age composition.

The results of the study showed that in seropositive patients (developing AT to TPO), there is a significantly more pronounced and significantly longer inflammation in the orbit (according to the average integral intragroup inflammation index in points). A direct correlation was established between the production of AT to TPO and the amplitude of inflammation (disease activity) in the orbit during EOP: in seropositive patients with HD, the amplitude of inflammation / EOP activity is significantly higher than in seronegative individuals.

In seropositive patients with circulating AT to TPO, the regression of EOP activity with the transition to the inactive phase is much slower than in seronegative patients with HD.

Thus, the production of AT to TPO is a risk factor contributing to an increase in the amplitude and duration of autoimmune inflammation in the orbit during EOP. At the same time, the risk of developing (RR) of medium-active and highly active forms of EOP in a patient-carrier AT to TPO reaches 1.99, the confidence interval - (95% CI) - 1.24-3.18, and the reliability of this event: p = 0.0015 (table 3). A direct positive correlation between AT to TPO and the severity of EOP was revealed: significantly more severe forms of EOP develop among seropositive patients with GB compared with seronegative individuals; the average integral indicator of EOP severity in patients carrying AT to TPO is significantly higher than that of seronegative patients. The established facts make it possible to consider AT to TPO a risk factor contributing to an increase in the severity level of autoimmune inflammation in the orbit during EOP. At the same time, the relative risk of developing (RR) severe EOP in a patient carrier AT to TPO reaches 2.54, the confidence interval is (95% CI) - 0.90-7.14, and the significance of the development of this event is p = 0.05 . The clinical manifestations of EOP in patients with Graves disease are indications for the study of AT for TPO.

Thus, taking into account the data obtained, as well as their high relationship with the clinical course of the disease, it should be considered that this marker of autoimmune disease can be used as a prognostic one.

The method is as follows. At the patient’s initial visit, blood is taken from the ulnar vein prior to radioiodine therapy. Get serum from it. The presence of antibodies to thyroperoxidase in the blood serum is determined, for example, using an ARCHITECT analyzer (Abbott, USA, by immunochemiluminescent analysis). When AT to TPO is detected, a pronounced, long-term inflammatory process and preservation of the level of activity of the course of endocrine ophthalmopathy are predicted.

Example 1. Patient M., 36 years old. Diagnosis: Graves disease. Against the background of taking thyreostatics, subcompensation of thyrotoxicosis takes place. In the study of blood serum revealed AT to TPO at the level of 120 IU / ml. The EOP at the initial visit to the ophthalmologist is regarded as subclinical (single clinical signs of the EOP are confirmed by MSCT data: an increase in extraocular muscles was revealed). During the 6 months of follow-up, the patient developed a highly active form with severe exophthalmos, edema of the eyelids, and limited eye mobility. The patient was treated with EOP using megadoses of glucocorticoids (the total dose was 5.0 grams). The treatment had a slightly positive effect. Performed total thyroidectomy of the thyroid gland. After 8 months, he developed optical neuropathy, for which fat decompression was performed against the background of a repeated course of glucocorticoids. The duration of disease relaxation was a total of 9.5 months, after which remission began. Thus, the presence of AT to TPO correlated with the severity of the disease, which reflects the prognostic value of this indicator.

Example 2. Patient S., 54 years old. Sick Graves disease for 12 months. Received thyrostatics according to the “block and replace” scheme. In the treatment of thyroid dysfunction, euthyroidism has occurred. Complained of severity with eye movement (a characteristic complaint with EOP). Clinically, no signs of EOP have been identified. Completed by MSCT. A slight increase in the size of the inner and lower direct extraocular muscles was noted. In the study of blood serum, no AT to TPO was detected. Performed total thyroidectomy of the thyroid gland. Over the next two years of observation, the activity and severity of the image intensifier did not increase, that is, the absence of AT to TPO indicated a favorable course of the disease.

Thus, the proposed method is highly effective for predicting the course of EOP in Graves' disease and can be used to further select the tactics of adequate management of patients with this pathology.

Claims (1)

A method for predicting the course of endocrine ophthalmopathy in Graves disease, characterized in that they determine the presence of antibodies to thyroperoxidase in the blood serum before radioiodine therapy and, in the presence of antibodies, a pronounced and prolonged inflammatory process and preservation of the level of activity of the course of endocrine ophthalmopathy are predicted.