Due to their incidence and severity, chronic inflammatory rheumatisms are one of the major public health problems [1] . These conditions affect the whole body, as they impede on the quality of life of the patients and often lead to death [2] . Despite the numerous attempts of identification of rheumatoid arthritis etiology, it is still not fully known [3] . The cytokine family, and especially IL_1α, IL_1β and TNF-α [4] [5] are thought to play an important part in rheumatoid arthritis pathogenesis [6] . Rheumatoid arthritis therapy has undergone radical changes these last few years, its main goal being disease amelioration, structural joint deterioration reduction and joint functioning improvement [7] . There are drugs that are able to stop the disease from progressing, that may ensure good joint functioning and improve the patient’s quality of life. Therefore, about 40% of the early diagnosed cases of rheumatoid arthritis may be cured.

Leflunomide (Arava) is the only orally administered drug for rheumatoid arthritis that seems to be associated with the best long lasting responses [8] . Leflunomide is a drug used to treat swelling and pain in arthritis [9] . It belongs to a class of medications called disease-modifying antirheumatic drugs (DMARDs). This class of medicines can decrease joint damage and disability. Leflunomide reduces inflammation in the joints that is responsible for both the symptoms of rheumatoid arthritis and the destruction of joints [10] . Leflunomide reduces inflammation by suppressing the activity of immune cells responsible for the inflammation [11] . Leflunomide is an immunomodulatory drug that achieves its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH)—an enzyme involved in de novo pyrimidine synthesis—which plays a key role in the de novo synthesis of the uridine monophosphate (rUMP), which is required for the synthesis of DNA and RNA [12] . Without DNA and RNA the immune cells (and most other types of cells) cannot multiply or function (or exist). The inhibition of human DHODH by teriflunomide, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of rheumatoid arthritis (RA). Teriflunomide also inhibits several tyrosine kinases [12] . Because of its unique and different mechanism of action, Leflunomide is of value when added to other medications used for treating rheumatoid arthritis.

The experimental study was conducted on female Wistar rats. We preferred female rats since rheumatoid arthritis is considerably more common in females. Chronic arthritis was induced by 1% carrageenan solution injected in the knee joint for 8 weeks [13] . The occurrence of inflammatory arthritis and the effects of Leflunomide on the evolution of the joint inflammation phenomena were followed by successive radiological, biochemical and osteodensimetric determinations [14] . The reason for which we preferred this drug was that so far it is the only medication with good clinical long-term results, but also with a series of adverse effects.

The knee joint and various organs, such as liver, kidney and heart, were sampled at the end of the experiment in order to reveal any possible side effects of Leflunomide and carrageenan, respectively. All the experimental procedures conducted on the animals included in this study strictly complied with the international ethical regulations. At the end of the study, the animals were euthanized under ether anesthesia. Their death was quick and painless. When the animals stopped showing any vital signs (breathing, heart beats, reflexes), they were dissected and we sampled their knee joints, liver, heart and kidney (Andrews, E. J., AVMA Euthanasia Protocol, 1993).

Experimental Design. Animals were randomized into three groups:

Group M—(n = 12) the control group, which included twelve 4.5 months (18 weeks) old animals weighing 300-350g;

Group A—(n = 12) the group of animals to which arthritis was induced by 0.02 ml of 1% carrageen an solution injected in their knee joint 3 times/week, for 8 weeks;

Group T—(n = 12) the group of animals to which arthritis was induced by 0.02 ml of 1% carrageen an solution injected in their knee joint 3 times/week, for 8 weeks and treated with 20 mg/kg of body weight of Leflunomide (Arava) force fed once every 2 days, for 8 weeks.

The animals were kept in plastic cages (a maximum of 4 rats per cage), in a room with controlled temperature (24˚C - 28˚C) and luminosity (a 12 h light: 12 h dark cycle) with free access to water and balanced foodrations. The animals were kept in accordance to the guidelines of the Committee on Care and Use of Laboratory Animals of the National Research Council of the National Institutes of Health.

Correlation intensity, both towards adult control rats and between the two study moments, reveals the mean severity of the forms of arthritis in the group of adult animals treated with Leflunomide, which supports the effectiveness of the therapy (Figure 1).

The hematological parameters showed strong statistically significant variations between the group of animals under Leflunomide therapy and the group of animals with chronic arthritis not receiving any treatment as well as the control group. The hemoglobin, erythrocyte and platelet levels dropped significantly in arthritic animals. The leukocyte level increased.

The IL_1β, fibrinogen, ceruloplasmin and uric acid levels were significantly higher in untreated animals than in animals under Leflunomide therapy, which reveals the protective effect of Leflunomide on the inflammatory carrageenan-induced bone and joint destruction.

Our animal trial (on female Wistar rats) consisted of an experimental model of inflammatory chronic arthritis induced by 1% carrageenan solution injection in the knee joint. The clinical appearance of non-specific inflame- matory chronic arthritis was revealed by radiological, biochemical, immunological, hematological and post- mortem exams. The morphological lesions occurring in adult arthritic animals were suggestive of erosive chro- nic arthritis, with cartilaginous area disorganization, replacement by and covering with inflammatory pannus. The joint space was filled with inflammatory pannus, and the underlying trabecular bone showed signs of osteolysis lesions.

The response to Leflunomide therapy was undeniable. The phenomenon was revealed by radiological, biochemical and post-mortem exams. Leflunomide therapy improved the course of the clinical and paraclinical parameters, but it did not cure the condition. The weight loss suffered by the groups of animals under Leflunomide therapy confirmed the literature data on its anorexigenic effect.

The experiment revealed the toxic visceral effects of Leflunomideon the liver, heart and kidney.

• The liver was extremely affected in the groups of animals under Leflunomide therapy, which supports the literature data on its hepatic toxicity;

• We revealed the toxic effect of Leflunomide on the heart;

• The post-mortem kidney examination revealed minor changes.

The deaths occurred in the group of animals under Leflunomide therapy were due to various phenomena such as acute liver failure, hemorrhage, local infections, appetite diminution and consequent weight loss.