Definition. Rheumatoid arthritis (RA) refers to a chronic systemic inflammatory disease of the connective tissue which is commonly characterised by progressing erosive-destructive polyarthritis, rapid development of functional changes in the affected joints and certain extraarticular manifestations. Epidemiology. The prevalence of RA among adults is about 1%. Clinical forms of RA are observed in 0.5% of women and 0.1% of men. Females are 3 times more likely to develop RA than males. The frequency of RA increases with age and the disease is observed both in females and males with similar prevalence rates. Rheumatoid arthritis affects all populations worldwide.   Aetiology. Nowadays no organism has been proven responsible for RA. Infectious factors. The revealing of virus-like particles in the synovial membrane at the early stage of the disease as well as the development of polyarthritis in some viral and infectious diseases has proven an infectious aetiology of RA. The following infectious agents have been suggested to induce RA: Streptoccocus B, Mycoplasma organisms, Epstein-Barr and rubella viruses. The frequency of getting lymphocytes infected with Epstein-Barr viruses increases in patients with RA compared to healthy people. Antibodies to Epstein-Barr viruses are present in 80% of patients with RA. As no infectious agent has been found responsible for RA, the infectious atiology of RA has not been proven yet. Genetic factors. First-degree relatives of patients with RA have an increased frequency of disease which is 4 times more than the prevalence of RA among the population. Kinsmen (relatives by blood) are 16 times more likely to develop RA. Approximately 10% of patients with RA have first-degree relatives suffering from RA. Disease concordance in monozygotic twins is 4 times more than in dizygotic twins or in siblings which is approximately 15 – 20%, suggesting that not only genetic factors play an important role in pathogenesis of the disease. It has been established that HLA-Dw4 (DRB1*0401) or НLА-Dw14 (DRB1*0404) carriers have the risk of developing RA 1: 35 (one to thirty-five) and 1:20 (one to twenty), respectively. The risk of developing the disease is more higher in carriers of both types. At the same time НLА-DR5, НLА-DR2, НLА-DR3 and НLА-DR7 clusters may prevent the person from developing RA, as the clusters are less commonly revealed in patients with RA than in healthy people. Hormonal factors. Sex hormones and prolactin may play a role, as evidenced by disproportionate number of females with RA under 50 (females are 2 – 3 times more likely to develop RA than males but with age the disease is observed in females and males with similar prevalence rates). Reduced incidence of RA during pregnancy and in women using oral contraceptives has also been reported. Pathogenesis. RA is associated with a number of autoimmune abnormalities as well as with imbalance of quantitative and qualitative composition of immunocompetent cells and impaired functional activity of cells and cellular cooperation. Th 1 cells are supposed to play a major role in the initiation of RA and they are the main producers of proinflammatory cytokines which are produced in excessive amounts in RA. It is suggested that at the early stage of RA joints are affected due to a nonspecific inflammatory reaction induced by different stimuli resulting in destruction of synovial cells in genetically predisposed people. As a result of the involvement of the immune cells in the articular cavity, an “ectopic” lymphoid organ is formed whose cells begin to synthesize autoantibodies to the components of the synovial membrane. T-lymphocytes CD4+ and CD8+ prevail in cellular infiltrates in the synovial membrane. In addition to T-lymphocytes, there are many B-lymphocytes in it.  Activated CD4-lymphocytes stimulate proliferation of B-lymphocytes and their arrival into plasma cells which secrete autoantibodies, including rheumatoid factor (RF). Fibroblasts become activated and begin to produce proteolytic enzymes. The number of osteoclasts increases in the areas of bone destruction. Activated cells of the synovial membrane produce great amounts of cytokines, such as TNF-alfa, interleukines 1, 2, 6, 8, 10, growth factors, interferons. These cytokines stimulate the inflammatory reaction, the arrival of cells and mediators of inflammation into the synovial fluid, proliferation of synoviocytes. They participate in cartilage and bone destruction as well as in the development of extraarticular manifestations of RA. Histamine and other vasoactive substances produced by mast cells of the synovial membrane stimulate migration of neutrophils and other cells into the synovial fluid. Finally, prostaglandin E2 which is produced in the synovial membrane has a vasodilatory action and contributes to the arrival of cells into the area of inflammation. It should be noted that progression of RA is a dynamic process which is divided into 3 stages:

1. Early (asymptomatic) stage of RA. It is characterized by vascular and cellular activation.
2. Extensive stage of  RA (progressing chronization of inflammation). It is characterized by impaired angiogenesis, activation of endothelium, cellular migration, infiltration of the synovial tissue by CD4+T-lymphocytes, serum RF (rheumatoid factor) and immune complexes, synthesis of proinflammatory cytokines, prostaglandins, collagenase, metalloproteinase.
3. Advanced stage of RA which is characterized by somatic mutation and defects of apoptosis of synovial cells.

  Pathomorphology. Morphologic processes of disorganization of the connective tissue occur mainly in joints. Synovitis is manifested clinically by various combinations of exudative-alterative and proliferative processes. It is often characterized by lymphoid infiltration of the synovial membrane, vasculitis with resultant perivascular infiltration, mucoid swelling and sclerosis of the synovial membrane. Formation of new vessels which is characterized by transudation and transmigration of lymphocytes into the synovial tissue and leukocytes into the synovial fluid is a typical early finding of rheumatoid synovitis. Lymphoid infiltration of the synovial membrane has a peculiar structure of rheumatoid granuloma in which fibrin is surrounded by mesenchimal cells on the surface of the synovial membrane covered  by lymphoid cells. Formation of an ectopic focus of hyperplasia of the synovial tissue is considered to be the most significant morphological characteristics of rheumatoid inflammation. Its invasive growth (pannus) often results in the destruction of the articular cartilage and subchondral bone. Loose granulation tissue (pannus) destroys the cartilage and epiphyses of bones resulting in erosive arthritis. Stages of joint involvement: I stage – hypertrophy of the synovial membrane; II stage – proliferation of pannus into the meniscus; III stage – focal destruction of the meniscus; IV – complete destruction of the meniscus and focal destruction of the articular surface; V stage – fibrous ankylosis resulting in bony ankylosis. Rheumatoid nodule is a specific histologic feature of RA and is considered to be a focus of fibrinoid necrosis surrounded by macrophages, lymphocytes and plasmocytes. Rheumatoid nodules may be present in the synovial membrane, tendon sheaths and they may be accumulated in the periarticular subcutaneous fatty tissue. Morphological substrates of extraarticular involvement in RA are considered to be vasculitis and rheumatoid granulema found in internal organs.   Clinical manifestations. In two-thirds of patients the disease progresses slowly and is clinically characterised by systemic features, such as malaise, loss of appetite, weakness and involvement of the musculoskeletal system before the appearance of overt joint inflammation and swelling. As the disease progresses, the patient develops common symptoms of RA, such as symmetric arthritis with involvement of hand, knee, ankle, and wrist joints. Joint involvement. Bilateral symmetric involvement of joints (except distal interphalangeal joints) is common in patients with RA. Small joints of the hands and feet are commonly affected. Those most commonly affected joints are the second and third metacarpophalangeal joints, proximal interphalangeal joints, the second and fifth metatarsophalangeal joints. Morning stiffness which occurs after a long period of rest is the characteristic feature of RA. The involved joints are usually painful when palpated and have a paste-like consistency. Their contours are smoothed and the joints are increased in size due to exudation, hypertrophy of the synovial membrane and thickening of the articular capsule. The temperature of the skin around joints is increased. The affected joints show decreased range of motion. Most patients have muscle atrophy, which is secondary to joint inflammation. “Rheumatoid hand” refers to a swelling of the wrist, metacarpophalangeal joints and atrophy of interosseous muscles. Most patients develop articular deviations due to the formation of an angle between two adjacent bones. When fingers are inclined to the ulna, the patient develops ulnar deviation due to the destruction of the heads of metacarpal bones and weakness of muscles. The hand looks like a sean-fin. Flexion deformities in metacarpophalangeal joints, hyperextension of proximal interphalangeal joints and flexion of distal joints of fingers may lead to swan-neck deformities. Excessive flexion of metacarpophalangeal joints, proximal interphalangeal joints and hyperextension of distal interphalangeal joints may lead to bouton deformities. Shortening of the phalanges with ulnar deviation may lead to deformities such as “a hand with a lorgnette”. Inflammatory involvement of the elbow may lead to limited movements of the joint resulting in the development of deformity in the position of semiflexion and semipronation as well as entrapment of the ulnar nerve and paresthesia of the nerve supply area. The most common clinical manifestations of shoulder involvement are swollen, painful joints when palpated or in active or passive movements as well as impaired mobility of the joint resulting in the atrophy of the interosseous muscles. Hip joint is less commonly affected in RA. When hip is involved, the patient has pain spreading to the inguinal or inferior parts of the gluteal region. Limited movements of the internal rotation of the low extremity is another commonly observed manifestation. Fixation of the hip in the position of semiflexion is a typical finding. Involvement of knee joints is characterized by their swelling due to synovitis and tenderness in performing active and passive movements. Due to high intraarticular pressure the posterior part of the articular bursa is often herniated into the popliteal space forming Baker`s cyst. Most commonly affected joints of foot are the second and forth metatarsophalangeal joints. Joint involvement may lead to its defiguration and deformity of foot due to multiple subluxations and joint ankylosis. Joint involvement may also lead to hallux valgus, subluxation of the heads of metatarsal bones resulting in their displacement to the side of the sole, widening of the anterior part of the foot, hallux valgus, subluxation of toes and their displacement upwards and towards the lateral side of the sole. Ankle involvement is manifested clinically by pain and swelling around the ankle. Inflammation of the synovial membrane of ligaments and tendons is the characteristic feature of patients with RA. Cervical spine is frequently affected. Arthritis of intravertebral joints of the upper cervical vertebrae may lead to atlantoaxial subluxation. Symptoms include pain spreading to the occiput, spinal cord compression and compression of the vertebral artery. Extraarticular (systemic) manifestations. Rheumatoid nodules are referred to as the most widespread extraarticular features of RA and they may be present in 20 – 30% of patients. They are localized in the area of the elbow, Achilles tendon, on the extensor surface of the forearm and in the occiput. Rheumatoid nodules are painless and motile. However, they may be connected with aponeurosis or bone. Skin involvement in patients with RA is manifested by impaired trophism, subcutaneous hemorrhages and piecemeal necrosis due to developing vasculitis. Eye involvement in patients with RA is manifested clinically by iritis, iridocyclitis, episcleritis and scleritis. Iridocyclitis is most common (3.5% of all cases) in patients with RA. Episcleritis is characterised by moderate pain, segmental reddening of the anterior part of the eye. Scleritis is characterised by severe pain, hyperemia of the sclera that may lead to loss of vision. Effect of RA on the heart. Pericarditis characterised by pericardial effusion is common in RA. Myocarditis in patients with RA is often asymptomatic. Rheumatoid nodules can involve myocardium. RA involvement of the lungs may take the following forms: pleuritis, chronic interstitial pneumonitis, rheumatoid nodules and pulmonary vasculitis. All these conditions are most commonly asymptomatic. Dry (fibrinous) pleuritis is more likely to develop than interstitial pneumonitis which is the ultimate cause of death associated with lung involvement. It is manifested clinically by progressing dyspnea, crepitation (crackling) in the basal parts of the lungs, bilateral interstitial or infiltrative changes on lung radiographs. Rheumatoid nodules are usually discovered accidentally on joint radiographs. Some patients with RA develop pulmonary vasculitis underlying immunocomplex impairment of pulmonary vessels and  microcirculation. Kidney involvement in patients with RA is observed in 10 –25% of cases. Amyloidosis is the most common causative factor of kidney involvement. It develops within 7 –10 years after the appearance of articular syndrome. Proteinuria is most common in patients with RA and is manifested by various clinical presentations. It may also cause disorders of concentration function and nitrogen-releasing function of kidneys, anemia, moderate hypertension and renal failure. Patients with RA may also develop mesangial-proliferative or membranous glomerulonephritis which is manifested clinically as urinary syndrome. Sometimes patients with RA may develop, however, complete or incomplete nephrotic syndrome (massive proteinuria, hypo-and disproteinemia, dislipidemia) resulting in pronounced edema and arterial hypertension. Unlike amyloidosis, the prognosis of rheumatoid glomerulonephritis is favourable. Patients with RA may have neuropathy which is the most common impairment of the nervous system. Three main types of neuropathy are singled out. They are the following:

1. Mononeuritis multiplex which is characterized by the impairment of certain nerve trunks with corresponding motor and sensitive dysfunctions.
2. Symmetric peripheric neuropathy. It may be either sensitive or motor-sensitive.
3. Compression neuropathy. It includes entrapment of the median nerve in the area of the wrist (carpal tunnel syndrome), entrapment of the tibial nerve in the area of the medial malleolus (tarsal tunnel syndrome).

Vegetative nervous system disturbances are common and they are manifested by hyper- or hypothermia, increased sweating and trophic disturbances. Rheumatoid vasculitis occurs in 8 – 20% of patients with RA. Males are more likely to develop rheumatoid vasculitis than females and it can affect any organ or system. The activity of vasculitis depends on the extent of rheumatoid inflammation and it usually complicates the course of the disease. Neuropathy is a common symptom of vasculitis. Muscle involvement is manifested clinically by myalgia at the early stage of the disease. It is manifested by myositis with foci of necrosis and muscular atrophy at the advanced stage. Peripheral lymphadenopathy is diagnosed in 40 – 60% of patients with RA. Anterior and posterior cervical lymph nodes, submandibular, sub- and supraclavicular lymph nodes, axillary lymph nodes and inguinal lymph nodes are most commonly affected. Splenomegaly is observed in 25 – 30% of patients with RA. Gastric and intestinal disturbances are reported in 50% of patients with RA and are often secondary to associated processes such as medication effects. Sometimes patients with RA develop amyloidosis of the gastrointestinal tract which is clinically manifested by malabsorption. Autoimmune thyroiditis is common in patients with RA. The most common clinical manifestations of autoimmune thyroiditis are swollen and painful  thyroid gland when palpated as well as formation of antibodies to the tissue of the  thyroid gland. Laboratory studies. No pathognomonic (specific) test is available to help confirm the diagnosis of RA. High-titered rheumatoid factor (RF) which is an antibody to Fc-receptor of IgG (immunoglobulin) is present in approximately 80% of patients with RA. Rheumatoid factor is not, however, specific for the diagnosis of RA and it cannot be used as a screening method. Anemia of chronic disease is common and correlates with disease activity. Leukocytosis is less common but it may occur in certain joint and organ involvement, serious infections or it may be a consequence of corticosteriod therapy. Neutrophilic leukocytosis is common in patients with Still’s disease (juvenile rheumatoid arthritis). Granulocytopenia, splenomegaly and severe joint involvement may occur in patients with Felty syndrome. Elevated ESR (erythrocyte sedimentation rate) is associated with disease activity. Elevated C-reactive protein is also common in patients with RA. Classification of Rheumatoid Arthritis

 

Clinical anatomical characteristics	Clinical immunological characteristics	Course of the disease	Stage of the disease activity	Stage of the disease determined according to X-ray examination	Functional status of the patient
Rheumatoid arthritis:-polyarthritis -oligoarthritis -monoarthritis   Systemic features of rheumatoid arthritis: – involvement of the reticuloendothelial system, lungs, heart, nervous system; amyloidosis of organs Specific symptoms: – pseudoseptic syndrome – Felty’s syndrome   Other commonly observed musculoskeletal manifestations: – osteoarthrosis; – diffuse diseases of the connective tissue; – rheumatism.   Juvenile arthritis (including Still’s disease)	SeropositiveSeronegative	The disease progresses rapidly  The disease progresses slowly   Without a well marked progression	I – slow progressionII – moderate progression III – severe progression IV – remission of RA	I – paraarticular osteoporosis;II – osteoporosis, narrowing of the articular space and occasionally the patient may suffer from early bone attrition; III – osteoporosis, narrowing of the articular space and the patient may suffer from extensive attrition of bone; IV –  osteoporosis, narrowing of the articular space and occasionally bony ankylosis.	0 – the patient is healthy;I – the patient is able to work and perform usual activities; II – the patient cannot work; III – the patient is limited in ability to perform usual self-care.