Kemerovo State Medical Academy,

Kemerovo, Russia

 

Rheumatoid arthritis (RA) is related to the diseases of high medical and social significance conditioned by its high incidence and progressing course leading to early disability in patients of working age [1]. RA takes leading place in the range of therapeutic pathology associated with secondary osteoporosis (OP), clinical significance of which is defined by high risk of skeletal fractures [2, 3, 4].

Juxta-articular OP is one of the earliest signs and diagnostic criteria of RA [5]. It can be diagnosed in 6^th week of the disease [6]. Diffuse OP associates itself at the later stages of disease development at the background of chronic inflammation and decrease in physical activity of patients. It is characterized by predominant decrease of bone mineral density (BMD) in the femoral neck and in the lumbar spine [7].

Generalized loss of BMD in RA is conditioned by many causes, which can be conventionally divided into two groups: traditional causes without dependence on the main disease, and the factors with direct association with RA. The traditional risk factors (RF) of OP include female, age, low body weight index, low BMD, family history of OP, low physical activity, smoking, alcohol abuse, vitamin D deficiency, insufficient calcium consumption, hypogonadism, early menopause, long term immobilization. The factors associated with RA include activation of cellular branch of immunity, increased production of pro-inflammatory cytokines, high activity of RA, functional insufficiency of joints, hormonal disorders, decreased creatinine clearance, decreased glomerular filtrate rate, increased level of homocysteine in blood plasma, complications after treatment with glucocorticosteroids and cytostatic agents. The absolute and relative contribution of each factor for development of OP in patients with RA is not defined clearly [8].

The progress in treatment of RA is associated with two moments. Firstly, it is widening opportunities for early diagnostics of RA permitting active, strictly controlled therapy with basic anti-inflammatory drugs (primarily, methotrexate) from disease onset. Secondly, it is development of the new class of anti-inflammatory drugs – genetically engineered biological agents (GEBA) [9]. One of GEBA representatives is anti-B-cellular agent – rituximab. It presents chimerical high-affinity monoclonal antibodies to membrane CD20-antigen of B-cells.

The objective of the study was assessment of influence of rituximab therapy on the modified RF of OP in patients with RA.                     

 

MATERIALS AND METHODS

There was a follow-up of 56 patients with confirmed RA diagnosis according to the criteria from American Board of Intensivists (1987). There were 14 men (25 %) and 42 women (75 %). The mean age was 50.61 ± 1.65, RA duration – 11.81 ± 1.04 years. The study was performed in concordance with the requirements of Helsinki Declaration of World Association “The Ethical Principles of conduction of scientific researches with human participation” with amendments from 2000, and “The Rules for Clinical Practice in Russian Federation” confirmed by the Order of Ministry of Health of Russian Federation from 19.06.2003, #266. The study was conducted with the approval from the ethic committee of Kemerovo State Medical Academy. All patients gave an informal consent for participation in the study.

The clinical characteristics of the patients are given in the table 1.

Table 1
Clinical characteristics of patients with RA

The patients received combined therapy with methotrexate (the mean dose – 13.3 ± 0.26 mg/a week) and rituximab (1000 mg i.v., by drop infusion, two times, interval of 14 days, the mean number of courses – 3.5 ± 0.12). RF of OP and BMD were assessed at the background of rituximab therapy over the time.

All patients were divided into two groups depending on BMD level: the group 1 – the patients with osteopenia (n = 34), the group 2 – the patients with OP (n = 22). For evaluation of RF the thematic chart of patient with RA was used; it is developed by Scientific Research Institute of Critical Care Medicine with relation to the program “Osteoporosis in rheumatoid arthritis: diagnostics, risk factors, fractures, treatment”.

Body mass index (BMI) was calculated as body weight in kilograms divided by squared height (kg/m²). BMI < 20 kg/m² was considered as low.

BMD was assessed with dual energy X-ray absorptiometry using the stationary dual energy X-ray bone densitometer Exceell XR-46 (Norland, USA) in grams per square centimeter (g/cm²) and with T-test. T-test was expressed as standard deviation (SD) from reference indices of peak bone mass in healthy individuals. The results of densitometry were considered according to the lowest value of t-test in certain points. BMD was assessed in the femoral neck.

The daily food consumption of calcium was calculated with the formula: calcium of milk products (mg) + 350 mg.

The low physical activity was considered as walking < 30 min per a day in case of absence of other physical activity.

The statistical analysis was performed with Statistica 6.1 for Windows (StatSoft, the license BXXR006B092218FAN11). With each sign in the compared groups the mean and error in mean (m) were defined. The materials of the study did not correspond to normal distribution. Therefore, the non-parametric tests for evaluation of statistical significance of results were used. The reliability of intergroup differences in means was assessed with Mann-Whitney non-parametric test for two independent samples. Wilcoxon test was used for comparison of indices which were measured in two different conditions in the same sample of the trial subjects. In all analyses the differences were considered as significant with p < 0.05.

 

RESULTS

It was found that at the background of treatment with rituximab the statistically significant increase in BMD in the patients with OP took place. So, basic BMD in the femoral neck was 0.6869 ± 0.02 g/cm², T-test was -2.9 ± 0.14 SD, Over time at the background of treatment the level of BMD increased to 0.733 ± 0.02 g/cm², T-test was -2.35 ± 0.14 g/cm² (p = 0.02 and p = 0.018 respectively). There were no statistically significant differences in BMD levels in the group of the patients with osteopenia at the background of treatment with rituximab (Table 2).

Table 2
Influence of rituximab therapy on densitometric indices of femoral neck in  patients with rheumatoid arthritis (M ± m)

Primarily, the patients with osteopenia had the following frequency of RF of OP: 11 persons (32.4 %) – two RF, 18 persons (52.9 %) – three RF, 4 persons (11.8 %) – four RF, 1 person (2.9 %) – six RF; mean 2.9 RF for one person. In the group of the patients with OP 1 patient (4.5 %) had 2 RF, 10 patients (45.5%) – three RF, 5 patients (22.7 %) – four RF, 3 patients (13.6 %) – five RF, 2 patients (9.1 %) – six RF, 1 patient (4.5 %) – seven RF; mean 3.9 RF for one patient.

In the group of patients with osteopenia RF of OP distributed as follows: insufficient calcium consumption with food – 17 persons (50 %), low physical activity – 12 (35.3 %), tendency to fallings – 6 (17.6 %), smoking – 3 (8.8 %), low body weight – 3 (8.8 %). In the patient group with OP low physical activity was noted in 21 persons (95.5 %), insufficient calcium consumption with food – 20 (90.9 %), smoking – 8 (36.4 %), tendency to fallings – 8 (36.4 %), age older 65 – 3 (13.6 %).

Initially, statistically significant differences between the groups were received for the following RF of OP: smoking (3 patients with osteopenia and 8 patients with OP, p = 0.0002), low physical activity (12 and 21 patients, p < 0.0001), insufficient calcium consumption with food (17 and 20 patients, p = 0.003) (Table 3).

Table 3
Dynamics of risk factors of osteoporosis in patients with rheumatoid arthritis during treatment with rituximab

It was established that in the patients with osteopenia the daily calcium consumption with food was 828.7 ± 49.6 mg that was statistically more significant than in the patients with OP – 507.5 ± 49.9 mg (p < 0.0001). Most patients with osteopenia (66.7 %) ate milk products more than 5 times a week; they preferred hard cheese and curd (55.6 %). The patients with OP did not eat milk products (41.6 %) or eat it less than 3 times a week (58.3 %).

At the background of rituximab therapy the patients with osteopenia demonstrated decrease of proportion with low body weight – 1 person (2.9 %), with low level of physical activity – 2 patients (5.9 %) and with low calcium consumption with food – 3 persons (8.8 %). During the treatment period of OP the level of physical activity increased in 5 patients (22.7 %), calcium consumption with food increased in 3 patients (13.6 %).

As the most significant risk factor of OP, the osteoporotic fractures after minimal trauma were registered in 3 patients with OP during their treatment (13.6 %). Possibly, it is conditioned by lower basic values of BMD and higher amount of RF for each patient with OP.

 

DISCUSSION

Decrease in BMD was noted in all patients with RA that comported with multiple clinical data about negative influence of RA on systemic remodeling of bone tissue [10].

The present study showed that rituximab therapy was associated with positive dynamics of BMD in the femoral neck in the patients with RA and OP. REFLEX and IMAGE studies demonstrated the ability of combined therapy with rituximab and methotrexate to slow down progressing joint destruction in RA [11. 12]. According to M.J. Boumans  et al. rituximab has suppressing influence on activity of osteoclasts and, as result, decreases bone resorption [13]. However, there are only few studies of influence of rituximab on systemic remodeling of bone tissue.

The absolute and relative contribution of each RF to development of OP in patients with RA is not defined clearly. For example, the simultaneous consequences of high activity of the disease can be weight loss, sedentary lifestyle, reproductive hormone deficit, vitamin D deficiency, increasing levels of proinflammatory cytokines, administration of glucocorticosteroids. It is supposed that the most important factors are severe course of disease, long tern non-adequate therapy with glucocorticosteroids, early menopause (in women), older age, low BMD and low body weight index [2].

One should note that combination of several factors of OP and fractures has cumulative effect. For example, if a patient has low BMD, history of fractures associated with minimal injury, or if a patient is older 65 with low BMD, the risk of osteoporotic fractures increases significantly, and such patient requires high priority prescription of appropriate therapy. 

Active inflammatory process is an apparent cause of not only subsequent persistent changes in the joints, muscular weakness resulting in functional disorders, but also immobilization, which on its own account is RF of decreasing BMD and fractures of bones. The present study showed increasing physical activity in the both groups of RA. Possibly it could be conditioned by decreasing activity of RA at the background of rituximab therapy. Rituximab causes depletion of different subpopulations of B-lymphocytes, differentiation and synthesis of proinflammatory cytokines. Among them the central role in development of synovial inflammation, progressing bone destruction and systemic manifestations of RA is related to TNF-α, IL-6 and IL-1ß [9].

Osteoporotic fractures often have subclinical character and require additional diagnostics (X-ray, CT, MRI), because they are the risk factors of refractures. Risk of vertebral fractures in RA is more than 2 times higher compared to population control [14, 15]. During the follow-up period in the group of the patients with OP 3 low traumatic fractures were identified. In the group of osteopenia the patients had no fractures.

Therefore, rituximab therapy is associated with increasing physical activity in all patients with RA, regardless of degree of decreasing bone mineral density, and with positive dynamics of BMD indices in patients with RA.