Clinical and immunological criteria of activity of different rheumatic arthritis courses and their treatment by Wobenzym.
Siziakina L.P., Artemenko N.A. Clinical and immunological criteria
of activity of different rheumatic arthritis courses and their
treatment by Wobenzym. III. Internat. Congress on
Immunorehabilitation and Rehabilitation in Medicine, Eilat, Israel,
1997. Russian version
Rheumatic arthritis (RA) is a chronical disease, its pathogenesity
includes deep immune system disorders with a disbalance of
qualitative and quantitative composition of immunocompetent cells
including functional and cell cooperation disorders (8). Joint
damage is the most obvious syndrome of rheumatic arthritis. But
other symptoms than joint damage mostly determine an aggressivity of
the disease and its prognosis. Role and place of different
components of inflammation immune complex in a rheumatic arthritis
process development is being currently discussed. A progresive
character of the disease with a formation of irreversible joint and
inner organ damage, an early invalidity of patients, and a decrease
of working ability define a medical and social importance of this
problem as well as a necessity of continuing study of clinical-pathogenetic
peculiarities of rheumatic arthritis and a search for optimal
treatment program.
An important role in a rheumatic arthritis diagnosis plays a
determination of IgG-RF (rheumatic factor) which seems to be an
autoantibody against IgG fragment (6). Both an existence of serum
negative variant of rheumatic factor and its detection in other
rheumatic and nonrheumatic diseases determine a necessity to
investigate RA serological markers, for example antibodies against
cardiolipins (aCL), associated with thromboses during rheumatic
diseases, and antibody against native DNA (n-DNA) determining a
formation of immunopathological component.
In many cases a rheumatic arthritis course is complicated by
systemic symptoms which cause a development of pathological process
(3, 13).
Various changes in rheological properties of blood during rheumatic
arthritis cause damages of microcirculation and seem to be one of
the factors which make the disease become chronic (2, 20).
Despite of different clinical symptoms of thrombohemorragical
syndrome and expression of damages of rheological, coagulational,
and fibrinolytical properties of blood (2, 3, 7), the most important
way to diagnose changes in microcirculation is the use of
immunological methods.
Such methods include determination of antigen factor van Billebrand
(FB) in blood plasma. FB is a macromolecular protein synthesized by
the vascular endothelium cells which define a function of
thrombocytes (TC) and an activity of VIII. coagulating factor
structural part of which FB makes (7).
Except this, investigation of new pathogenetic mechanisms of a
rheumatic arthritis formation, insufficient efficacy of existing
preparations for treatment, and serious side effects (treatment by
corticosteroids, nonsteroidal antirheumatic substances, cytostatics)
show a need for new treatment methods of different types of
rheumatic arthritis.
45 patients (9 men, 36 women) with reliable rheumatic arthritis
(criteria of American Rheumatological Association, 1987) were
observed. An average age was 46.9 (from 23 to 76) years. 38 patients
were serum positive on IgM-RF and 7 were serum negative. 5 patients
showed activity of rheumatic arthritis corresponding to degree I, 24
patients to degree II and 16 patients to degree III. Confirmation of
diagnosis by X-ray for all patients is available (Table 1).
In 28 patients syndromes such as fever, rheumatic nodes, amiotrophic
syndrome, damage of cardiovascular system, digestive system and
others occured.
In some cases concomitant diseases appeared: tuberculosis - 1,
malignant tumors - 1, diabetes - 1, periodical illness - 1.
During clinical observations of patients joint index, oedema index,
joint sum (by Richi), functional test by Li and an intensity of hand
clasp (mm.rt.st) were followed.
All patients were subjected to a general clinical observation and
also basic signs of immunological statute (9) were observed. Using
IFA a titer of antibody against n-DNA was determined. IgM-RF and a
presence of antibody against cardiolipins and antigen factor von
Billebrand (FB) were determined in patients’ serum (test of the
“AGAB” system, Moscow).
Wobenzym (Mucos Pharma) was administred together with methotrexate 15mg on Sunday; 10 dragees three times a day, 40 minutes before meals - 15 days, then 7 dragees three times a day - 15 days, followed by 5 dragees three times a day - 30 days. To observe an efficacy of the preparation, a group of 8 people (serum positive, joint form) was established. Control group included 9 people treated with
nonsteroidal antirheumatic substances and methotrexate (15 mg).
Results were evaluated statistically using nonparametrical criterium
by Mann-Whitney.
Observed group included 38 patients (84.4%), positive on IgM-RF, and
7 (15.6%) serum negative patients.
Comparison of clinical signs in both groups showed an absence of
significant differences (Table II). In serum negative group
dominated patients with inner organ damage 85.7%, in serum positive
group inner organ damage occured in 57.9% patients.
Presence of antibodies against cardiolipins was tested in serum
positive group. A positive result was obtained in 24 patients
(63.2%). In 17 patients (70.8%) inner organ damage developed and
only in 7 patients (29.2%) joint form of rheumatic arthritis was
diagnosed.
Table I General clinical characterization of patients
|
Signs |
Number of serum positive patients |
Number of serum negative patients |
Total number of patients |
|
Sex M |
8 |
1 |
9 |
|
Age 0-40 |
14 |
1 |
15 |
|
Degree of activity I |
5 |
- |
5 |
|
Functional I |
14 |
- |
14 |
|
X-ray stadium I |
4 |
- |
4 |
|
Form joint |
16 |
1 |
17 |
Table II Basic clinical signs of joint syndrome
|
Signs |
Serum positive patients |
Serum negative patients |
|
Joint index by Richi |
25.9 + 0.12* |
24 + 0.69* |
|
Joint sum by Richi |
25.9 + 0.13* |
24.1 + 0.7* |
|
Oedema index by Richi |
26.2 + 0.13 |
26.6 + 0.74 |
|
Functional index by Li |
13.4 + 0.10* |
16.4 + 0.58* |
|
Intensity of a hand clasp R |
97.5 + 0.26* |
85.0 + 1.32* |
* - statistically significant differences p< 0.05 as compared to
control
A degree of autoimmune process activity can be derived from a titer
of antibody against n-DNA. Among serum positive patients antibody
against n-DNA was detected in 22 patients (57.9%) - 8 (36.4%) with
the joint form and 14 (63.6%) with the inner organ damage.
In the serum negative group aCL were detected in 85.7% of patients
(83.3% with the inner organ damage and only 16.7% of patients with
the joint form of rheumatic arthritis).
Among observed patients antibody against n-DNA was detected in 4
patients (57.1%). Interestingly, all of them had a rheumatic
arthritis with inner organ damage (Table III).
Table III Changes in signs of immunological statute dependent on a
type of rheumatic arthritis course
|
Groups |
Signs of immunological statute |
|||
|
Sedimentation |
CIC |
Titer of antibody |
aCL |
|
|
Serum positive |
28.8 + 0.14* |
119.2 + 0.29* |
1.68 |
63.16 |
|
Serum negative |
33.0 + 0.82* |
81.0 + 1.29* |
1.34 |
85.7 |
* - statistically significant differences p< 0.05
From obtained results it can be concluded that aCL occur in rheumatic arthritis patients sufficiantly frequently - in 66.7% of cases. In patients with inner organ damage aCL were detected more often - in 73.3%. In the groups of serum negative and serum positive patients on IgM -RF, aCL occured with the same frequency - in 83.3% and 70.8%, respectively (Figure 1).
Figure 1: Frequency of an aCL occurance in patients with rheumatic arthritis with different courses.
Analysis of antibody against n-DNA showed that higher titer of the
antibody appeared in rheumatic arthritis patients with inner organ
damage - 64.3%. When compared serum positive and serum negative
groups, antibody against n-DNA was detected in approximately same
number of patients - 57.1% and 57.9%, resp.
Based on the results of our investigation it could be concluded that
inner organ damage (accompanied with an increase of polyclonal
hyperglobulinemy, CIC level and of the titer of antibodies against
n-DNA and aCL) is considered to be an undesirable symptom caused by
a high activity of autoimmune process. Therefore, there is a need
for an improvement of the current treatment therapy.
Serum negativity on IgM-RF does not presume a favourable course of
rheumatic arthritis with a high titer of antibody against n-DNA,
high value of CIC and a presence of aCL. Additionally, in such cases
a positivity on IgG or IgA-RF is possible.
Clinical sign analysis of rheumatic arthritis patients, administred with methotrexate and Wobenzym, gave following results. In patients treated with Wobenzym a faster reduction of joint swelling, reduction of a degree of morning tightness and a lessening of Li index was observed compared to a control group
(Figure 2). Analysis of immunological statute signs showed that in
patients treated with Wobenzym a more significant lessening of IgM
level occured as well as a faster normalization of sedimentation.
CIC degree remained higher ( Figure 2).
A faster clinical and immunological remission in patients treated
with Wobenzym and methotrexate enabled to lessen a dosage of
methotrexate to 7.5 mg. Two patients voluntarily gave up on
methotrexate. During next three months an activation of pathological
process did not occur. In the case of one patient an effect of
Wobenzym treatment was negligible, glucocorticoids were therefore
administred. Comparison of a treatment efficacy in Wobenzym group
and a control group is shown in Figure 3.
Figure 2: Signs of immunological statute in RA patients treated with
and without Wobenzym.
Figure 3: Effect of Wobenzym in the rheumatic arthritis treatment.
With regard to a higher CIC values after Wobenzym administration it
is necessary to include a plasmapheresis during first month of
treatment.
Based on all above mentioned facts it can be concluded that a presence of antibodies against cardiolipins and n-DNA is associated with inner organ damage at IgM-RF serum positive and serum negative rheumatic arthritis
Rheumatic arthritis with inner organ damage, accompanied with an
increased titer of antibody against n-DNA, CIC level and a presence
of an antibody against cardiolipins, is considered a unfavourable
course which needs a therapy improvement.
An increase of n-DNA antibody titer, CIC level and a presence of antibodies against cardiolipins appear to be a more informative signs of an autoimmune process activity in comparison to general clinical observations. Therefore, it is suggested to use these immunological tests for prognosis of a disease course and for control of the therapy efficacy.