Rheumatoid arthritis

Rheumatoid arthritis.

 

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks the joints producing a inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints RA is the most common form of chronic inflammatory joint disease. In its typical form RA is a symmetrical, destructive and deforming polyarthritis affecting small and large synovial joints, with associated systemic disturbance, a variety of extra-articular features and the presence of circulating antiglobulin antibodies (rheumatoid factors). Rheumatoid arthritis can also produce diffuse inflammation in the lungs, pericardium, pleura, and sclera, and also nodular lesions, most common in subcutaneous tissue under the skin. Although the cause of rheumatoid arthritis is unknown, autoimmunity plays a pivotal role in its chronicity and progression. Characteristically, the course of the disease is prolonged with exacerbations and remissions but atypical, asymmetrical and incomplete forms are not uncommon.

Etiology

The cause of RA is unknown. Genetic, environmental, hormonal, immunologic, and infectious factors may play significant roles. Socioeconomic, psychological, and lifestyle factors (eg, tobacco use, the main environmental risk ) may influence disease outcome.

Genetic factors

Genetic factors account for 50% of the risk for developing RA. About 60% of RA patients in the United States carry a shared epitope of the human leukocyte antigen (HLA)-DR4 cluster, which constitutes one of the peptide-binding sites of certain HLA-DR molecules associated with RA (eg, HLA-DR beta *0401, 0404, or 0405); HLA-DR1 (HLA-DR beta *0101) also carries this shared epitope and confers risk, particularly in certain southern European areas. Other HLA-DR4 molecules (eg, HLA-DR beta *0402) lack this epitope and do not confer this risk.

 

Classification

Clinical characteristics:

1. Rheumatoid arthritis:

– polyarthritis (5 and more)

– oligoarthritis (2-4 joints)

– monoarthritis ( 1 joint)

2. Rheumatoid arthritis with visceratis  and disorders of reticuloendothelial system of serous membranes, lungs, heart, blood vessels, eyes, kidneys Feltie’s syndrome .

3. Rheumatoid arthritis in combination with:

– Osteoarthrosis

– Diffuse connective tissue disorders

– Juvenile arthritis (including Still’s disease)

Immunological characteristics:

– Seropositive

– Seronegative

The course of the disease:

– Rapidly progressive

– Slowly progressive

– No significant progression

The level of activity:

      I   Minimal

     II   Average

     III  High

0       Remission

 

Slowing the progression of RA is more dependent on the possibility of suppressing the activity of the inflammatory process, so the selection rubric of “activity” is a necessary component of RA classification:

 

The table shows the determination of the activity of RA:

      I   Minimal

     II  Average

     III High

0       Remission

 

Radiographic stage:

I periarticular osteoporosis

II Osteoporosis + joint space narrowing (can be 1-3 lesions)

III + The same + multiple lesions

IV The same + bony ankylosis

 

Functional capacity of the patient:

I   kept employability

II  employability lost

III lost the ability to self-service

 

Clinic

In the majority of patients the onset is insidious, with joint pain, stiffness and symmetrical swelling of a number of peripheral joints, but other disease patterns can occur. Initially, pain may be experienced only on movement of joints, but rest pain and prolonged early morning stiffness are characteristic features of all kinds of inflammatory arthritis.

While rheumatoid arthritis primarily affects joints, problems involving other organs of the body are known to occur. Extra-articular (“outside the joints”) manifestations other than anemia (which is very common) are clinically evident in about 15-25% of individuals with rheumatoid arthritis. It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process  it  self, or from side effects of the medications commonly used to treat it – for example, lung fibrosis from methotrexate, or osteoporosis from corticosteroids.

Joints

The arthritis of rheumatoid arthritis is due to synovitis, which is inflammation of the synovial membrane that lines joints and tendon sheaths. Joints become swollen, tender and warm, and stiffness limits their movement. With time, RA nearly always affects multiple joints (it is a polyarthritis). Most commonly, small joints of the hands, feet and cervical spine are affected, but larger joints like the shoulder and knee can also be involved, differing per individual. Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface, causing deformity and loss of function.

Rheumatoid arthritis typically manifests with signs of inflammation and the affected joints are swollen, warm, painful and stiff early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the inflammatory disease which the person may experience and may last for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, often referred to as osteoarthritis or “wear-and-tear” arthritis. In arthritis of non-inflammatory causes signs of inflammation and early morning stiffness are absent and also movements aggravate pain due to the wear-and-tear. In RA, the joints are often affected in a fairly symmetrical fashion although this is not specific and the initial presentation may be asymmetrical.

 

Hands

As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs range of movement and leads to deformity. The fingers may suffer from almost any deformity, depending on which joints are most involved.

Specific deformities: like ulnar deviation, boutonniere deformity, swaeck deformity and “Z-thumb” but these are of no more significance to diagnosis or disability than other variants.

In the typical case the small joints of the fingers and toes are the first to be affected. Swelling of the proximal, but not the distal, interphalangeal joints gives the fingers a ‘spindled’ appearance, and swelling of the metatarsophalangeal joints results in ‘broadening’ of the forefoot. As the disease progresses with or without inter­vening remissions, it tends to spread to involve the wrists, elbows, shoulders, knees, ankles, subtalar and midtarsal joints. The hips become involved only in the more severely affected, but neck pain and stiffness from cervical spine disease is common. The temporomandibular, acromio-clavicular, sternoclavicular and crico-arytenoid joints are sometimes affected.

In 10-15% of patients the disease starts as an acute polyarthritis with severe systemic symptoms. A systemic onset, with fever, weight loss, profound fatigue and malaise without joint symptoms, occurs less often, particularly in middle-aged men, and this can cause diagnostic confusion with malignant disease or chronic infections. The onset is palindromic in some patients, with recurrent acute episodes of joint pain and stiffness in individual joints lasting only a few hours or days. In about one-third of such cases the disease evolves into one more typical of arthritis. The onset of RA in the elderly can be indistinguishable from polymyalgia rheumatica with pain and stiffness in the region of the hip and shoulder girdles but no apparent synovitis. The presence of rheumatoid factor in such patients may be a clue to the true diagnosis before typical joint changes have developed.

Involvement of the proximal interphalangeal (PIP) joints usually is easily recognized from the fusiform soft tissue swelling, often accompanied by regional osteopenia. Uniform cartilage loss occurs early at this site and erosion appears somewhat later. Erosive disease parallels the synovial and capsular anatomy, being extensive over the proximal phalangeal condyles and more limited over the base of the distal phalanges. Flexion or extension deformities are frequent in advanced disease; bony ankylosis is rare. Erosive artic­ular disease rarely is seen in the distal interphalangeal joints, although swelling and tenderness are common.

Metacarpophalangeal Joints.

Soft tissue swelling in the metacarpophalangeal (MCP) joints, although clinically prominent, is more difficult to evaluate than in the proximal interphalangeal joints, but in high-quality radiographs appears as discrete capsular distention. The cartilage at this site becomes narrow later, whereas erosion, particularly of the radial aspect of the metacarpal head, is an early and important sign of rheumatoid arthritis. Small, discrete, pocketed erosions develop at the proximal phalangeal base near the capsular insertion. As the erosive process evolves, narrowing ensues, and eventually complete destruction of the joint with “pencil in cup” deformity is seen, accompanied by palmar subluxation and ulnar deviation.

Early ulnar deviation of the metacarpophalangeal joints without subluxation. Extensor tendons have slipped to the ulnar side. The fifth finger, in particular, is compromised with weak flexion, causing a loss of power grip.

 

Wrist

In the wrist, soft tissue swelling is usually prominent and recognized relatively easily, particularly adjacent to the ulnar styloid, as a result of synovitis of the extensor carpi ulnaris tendon sheath. This involve­ment frequently leads to characteristic focal demin-eralization and surface erosion of the medial ulnar styloid. Additional erosion of the distal ulna results from synovitis of the prestyloid recess, eroding the tip of the styloid, and from synovitis in the inferior radio-ulnar compartment that erodes the foveal region. Other early and common sites of erosion include the waist of the navicular, the radial styloid, the pisiform and tri-quetrum, and the palmar aspect of the distal radial articular surface. Cartilaginous loss occurs relatively early at the wrist and tends to cause a uniform loss throughout the various compartments because of the development of early, abnormal communications between these separate spaces. In rheumatoid arthri­tis, joints that communicate are involved simultan­eously and uniformly.

Subchondral cortical line, a result of focal absorption and erosion accompanied by reactive sclerosis in the adjacent cancellous bone. The iliac side of the articulation is affected first because of its thinner cartilage; the sacral side may appear normal initially. At its inception, the process may be unilateral or asymmetric, but soon becomes bilateral, and eventually remarkably symmet­ric. With progressive erosion, joint widening becomes apparent in association with pronounced patchy scle­rosis that extends some distance into the subarticular bone. The process may arrest at any phase but charac­teristically progresses to narrowing of the joint and finally to intracapsular and intra-articular bony ankylosis. Occasionally part of the original joint line may persist. Once the joint has fused solidly, the sclerosis resolves gradually and a generalized osteopenia of the pelvis develops.

Constitutional symptoms

Constitutional symptoms including fatigue, low grade fever, malaise, morning stiffness, loss of appetite and loss of weight are common systemic manifestations seen in patients with active rheumatoid arthritis.

Rheumatoid arthritis is a systemic disease. Anorexia, weight loss, lethargy, myalgia and Raynaud’s phenomenon  occur commonly throughout its course and may precede the onset of articular symptoms by weeks or months. Lymphadenopathy is usually found iodes draining actively inflamed joints but more generalised lymph-adenopathy can give rise to diagnostic confusion when arthritis is minimal or quiescent. The nodes are discrete and non-tender. Histology shows a reactive hyperplasia which can be mistaken for lymphoma.

Periarticular osteoporosis, muscle weakness and wasting are prominent adjacent to inflamed and functionally impaired joints. Generalised osteoporosis, muscle wasting and skin atrophy occur as global secondary complications of systemic inflammation and circulating Th1 proinflammatory cytokines (IL-1, IL-6, TNF-a). Often seen early in the course of the disease, they progress to become major features in very active or advanced cases.

Skin

Subcutaneous nodules occur in about 20% of patients. They are usually seen at sites of pressure or friction, such as the extensor surfaces of the forearms below the elbow, the scalp, sacrum, scapula and Achilles tendon, as well as the fingers and toes. Ulceration and secondary infection are common. Nodules are almost invariably associated with the presence of rheumatoid factor.

The rheumatoid nodule, which is often subcutaneous, is the feature most characteristic of rheumatoid arthritis. The initial pathologic process in nodule formation is unknown but may be essentially the same as the synovitis, since similar structural features occur in both. The nodule has a central area of fibrinoid necrosis that may be fissured and which corresponds to the fibrin-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of palisading macrophages and fibroblasts, corresponding to the intimal layer in synovium and a cuff of connective tissue containing clusters of lymphocytes and plasma cells, corresponding to the subintimal zone in synovitis. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the olecranon, the calcaneal tuberosity, the metacarpophalangeal joints, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF (rheumatoid factor) titer and severe erosive arthritis. Rarely, they can occur in internal organs.

Several forms of vasculitis occur in rheumatoid arthritis. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin due to the presence of an obliterative cutaneous capillaropathy.

Other, rather rare, skin associated symtoms include:

·                     pyoderma gangrenosum, a necrotizing, ulcerative, noninfectious neutrophilic dermatosis.

·                     Sweet’s syndrome, a neutrophilic dermatosis usually associated with myeloproliferative disorders

·                     drug reactions

·                     erythema nodosum

·                     lobular panniculitis

·                     atrophy of digital skin

·                     palmar erythema

·                     diffuse thinning (rice paper skin), and skin fragility (often worsened by corticosteroid use).

 

Ocular manifestations

Episcleritis is a frequent, painless and benign feature in patients with nodular seropositive disease. It is not associated with visual disturbance and requires no specific therapy. Scleritis is rarer but more serious. Rather more common is the indirect effect of keratoconjunctivitis sicca which is a dryness of eyes and mouth due to lymphocyte infiltration of lachrymal and salivary glands. When severe, dryness of the cornea can lead to keratitis and loss of vision. Preventive treatment of severe dryness with measures such as nasolacrimal duct occlusion is important.

The eye is red and painful with inflammatory changes throughout the sclera and uveal tract. The pupil may be irregular from adhesions (synechiae), which can cause secondary glaucoma and visual impair­ment. Scleromalacia may follow episodes of scleritis and is seen as a blue discoloration of the white of the eye. Scleromalacia perforans follows necrosis of the sclera and may require grafting or enucleation of the eye. Keratoconjunctivitis sicca (secondary Sjogren’s syndrome) occurs in 10% of RA patients. Lack of lacrimal secretions results in grittiness, burning or itching associated with sticky mucous threads. Diagnosis can be confirmed by finding a reduction in the rate of tear secretion (Schirmer test).

Lungs

Fibrosis of the lungs is a recognised response to rheumatoid disease. It is also a rare but well recognised consequence of therapy (for example with methotrexate and leflunomide). Caplan’s syndrome describes lung nodules in individuals with rheumatoid arthritis and additional exposure to coal dust. Pleural effusions are also associated with rheumatoid arthritis.

Kidneys

Renal amyloidosis can occur as a consequence of chronic inflammation. Rheumatoid arthritis may affect the kidney glomerulus directly through a vasculopathy or a mesangial infiltrate but this is less well documented. Treatment with Penicillamine and gold salts are recognized causes of membranous nephropathy.

Cardiovascular manifestations

Asymptomatic pericarditis occurs in about one-third of patients with seropositive RA. Pericardial effusions and constrictive pericarditis are rarer complications. Very rarely, granulomatous lesions lead to heart block, cardiomyopathy, coronary artery occlusion or aortic regurgitation. People with rheumatoid arthritis are more prone to atherosclerosis, and risk of myocardial infarction (heart attack) and stroke is markedly increased Other possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis.

Vasculitis

Diffuse necrotising vasculitis is seen particularly in patients with nodules and positive tests for rheumatoid factor, Clinical manifestations vary with the size and site of the vessel involved. Small-vessel disease of the terminal arterioles or capillaries is often associated with no more thaail fold infarcts, leg ulcers or purpura. Large areas of skiecrosis or digital gangrene have more serious clinical significance and may herald the onset of malignant rheumatoid disease. Such patients are often febrile, with severe systemic disturb­ance and multiple extra-articular manifestations. A medium-vessel arteritis, histologically resembling polyarteritis nodosa. may result in catastrophic mesenteric, renal, cerebrovascular or coronary artery occlusion. Such patients frequently have evidence of circulating immune complexes, hypergamma-globulinaemia, cryoglobulins and hypocomplementaemia.

Neurological manifestations

Entrapment neuropathies result from compression of peri­pheral nerves by hypertrophied synovium. Mediaerve compression in the carpal tunnel is the most common and may be an early clinical manifestation of the disease. Others include ulnar nerve compression at the elbow. peroneal nerve palsy at the knee and posterior tibial nerve entrapment in the flexor retinaculum at the ankle (tarsal tunnel syndrome).

Hepatic

Cytokine production in joints and/or hepatic Kupffer cells leads to increased activity of hepatocytes with increased production of acute phase proteins such as C-reactive protein and increased release of enzymes such as alkaline phosphatase into the blood.  In Felty’s syndrome Kuppfer cell activation is so marked that the resulting increase in hepatocyte activity is associated with nodular hyperplasia of the liver, which may be palpably enlarged. Because Kuppfer cells are not within the liver parenchyma there is little or no evidence of hepatitis. Hepatic involvement in RA is essentially asymptomatic.

ACR/EULAR 2010 criteria RA

Arget population (Who should be tested?): Patients who 1.                 have at least 1 joint with definite clinical synovitis (swelling)* 2.                 with the synovitis not better explained by another disease†
Classification criteria for RA (score-based algorithm: add score of categories A–D; a score of ≥6/10 is needed for classification of a patient as having definite RA)‡
A. Joint involvement §
1 large joint¶	0
2-10 large joints	1
1-3 small joints (with or without involvement of large joints)#	2
4-10 small joints (with or without involvement of large joints)	3
>10 joints (at least 1 small joint)**	5
B. Serology (at least 1 test result is needed for classification)††
Negative RF and negative ACPA	0
Low-positive RF or low-positive ACPA	2
High-positive RF or high-positive ACPA	3
C. Acute-phase reactants (at least 1 test result is needed for classification)‡‡
Normal CRP and normal ESR	0
Abnormal CRP or abnormal ESR	1
D. Duration of symptoms§§
<6 weeks	0
≥6 weeks	1

 

Diagnostics

Laboratory analysis :

Complete blood count: evidence of moderate normochromic anemia (hemoglobin level not lower than 90 g / L), high activity and long duration of the disease was more pronounced anemia (may be reduced to 35-40 g / l). WBC count and erythrocyte sedimentation rate value dependent on the degree of activity of the process. With long-term course of rheumatoid arthritis is possible leukopenia. Wbc varies with severe rheumatoid arthritis vasculitis, pericarditis, pulmonary fibrosis, rheumatoid nodulezom, Still’s syndrome in adults (at these embodiments a shift to the left), and Felty syndrome (leukopenia, neutropenia). The most important and regularly changing indicator – increased erythrocyte sedimentation rate.

Biochemical studies are non-specific and are used to establish the degree of inflammatory activity. Identifies disproteinemia – reducing the level of albumin and globulin increase primarily alpha1 and alpha2,  and y-globulin, elevated fibrinogen, seromucoid, haptoglobin, the sialic acid according to the process activity. Increased C-reactive protein observed in the active phase of the disease in 77% of patients. It is produced by hepatocytes under the influence of IL-6 synthesis is induced by IL-1, tumor necrosis factor.

Immunological studies:

In the diagnosis of early RA it should always be the detection of RF identification antitcitrullinic antibodies (ANCA). Among them best clinical and laboratory parameters have antibodies to cyclic peptide (anti-CCP / anti-CCP) antibodies.Due to the high specificity of the best parameters for the early diagnosis have anti-CCP (CCPA / SSR), as their detection is a high risk factor, i.e. it increases the probability of detection of the disease by 15 times and has a very high predictive value of a positive result.

Often reduced number of T-lymphocytes, T-suppressor function disimmunoglobulinemii;

Characterized by increased levels of cryoglobulins, cryoglobulinemia is found in 30-50% of patients, usually at vistseropatiyah, Felty’s syndrome, vasculitis;

Detection of antibodies in the blood antikeratinovyh specifically for rheumatoid arthritis;

LE-cells found in the blood of patients with 8-27%, antinuclear factor – from 3-14% of patients.

Treatment of Rheumatoid arthritis

Treatment is empirically directed towards:

• relief of symptoms

• suppression of active and progressive disease

• conservation and restoration of function in affected joints.

To a greater or lesser extent these are achieved by combining:

• treatment of the patient—drugs, rest, physiotherapy, surgery

• modification of the environment—aids, appliances, housing, occupation, statutory social benefits.

Treatment

I. Disease-Modifying Antirheumatic Drugs (DMARD) decrease and prevent retard, retard the development of bone erosions or facilitate their healing, keep the function of joints, decrease expense for the treatment, keep economic activity of the patients with the RA:

a) cytotoxic immunosuppressive therapy:

1) methotrexate 7,5 mg (10-15 mg, sometimes 20 mg) once weekly 1-2 months, followed by a maintenance dose of  7,5 – 10 mg once weekly;

2) cyclophosphamide 100-200 mg/daily iv until a total dose – 1,5-2 g, followed by a maintenance dose of 50 mg daily;

3) azathioprine 100-150 mg daily 2-3 months, followed by a maintenance dose of 50 mg daily;

4) cyclosporine 2,53 mg/kg daily;

5) leflunomide initially 100 mg once a day for three days, followed by a maintenance dose of 20 mg a day;

6) gold salts (chrysotherapy):

– auranofin – 6 mg once a day or 3 mg twice a day;

– aurothioglucose (intramuscular injection) initial 10 mg the first week, 25 mg the second and third weeks, then 25 to 50 mg once a week until a total dose of 800 mg to 1 gram has been given, maintenance – intramuscular, 25 to 50 mg every two weeks for two to twenty weeks, then 25 to 50 mg every three to four weeks;

– gold sodium thiomalate (intramuscular injection)  initial 10 mg the first week, 25 mg the second week, then 25 to 50 mg once a week until the desired therapeutic response is obtained or until toxicity occurs, up to a total dose of 1 gram. Maintenance – intramuscular, 25 to 50 mg every two weeks for two to twenty weeks, then 25 to mg every three or four weeks.

7) sulfasalazine 1 gram 2-3 times a day 1-2 months;

8) D-penicillamine Oral, initially 125 or 250 mg once a day as a single dose, the dosage being increased, if necessary and tolerated, by adding 125 or 250 mg per day at two- to three-month intervals up to a maximum of 1.5 grams per day.

9) antimalarials – hydroxychloroquine sulphate 200-400 mg/d.

Combination therapy:

 methotrexate + hydroxychloroquine sulphate, methotrexate + sulfasalazine, gold salts + hydroxychloroquine sulphate;

methotrexate + hydroxychloroquine sulphate + sulfasalazine;

II. Antiinflammatory therapy:

Corticosteroids – prednisolone 10 mg/d (RA without complications), methylprednisolone or triamcinolone 8 mg/d (to patients with moderate activity of RA) with following gradually decrease of dose;

– Patients with severe activity of RA and involvement of internal organs can be treated with 3 days of 1000 mg intravenous “pulses” of methylprednisolone or

– first day – intravenous 1 g methylprednisolone and 1 g cyclophosphamide,

– second day – intravenous 1 g methylprednisolone,

– third day – intravenous 1 g methylprednisolone.

III. Local treatment:

– Intra-articular corticosteroids may be helpful if one or two joints are the chief source of difficulty. (diprospan (betamethasone) once two-three weeks, 10-40 mg depending on the size of the joint to be injected).

– ointment gel with NSAIDs;

– physiotherapy.

Perspectives of the treatment:

* Biological agents

Biological agents (biologics) are produced through genetic engineering, and include:

–                     tumor necrosis factor alpha (TNFα) blockers – etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira)

–                     Interleukin 1 (IL-1) blockers – anakinra (Kineret)

–                     monoclonal antibodies against B cells – rituximab (Rituxan)

–                     T cell costimulation blocker – abatacept (Orencia)

–                     Interleukin 6 (IL-6) blockers – tocilizumab (an anti-IL-6 receptor antibody) (RoActemra, Actemra)

* new immunomodulator:

– subreum – bacterial immunomodulator receiving by thermal processing of bacterials