Art of Medicine
Volume-2
International Medical Scientific Journal
Issue-1
10.5281/zenodo.6556141
204
EVALUATION OF THE EFFECTIVENESS OF GENETIC ENGINEERING
BIOLOGICAL THERAPY IN CHILDREN WITH JUVENILE ARTHRITIS
WITH A SYSTEMIC BEGINNING
Akhmedova D.I., Ibragimov A.A., Akhmedova N.R.
Republican Specialized Scientific and Practical Medical Center of Pediatrics
Tashkent Pediatric Medical Institute
Abstract:
The article presents the results of evaluating the effectiveness of a
genetically engineered biological drug (tocilizumab) in children with juvenile arthritis
with a systemic onset. Analysis of the results of the study showed that the use of a
genetically engineered biological drug (tocilizumab) in the treatment of patients with
juvenile arthritis with systemic onset contributes to a decrease in disease activity,
regression of systemic signs and normalization of laboratory parameters in a
significantly short time and improves the prognosis of the disease in these children.
Keywords:
children, juvenile arthritis with systemic onset, tocilizumab.
Among the various variants of the course of juvenile arthritis, arthritis with
systemic onset (JASCH) is characterized by a pronounced severity of the general
inflammatory
response,
pronounced
polysyndromicity,
severe
functional
insufficiency in the acute period, and is distinguished by its various forms of course
and outcomes, from favorable to extremely severe. The disease is characterized by an
undulating course and damage to internal organs, the complexity of determining the
period of remission of the disease [2, 8, 9, 10].
The protracted process of diagnosis and improper treatment at the initial stage
leads to aggravation of the further course of the disease and response to therapy. The
overall strategy for the treatment of systemic arthritis, aimed at the rapid and
aggressive arrest of inflammatory activity, is the most important in therapy and may
include various medical therapeutic agents. High disease activity and unfavorable
prognosis in relation to deforming complications require the earliest possible
appointment of basic therapy [1, 3, 4].
Recently, a lot of evidence has been accumulated about the leading role of
inflammatory mediators, namely pro-inflammatory cytokines - interlekin-1 (IL-1) and
interlekin-6 (IL-6), in the pathogenesis of this disease [2, 5, 6, 7]. Accumulated
knowledge about the influence of pro-inflammatory cytokines distinguishes JAcCH
with its pronounced activity of the laboratory inflammatory response and pronounced
polysyndromicity from other JA variants. They cause a spectrum of various multi-
organ extra-articular clinical manifestations [7, 10].
In addition, the local effects of IL-6, manifested in muscular-articular
symptoms, are very diverse and are associated with its influence on the pathogenetic
mechanisms of sinusitis and destructive joint damage [8, 9, 10].
A large evidence base created in the last decade has made it possible to revise
the tactics of treating JAHF, according to which it is necessary to suppress the
cytokine cascade at the earliest stages of pathology development through the use of
basic immunobiological preparations.
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International Medical Scientific Journal
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In this regard, the use of a recombinant humanized monoclonal antidiv to the
human interleukin-6 receptor (IL-6) from the IgG immunoglobulin subclass, which
selectively binds and suppresses both soluble and membrane IL-6 receptors (sIL-6R
and mIL-6R), in the form of the drug tocilizumab is currently the standard in the
treatment of JASHF [5].
In addition, the effectiveness of NSAIDs and basal immunosuppressive therapy
in JASHF, the short-term effectiveness of glucocorticoid drugs (GCS), and a large
number of side effects have led to the widespread use of genetically engineered
biological drugs (GEBDs) [9, 10].
Purpose of the study.
To evaluate the effectiveness of genetically engineered
biological therapy in children with juvenile arthritis with systemic onset.
Materials and research methods.
We examined 32 patients with JASHF aged
1 to 18 years, hospitalized in the cardio-rheumatology department of the Republican
Specialized Scientific and Practical Medical Center for Pediatrics from the beginning
of 2017 to the present. The diagnosis was made according to the ILAR Edmonton
criteria (2001).
All patients underwent general clinical, biochemical and instrumental research
methods. Immunological studies included the determination of interleukin-6 (IL-6)
and antibodies to modified citrullinated vimentin (anti-MCV/AMCV).
Out of 32 patients, in addition to complex treatment, 12 (31.2%) patients
received a genetically engineered biological drug (GIBP) - tocilizumab (Actemra),
which made up the 1st main group.
The comparison group 2 consisted of 20 (68.8%)
patients who received complex treatment, including immunosuppressant,
corticosteroids and NSAIDs. Patients of the 1st group included in the study received
tocilizumab therapy at a dose of 12 mg/kg of div weight (weighing < 30 kg) or 8
mg/kg (weighing 30 kg) intravenously every 4 weeks. Clinical, instrumental and
laboratory assessment of the disease dynamics was carried out immediately before
the start of therapy with tocilizumab and then every 3 months.
Statistical analysis of the obtained results was carried out using the software
package "SPSS for Windows (2003) with the processing of material by groups using
the methods of variation statistics, including the calculation of the arithmetic mean
value (M), the arithmetic mean error (m), expressing the reliability of the obtained
mean value of the studied trait, t-confidence coefficient (Student-Fisher difference
significance test).
Results and discussion.
The study of the timing of the onset of the disease
showed that the earliest age of onset was 1.2 years, and the latest age was 10.8 years.
At the same time, on average, the onset of the disease was noted at 5.4±3.2 years.
According to foreign authors, the onset of the disease occurs at 1–5 years of age [1].
In the sexual aspect, boys (65.6%) predominated among all 32 examined patients
with JASHF.
An analysis of the degree of disease activity in children revealed that the activity
of the first degree was not recorded in any patient with JASHF. Grade II activity was
detected in 56.2% of 18 patients, grade III activity - in 43.7% of 14 patients.
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Fig.1. The frequency of clinical symptoms before treatment with GIBD in
patients with JASHF.
The main clinical signs of the disease begin with an increase in div
temperature, followed by joint pain, morning stiffness due to joint pain, swollen
lymph nodes, enlarged liver and spleen, which are detected in the early stages of the
disease. The main clinical manifestations of the disease in the examined children in
both groups were fever (39-40ºС), the peak of which was in the daytime, transient
maculopapular rash and arthritis. Other symptoms frequently included serositis
(100%), generalized lymphadenopathy (100%), and hepatosplenomegaly (93.8%)
(Figure 1).
The study of laboratory data during the acute phase showed the presence of
varying degrees of severity of anemia in 84.4%, an increase in the number of
leukocytes in 81.3% of patients. The most pronounced were an increase in ESR and
an increase in the number of platelets, which were equally often recorded in 87.5% of
patients. In 29 (90.6%) of 32 (100%) patients, the platelet count was higher than
normal.
The presence of concomitant diseases also played a significant role in the course
of the disease. Analysis of comorbidities revealed that among 32 patients, 26 (81.3%)
were diagnosed with TORCH infections, 18 (56.3%) had chronic tonsillitis, 11
(34.4%) had gastroduodenitis, 8 (25) %) - minimal brain dysfunction, in 13 (40.6%) -
autonomic dystonia syndrome, in 1 (3.1%) - community-acquired pneumonia, in 3
(9.4%) - urinary tract infection and in 4 (12, 5%) chronic cholecystitis.
Treatment of the patient was carried out with the consent of the parents or
official representative.
Table 1
Drugs used at the start of treatment for systemic-onset juvenile arthritis
Name of the drug
1 group with GIBP n-12
group 2 without GIBP
n-20
Ibuprofen
41.6%
15%
Diclofenac
33.3%
40%
84,4
46,9
31,3
93,8
93,8
100
100
96,9
0
20
40
60
80
100
120
1 группа
Лихорадка
Сыпь
Серозит
Артрит
Гепатоспленомегалия
Лимфоаденопатия
Артралгия
Утренний скованность
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Meloxicam
16.6%
20%
Naproxen
-
5%
Nimesulide
8.3%
20%
Methotrexate
91.6%
90%
Leflunomide
8.3%
10%
Prednisolone
100%
100%
Tocilizumab (Actemra)
100%
-
IL-6 in the presence of the soluble IL-6 receptor (pIL-6R) stimulates the
production of vasculo-endothelial growth factor (VEGF) by synovial fibroblasts,
thereby activating the synthesis of such chemokines by endotheliocytes, mononuclear
cells and synovial fibroblasts, which in turn promote the migration of inflammatory
cells into the joint cavity. As a result, under the influence of IL-6 there is an increase
in osteoclastogenesis and bone resorption, which are of central importance in the
progression of erosive damage to the joints in JA [5]. According to the
recommendation of the American College of Rheumatology (ACR), IL-6 and IL-1
blockers are first-line drugs in the treatment of JASHF, which was proven by a
randomized placebo control trial [2].
Fig.2. Dynamics of clinical and laboratory parameters in the compared
groups 3 months after the use of GIBP
The main outcome of treatment was aimed at achieving the status of inactive
disease in children with JASHF during therapy with tocilizumab. The timing and
possibility of achieving the status of an inactive disease were assessed according to
the criteria of C. Wallace [8], and the achievement of the status of "low disease
activity" according to the criteria of A. Consolaro [9].
0
16.6
0
16.6
16.6
8.3
16.6
16.6
41.6
25
50
8.3
16.6
60
80
45
50
45
40
25
50
60
30
70
55
60
0%
20%
40%
60%
80%
100%
120%
140%
1 Группа
2 Группа
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Additional outcomes during the study included changes in disease activity
scores (number of active joints, hemoglobin, leukocytes, platelets; ESR; C-reactive
protein), change in concomitant antirheumatic therapy from first tocilizumab infusion
to last visit, lipid profile, and the occurrence of adverse events during therapy.
After 3 months, during treatment, there was a rapid regression of systemic
manifestations of the disease, including articular syndrome in the 1st group of
patients, and in the 2nd group, the improvement of these indicators occurred
relatively more slowly (p≤0.01). During the first 3 months, no side effects were noted
in group 1 of patients, and in patients without systemic symptoms in this group, the
dose of GCS was reduced. However, in the 2nd group, due to the long-term
regression of systemic manifestations and articular symptoms, the dose of GCS was
reduced much more slowly than in the 1st group.
After 6 months of treatment in patients of group 1, all clinical signs of the
disease disappeared, only such laboratory changes remained as anemia in 3 (25%)
patients and thrombocytosis in 4 (33.3%) patients. In the 2nd group of clinical
manifestations of JA, 8 (40%) patients had fever, 14 (70%) had skin rashes, 8 (40%)
had symptoms of arthralgia and arthritis. Laboratory indicators indicated the presence
of anemia in 10 (50%) patients, thrombocytosis in 11 (55%) patients, leukocytosis in
5 (25%) patients, accelerated ESR in 9 (45%) patients and an increase in CRP in 8
(40%) patients of the 2nd group. By this time, changes in the joints have decreased in
patients of the 1st group, and the reduction in the dose of GCS was successful.
However, in patients of the 2nd group, despite the treatment, deformities and
limitation of movements in the joints occurred, which caused difficulties in reducing
the dose of GCS and contributed to the recurrence of the disease.
Fig.3. Dynamics of clinical and laboratory parameters in the compared groups 9
months after the use of GIBP
0
0
0
8.3
8.3
0
8.3
8.3
8.3
0%
8.3
0%
0%
30
50
15
30
25
10
10
30
35
20
30
30
30
0%
10%
20%
30%
40%
50%
60%
1 Группа
2 Группа
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Evaluation of the effectiveness of tocilizumab therapy carried out 9 months after
the start of treatment indicated the normalization of clinical symptoms and laboratory
parameters in 91.6% of patients. The exception was 1 patient from group 1 with
preserved changes in the joints.
Among patients of the 2nd group, by the 9th month
from the start of treatment, 30% retained such clinical manifestations as fever,
arthritis and arthralgia, high levels of CRP, ESR and platelet count, which indicated a
high activity of the disease in these patients. In children of the 1st group, no side
effects of GEBA were observed during treatment, and glucocorticosteroids were
successfully canceled in 75% of patients. In the 2nd group, side effects from drugs
were observed in 2 patients with arterial hypertension, 3 patients with Cushing's
syndrome, 1 patient with cataracts, 1 patient with tuberculosis, 1 patient with sepsis
and 2 patients with macrophage activation syndrome.
Conclusion
. Thus, the use of GEBAs in the treatment of patients with juvenile
arthritis with systemic onset contributes to a decrease in disease activity, regression
of systemic signs and normalization of laboratory parameters in a much shorter time
and improves the prognosis of the disease in these children.
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