Rheumatoid Arthritis. Reactive 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.
the annual incidence of RA is approximately 3 cases per 10,000 population, and the prevalence rate is approximately 1%,
increasing with age and peaking between the ages of 35 and 50 years. RA affects
all populations, though it is much more prevalent in some groups (5-6% in some
Native American groups) and much less prevalent in others (persons from the
relatives of individuals with RA are at 2- to 3-fold higher risk for the
disease. Disease concordance in monozygotic twins is approximately 15-20%,
suggesting that nongenetic factors play an important role. Because the
worldwide frequency of RA is relatively constant, a ubiquitous infectious agent
has been postulated to play an etiologic role. Women are affected by RA
approximately 3 times more often than men are, but sex differences diminish in
older age groups. In investigating whether the higher rate of RA among women
could be linked to certain reproductive risk factors, a study from
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 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.
Genes other than those of the major histocompatibility complex (MHC) are also involved, and results from sequencing genes of families with RA suggest the presence of several resistance and susceptibility genes, including PTPN22 andTRAF5.
Juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis (JRA), is a heterogeneous group of diseases that differs markedly from adult RA. JIA is known to have genetically complex traits in which multiple genes are important for disease onset and manifestations, and it is characterized by arthritis that begins before the age of 16 years, persists for more than 6 weeks, and is of unknown origin.The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene.
Some investigators suggest that the future of treatment and understanding of RA may be based on imprinting and epigenetics. RA is significantly more prevalent in women than in men, which suggests that genomic imprinting from parents participates in its expression. Imprinting is characterized by differential methylation of chromosomes by the parent of origin, resulting in differential expression of maternal over paternal genes.
Epigenetics is the change in DNA expression that is due to environmentally induced methylation and not to a change in DNA structure. Clearly, the research focus will be on environmental factors in combination with immune genetics.
For many decades, numerous infectious agents have been suggested as potential causes of RA, including Mycoplasma organisms, Epstein-Barr virus (EBV), and rubella virus. This suggestion is indirectly supported by the following evidence:
Emerging evidence also points to an association between RA and periodontopathic bacteria. For example, the synovial fluid of RA patients has been found to contain high levels of oral anaerobic bacterial antibodies common in periodontal infection, including Porphyromonas gingivalis.
Sex hormones may play a role in RA, as evidenced by the disproportionate number of females with this disease, its amelioration during pregnancy, its recurrence in the early postpartum period, and its reduced incidence in women using oral contraceptives. Hyperprolactinemia may be a risk factor for RA.
All of the major immunologic elements play fundamental roles in initiating, propagating, and maintaining the autoimmune process of RA. The exact orchestration of the cellular and cytokine events that lead to pathologic consequences (eg, synovial proliferation and subsequent joint destruction) is complex, involving T and B cells, antigen-presenting cells (eg, B cells, macrophages, and dendritic cells), and various cytokines. Aberrant production and regulation of both proinflammatory and anti-inflammatory cytokines and cytokine pathways are found in RA.
T cells are assumed to play a pivotal role in the initiation of RA, and the key player in this respect is assumed to be the T helper 1 (Th1) CD4 cells. (Th1 cells produce IL-2 and interferon [IFN] gamma.) These cells may subsequently activate macrophages and other cell populations, including synovial fibroblasts. Macrophages and synovial fibroblasts are the main producers of TNF-a and IL-1. Experimental models suggest that synovial macrophages and fibroblasts may become autonomous and thus lose responsiveness to T-cell activities in the course of RA.
B cells are important in the pathologic process and may serve as antigen-presenting cells. B cells also produce numerous autoantibodies (eg, RF and ACPA) and secrete cytokines.
The hyperactive and hyperplastic synovial membrane is ultimately transformed into pannus tissue and invades cartilage and bone, with the latter being degraded by activated osteoclasts. The major difference between RA and other forms of inflammatory arthritis, such as psoriatic arthritis, lies not in their respective cytokine patterns but, rather, in the highly destructive potential of the RA synovial membrane and in the local and systemic autoimmunity.
Whether these 2 events are linked is unclear; however, the autoimmune response conceivably leads to the formation of immune complexes that activate the inflammatory process to a much higher degree than normal. This theory is supported by the much worse prognosis of RA among patients with positive RF results.
The pathology of RA is characterized by the infiltration of several inflammatory cells into both the pannus and the joint fluid, and by subsequent tissue destruction. Chemokines, as well as other inflammatory mediators play key roles in the pathogenesis of RA, and the coordinated production of chemokines and proinflammatory cytokines is important in the orchestration of the inflammatory responses observed in patients with RA. Imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. Monocytes that are attracted to the RA joint differentiate into macrophages and become activated. These macrophages play a pivotal role in RA because they are numerous in the inflamed synovial membrane and at the cartilage-pannus junction.
They activate MHC Class-II (Major Histocompatibility Complex Class-II) molecules, and secrete proinflammatory or regulatory cytokines and growth factors like IL-1, IL-2, IL-6, IL-10, IL-13, IL-15, IL-17, IL-18, TNF-Alpha (Tumor Necrosis Factor), GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor), chemokines and chemoattractants (eg IL-8, MIP1 [Macrophage Inflammatory Protein-1] and MCP1 [Monocyte Chemoattractant Protein]), metalloproteinases and neopterin. TNF regulates IL-1Beta expression, which is important for the induction of prostanoid and MMP (Matrix Metalloproteinases) production by synovial fibroblasts and chondrocytes. Cellular interactions mediated by TNF and IL-1, cytokines that are mainly produced by activated macrophages are prominent factors leading to cartilage damage in RA (Ref.5). TNF increases the expression of adhesion molecules on endothelial cells, which recruit more cells to the joint. MCP1 and IL-8 are also secreted by macrophages and attract more cells into the joint. IL-1 and TNF induce synovial fibroblasts to express IL-6, chemokines (IL-8), GM-CSF and MMPs, which contribute to cartilage and bone destruction. TNF contributes to osteoclast activation and differentiation. In addition, IL-1 mediates cartilage degradation directly by inducing the expression of MMPs by chondrocytes. However, these cells of the innate immune system possess broad proinflammatory, destructive and remodeling capacities, and considerably contribute to inflammation and joint destruction both in the acute and chronic phases of RA. In addition, these chemokines, produced by RA synovial stromal cells also stimulate monocyte migration. Other cytokines such as IFN-Gamma (Interferon-Gamma) induced chemokines also contribute to the documented morphologic and clinical features of RA.
Autoreactive B cells can be driven by the T cells to produce IgG autoantibodies that may be directly involved in joint damage, and B cells are known to be critical in activating CD4+ T cells. As the B cell appears to play an important role in the RA process, it is appropriate to consider how B cell-mediated effects might be reduced or prevented in patients with this disease. Their presence and persistence implies that clones of autoreactive B cells survive and proliferate in RA patients under a continuous stimulation. Being much more than simple autoantibody producers, B cells are able to secrete many important cytokines and to efficiently present antigens to T lymphocytes in the synovial environment.
The etiology of RA also involves abnormal presentation of self antigen(s) by APCs (Antigen Presenting Cells) and activation of autoreactive T-Cells. T lymphocytes play a central role in the disease process. The rheumatoid synovial membrane is rich in MHC Class-II, APCs, and CD4+ T-Cells. However, it is not clear whether T-Cell activation occurs before entry to the tissue, during transendothelial migration, or in the synovium. APCs require signals from activated T-Cells for their differentiation and maturation; this subsequently enables APCs to activate newly arrived T-Cells in a specific or unspecific manner in the local inflammation. Activated T-Cells promote the disease progression by inducing the secretion of pro-inflammatory cytokines (in particular, TNF-Alpha) from macrophages and synovial cells in a contact-dependent manner. Several costimulatory molecules are involved during APC–T-Cell interactions, including CD28/CD80-86 and CD40-CD40L.
Some of these molecules are critical in initiation of the immune response (CD28/CD80/86), while CD40-CD40L is required for the amplification of the inflammatory response. Early indications of RA are swelling and pain of the proximal interphalangeal and metacarpophalangeal joints. Later, the larger joints become affected, especially those of the knee, elbow and ankle. Large numbers of activated leukocytes infiltrate the synovial membrane, causing hyperplasia and inflammation, which in most cases lead to progressive destruction of cartilage and bone. Since RA is a systemic autoimmune disease, other parts/organs of the body may become affected at a later stage. An example of this is the formation of rheumatoid noduli. Peak onset typically occurs in the fourth and fifth decades of life (Ref.7). Like many autoimmune diseases, RA occurs more frequently in women than in men (3:1 ratio), suggesting a role for sex hormones. Thyroid or other neuroendocrine hormones can also influence RA, at least partly through actions on macrophages . There is also evidence that environmental factors, such as infectious agents, oral contraceptives and smoking, may play a role (Ref.8). Although the mechanisms that contribute to the pathogenesis of RA are unknown, a genetic predisposition has been identified in certain ethnic groups. This genetic predisposition, as well as the activation and affinity maturation of autoreactive T-Cells and B-Cells that are present in the joint, indicates a role for adaptive immunity in the pathogenesis of RA.
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:
- Diffuse connective tissue disorders
- Juvenile arthritis (including Still's disease)
The course of the disease:
- Rapidly progressive
- Slowly progressive
- No significant progression
Disease Activity Score (DAS) is used in
determination of stage activity. Its used to determine whether it is under control
and if any treatment adjustments are required. It can also assist in
establishing a target score to aim for, to help inform treatment decisions and
optimise disease management.
DAS28 is a composite outcome measure that assesses:
• How many joints in the hands, wrists, elbows, shoulders, and knees are swollen and/or tender.
• The erythrocyte sedimentation rate (ESR) or C reactive protein (CRP) in the blood to measure the degree of inflammation.
• The patient’s Visual Analogue Score (a simple scale) to assess how they are feeling on that day from 0 (very good) to 10 (very bad).
The results are combined to produce the DAS28 score, which correlates with the extent of disease activity:
• < 2.6: Disease remission
• 2.6 – 3.2: Low disease activity
• 3.2 – 5.1: Moderate disease activity
• > 5.1: High disease activity
A score of less than 2.6, classified as ‘remission’, is the ultimate goal for patients with RA, though it’s important to recognise that not everyone can achieve this. However, the vast majority of patients can, if treated early and appropriately, achieve DAS disease remission or low disease activity, which will bring about a great improvement, long-term, to their quality of life.
Stage activity calculator example you can download as phone program or find at this website: http://www.4s-dawn.com/DAS28/.
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
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.
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.
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.
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.
RA: Proximal Interphalangeal Joints.
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.
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.
subluxation with marked ulnar deviation at the metacarpophalangeal joints of a
90-year-old woman with rheumatoid arthritis (RA). Arrows mark the heads of the metacarpals, now in direct contact with
the joint capsule instead of the proximal phalanges.
Ulnar Deviation and Subluxation.
This left hand shows typical manifestations of end-stage erosive changes about the metacarpophalangeal (MP) joints, with volar dislocation and ulnar drift of the fingers.
This is a right thumb demonstrating typical soft tissue imbalance found in rheumatoid arthritis. The metacarpophalangeal (MP) joint is hyperflexed, and the interphalangeal joint is hyperextended.
Swan neck deformity with hyperextension of the proximal interphalangeal joints and flexion of the distal interphalangeal joints of the second, third, and fourth digits of the hand. The fifth digit displays the boutonniere deformity, with flexion at the proximal interphalangeal joint and hyperextension at the distal interphalangeal joint.
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.
Anatomic alignment at the wrist generally becomes altered with medial migration of the carpus at the radiocarpal joint, allowing the navicular to occupy the hollow of the radius. This rotational change may result in foreshortening of the navicular and lunate. Frequently, a widened space is seen between the navicular and capitate. Involvement of the inferior radioulnar compartment with destruction of the triangular cartilage results in diastasis and, occasionally, in complete dorsal dislocation of the distal ulna. In the lateral view, either dorsal or palmar subluxation and deviation of the carpus in regard to the distal radius may be seen. Bony ankylosis is more common at the carpus than at any other site in rheumatoid arthritis. Finally, a near-total resorption or fragmentation, or both, of the carpus, penciling of the distal ulna, and cup-shape resorption of the distal radius are seen in end-stage disease.
The hand and wrist are common sites of synovitis in rheumatoid arthritis. Marked swelling in the wrist and metacarpophalangeal joints is caused by synovial proliferation.
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.
Arthritis of the temporomandibular joints, which presented in the onset phase and impeded normal opening of the mouth
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 in nodes 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.
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
· lobular panniculitis
· atrophy of digital skin
· diffuse thinning (rice paper skin), and skin fragility (often worsened by corticosteroid use).
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).
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.
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.
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.
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 than nail fold infarcts, leg ulcers or purpura. Large areas of skin necrosis 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.
Digital vasculitis in a 65-year-old man with Seropositive Rheumatoid Arthritis (RA)
Entrapment neuropathies result from compression of peripheral nerves by hypertrophied synovium. Median nerve 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). A more diffuse symmetrical peripheral neuropathy can occur and is usually limited to symptoms and signs of mild 'glove and stocking' sensory loss. Mononeuritis multiplex follows occlusion of vasa nervorum in patients with arteritis. Cervical cord compression can result from subluxation of the cervical spine at the atlantoaxial joint or at a subaxial level. Atlantoaxial sub-luxation is a common finding in long-standing RA and can be diagnosed from lateral radiographs of the cervical spine taken in full flexion. Although usually associated with no more than neck pain radiating to the occiput, it can result in cord compression and sudden death if the neck is manipulated inadvertently under an anaesthetic. Progressive cervical myelopathy may develop more insidiously with limb weakness, difficulty in holding up the head and tetraparesis. These problems occur more often following subluxation at a subaxial level and may require operative decompression and fixation.
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
A. Joint involvement §
1 large joint¶
2-10 large joints
1-3 small joints (with or without involvement of large joints)#
4-10 small joints (with or without involvement of large joints)
>10 joints (at least 1 small joint)**
B. Serology (at least 1 test result is needed for classification)††
Negative RF and negative ACPA
Low-positive RF or low-positive ACPA
High-positive RF or high-positive ACPA
C. Acute-phase reactants (at least 1 test result is needed for classification)‡‡
Normal CRP and normal ESR
Abnormal CRP or abnormal ESR
D. Duration of symptoms§§
* The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA. Patients with longstanding disease, including those whose disease is inactive (with or without treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having RA.
† Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted.
§ Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment. Categories of joint distribution are classified according to the location and number of involved joints, with placement into the highest category possible based on the pattern of joint involvement.
** In this category, at least 1 of the involved joints must be a small joint; the other joints can include any combination of large and additional small joints, as well as other joints not specifically listed elsewhere (e.g., temporomandibular, acromioclavicular, sternoclavicular, etc.).
†† Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay; low-positive refers to IU values that are higher than the ULN but ≤3 times the ULN for the laboratory and assay; high-positive refers to IU values that are >3 times the ULN for the laboratory and assay. Where rheumatoid factor (RF) information is only available as positive or negative, a positive result should be scored as low-positive for RF. ACPA = anti-citrullinated protein antibody.
§§ Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status.
Laboratory analysis :
blood count: evidence of moderate normochromic anemia (hemoglobin level not
Laboratory and Imaging Findings Associated with Rheumatoid Arthritis
Typically increased to >0.7 picograms per mL; may be used to monitor disease course.
increased to >
decreased; hemoglobin averages around
Normal or slightly elevated alkaline phosphatase
Radiographic findings of involved joints*
May be normal or show osteopenia or erosions near joint spaces in early disease; wrist and ankle films are useful as baselines for comparison with future studies.
Negative in 30 percent of patients early in illness; if initially negative, can repeat six to 12 months after disease onset; can be positive in numerous other processes (e.g., lupus; scleroderma; Sjögren's syndrome; neoplastic disease; sarcoidosis; various viral, parasitic, or bacterial infections); not an accurate measure of disease progression.
White blood count*
May be increased
Anticyclic citrullinated peptide antibody
Tends to correlate well with disease progression; increases sensitivity when used in combination with rheumatoid factor; more specific than rheumatoid factor (90 versus 80 percent); not readily available in many laboratories.
Limited value as a screening study for rheumatoid arthritis
Normal or elevated
Elevated alpha-1 and alpha-2 globulins possible.
Joint fluid evaluation
Consider if an affected joint can be tapped and diagnosis is uncertain; straw-colored fluid with fibrin flecks often seen; fluid may clot at room temperature; 5,000 to 25,000 white blood cells per mm3 (5 to 25 X 109 per L) with 85 percent polymorphonuclear leukocytes a common finding; in rheumatoid arthritis, cultures are negative, there are no crystals, and fluid glucose level typically is low.
Microscopic hematuria or proteinuria may be present in many connective tissue diseases.
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 examination is particularly relevant in the early stages of the disease when serological testing is the only available method of objectifying clinical assumptions. Often atypical clinical picture at the beginning of the disease, such as oligoarthritis and the lack of bone erosions, despite the length of the patient's complaints, and the fact that the use of active therapy at the onset of the disease can slow the rapid development of joint deformities, doing laboratory tests are extremely valuable tool for differential diagnosis in the opening RA. It is important to emphasize that a correct diagnosis of RA, delivered at an early stage is an effective primary immunosuppressive therapy.
cheapness and availability of determination of rheumatoid factor (RF), make it
the first serological test in the evaluation of patients with diseases of the
joints. Identification of the
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.
3. Often reduced number of T-lymphocytes, T-suppressor function disimmunoglobulinemii;
4. Characterized by increased levels of cryoglobulins, cryoglobulinemia is found in 30-50% of patients, usually at vistseropatiyah, Felty's syndrome, vasculitis;
5. Detection of antibodies in the blood antikeratinovyh specifically for rheumatoid arthritis;
6. LE-cells found in the blood of patients with 8-27%, antinuclear factor - from 3-14% of patients.
Early in the disease, roentgenograms of the affected joints are usually not helpful in establishing a diagnosis. They reveal only that which is apparent from physical examination, namely, evidence of soft tissue swelling and joint effusion. As the disease progresses, abnormalities become more pronounced, but none of the radiographic findings is diagnostic of RA. The diagnosis, however, is supported by a characteristic pattern of abnormalities, including the tendency toward symmetric involvement. Juxtaarticular osteopenia may become apparent within weeks of onset. Loss of articular cartilage and bone erosions develop after months of sustained activity. The primary value of radiography is to determine the extent of cartilage destruction and bone erosion produced by the disease, particularly when one is monitoring the impact of therapy with disease-modifying drugs or surgical intervention. Other means of imaging bones and joints, including 99mTc bisphosphonate bone scanning and magnetic resonance imaging, may be capable of detecting early inflammatory changes that are not apparent from standard radiography but are rarely necessary in the routine evaluation of patients with RA.
Radiographic evaluation of the hand is of considerable importance in the assessment of rheumatoid arthritis and primary osteoarthritis since both of these conditions manifest themselves early and rather distinctly in this anatomic location. By careful radio-graphic analysis the differentiation between these two clinical entities can be made readily. This discussion will focus first on the radiographic findings of rheumatoid arthritis, both on the hands and in other joints. In a later section, the findings in osteoarthritis will be discussed in detail and contrasted with those seen in rheumatoid arthritis. The distinguishing radiographic features of rheumatoid arthritis in the hands consist of prominent, fusiform, soft tissue swelling, periarticular demineral-ization, juxta-articular and articular erosions with minimal reactive bone formation. The distribution is predominantly proximal: the most common sites of early involvement include the ulnar styloid, the first through the third metacarpophalangeal joints, and the second and third proximal interphalangeal joints.
Schematic representation of the hand demonstrating the frequent sites of early erosion in rheumatoid arthritis.
The most commonly used in everyday practice radiological classification is the division of RA on stage at Shteynbrokeru. Are 4 radiographic stage.
Radiographic stage of joint damage in RA:
Stage I - periarticular thickening and sealing of soft tissue + periarticular osteoporosis.
RA, I stage. XR of hands in a straight projection. Moderate periarticular osteoporosis. Single cystoid enlightenment bone. A slight narrowing of the gaps of individual metacarpophalangeal joints.
Stage - II –the same + single erosions (1-4) indicates the progression of arthritis.
RA, II stage. XR of hands.
Expressed periarticular OP. Numerous cystoid enlightenment bone. Narrowing the slots most joints. Single erosion in the metacarpophalangeal joints.
Stage-III is characterized by the addition to the existing pattern of multiple erosions (> 5) in the typical joints.
RA, III stage. XR of hands in a straight projection. Common OP. Numerous erosion of the articular surfaces. The narrowing of the joint gaps of multiple joints. Deformation of the wrist bones.
RA. Multiple erosions of the metacarpophalangeal joints. Compression erosion II metacarpophalangeal joint
Stage IV - is characterized by the appearance of a partial or complete ankylosis intercarpal joints or one of the carpal-metacarpal joints except I carpal-metacarpal joint.
RA, IV stage. XR of hands. Expressed common OP. Multiple bone
ankylosis of the wrist joint.
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.
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-
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
- 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
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
9) antimalarials – hydroxychloroquine sulphate 200-400 mg/d.
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
second day - intravenous
third day - intravenous
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;
Perspectives of the treatment:
* Biological agents
Biological agents (biologics) are produced through genetic engineering, and include:
* new immunomodulator:
- subreum – bacterial immunomodulator receiving by thermal processing of bacterials
Other therapies are weight loss, occupational therapy, podiatry, physiotherapy, immunoadsorbtion therapy, joint injections, and special tools to improve hard movements (e.g. special tin-openers). Regular exercise is important for maintaining joint mobility and making the joint muscles stronger. Swimming is especially good, as it allows for exercise with a minimum of stress on the joints. Heat and cold applications are modalities that can ease symptoms before and after exercise. Pain in the joints is sometimes alleviated by oral ibuprofen or other anti-inflammatory. Other areas of the body, such as the eyes and lining of the heart, are treated individually. Fish oil may have anti-inflammatory effects.
The course of the disease varies greatly. Some people have mild short-term symptoms, but in most the disease is progressive for life. Around 20%-30% will have subcutaneous nodules (known as rheumatoid nodules); this is associated with a poor prognosis.
· Daily living activities are impaired in most individuals.
· After 5 years of disease, approximately 33% of sufferers will not be working.
· After 10 years, approximately half will have substantial functional disability.
Poor prognostic factors include persistent synovitis, early erosive disease, extra-articular findings (including subcutaneous rheumatoid nodules), positive serum RF findings, positive serum anti-CCP autoantibodies, carriership of HLA-DR4 "Shared Epitope" alleles, family history of RA, poor functional status, socioeconomic factors, elevated acute phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), and increased clinical severity.
Estimates of the life-shortening effect of RA vary; most sources cite a lifespan reduction of 5 to 10 years. According to the UK's National Rheumatoid Arthritis Society, "Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA – such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints – have been shown to associate with higher mortality". Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic noted that RA sufferers suffer a doubled risk of heart disease, independent of other risk factors such as diabetes, alcohol abuse, and elevated cholesterol, blood pressure and body mass index. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor.
Reactive arthritis (ReA) is an autoimmune condition that develops in response to an infection in another part of the body. Coming into contact with bacteria and developing an infection can trigger reactive arthritis. It has symptoms similar to various other conditions collectively known as "arthritis," such as rheumatism. It is caused by another infection and is thus "reactive", i.e., dependent on the other condition. The "trigger" infection has often been cured or is in remission in chronic cases, thus making determination of the initial cause difficult.
Reiter's disease is the triad of non-specific urethritis, conjunctivitis and reactive arthritis that follows bacterial dysentery or exposure to sexually transmitted infection. Incomplete forms are frequent and include the most common variety of inflammatory arthritis seen in young men.
The symptoms of reactive arthritis very often include a combination of three seemingly unlinked symptoms—an inflammatory arthritis of large joints, inflammation of the eyes (conjunctivitis and uveitis), and urethritis. A useful mnemonic is "the patient can't see, can't pee and can't bend the knee" or "the patient can't see, can't pee and can't climb a tree". Also known as Reiter’s syndrome, after German physician Hans Conrad Julius Reiter, it is also known as arthritis urethritica, venereal arthritis and polyarteritis enterica. It is a type of seronegative spondyloarthropathy.
Reactive arthritis (also known as Reiter's syndrome) is a type of arthritis that occurs as a "reaction" to an infection in the body. Reactive arthritis itself is not contagious, but the infection can be passed from person to person.
In 1916, Hans Reiter described the classic triad of arthritis, nongonococcal urethritis, and conjunctivitis. However, he mistakenly dubbed this disease as "spirochetosis arthritica."This condition used to be known as Reiter syndrome but is now referred to as reactive arthritis (ReA). This change has occurred in part because of Hans Reiter's affiliation and activities with the Nazis during WWII. Cases of "Reiter's disease" have likely been described dating back many centuries. In fact, Christopher Columbus may have suffered from its effects having described symptoms such as fever, arthritis, eye hemorrhage, and pain, following a bout of dysentery. His arthritis later progressed to a chronic bedridden state he attributed to "gout."
Reactive arthritis refers to acute nonpurulent arthritis complicating an infection elsewhere in the body.
Data on the incidence
and prevalence of ReA are scarce, partly because of a lack of a disease
definition and classification criteria; these factors complicate differentiation
of ReA from other arthritides. The reported annual incidence of ReA is
approximately 30-40 cases per 100,000 adults, with a prevalence of 1%-7%, but
this varies greatly among different geographic locations.Reports from Latin
ReA typically follows a self-limited course, with resolution of symptoms by 3-12 months, even in patients who are acutely incapacitated. However, reactive arthritis has a high tendency to recur, particularly with ocular and urogenital inflammation. Individuals who are HLA-B27–positive are at a higher risk of recurrence. A new infection or other stress factor could cause reactivation of the disease.
About 15% of patients with ReA develop a long-term, sometimes destructive, arthritis or enthesitis or spondylitis
As with other spondyloarthropathies, HLA-B27 and ReA are more common in white people than in black people.
ReA following foodborne enteric infections is equally common in males and females. The male-to-female ratio of disease associated with venereally acquired infections is 9:1.
Most patients with ReA are aged 20-40 years.
It is set off by a preceding infection,
the most common of which would be a genital infection with Chlamydia trachomatis in the
Sexually transmitted urethritis, cervicitis, proctitis, and pharyngitis not due to gonorrhea are caused predominantly by chlamydiae and infrequently by mycoplasmas or Ureaplasma sp. Chlamydiae may also cause salpingitis, epididymitis, perihepatitis, neonatal conjunctivitis, and infant pneumonia. Untreated chlamydial salpingitis can become chronic, causing minimal symptoms but having serious consequences.
Approximately 80% of people with reactive arthritis test positive for HLA-B27. However, inheriting the HLA-B27 gene does not necessarily mean you will get reactive arthritis. Eight percent of healthy people have the HLA-B27 gene, and only about one-fifth of them will develop reactive arthritis if they contract the triggering infections. Patients with HLA-B27, as well as those with a strong family clustering of the disease, tend to develop more severe and long-term disease. The frequency of ReA after enteric infection averages 1%-4% but varies greatly, even among outbreaks of the same organism.
ReA usually develops 2-6 weeks after a
genitourinary or gastrointestinal infection. Recent evidence indicates that a
preceding Chlamydia respiratory infection may also trigger
reactive arthritis. Hereditary factors are noted and there is a possibility of different
variants of these syndromes, occuring within families.Pathogenesis is felt to
be related to an autoimmune phenomenon - with molecular mimicry. There is a
cross reaction between an environmental and the bodies’ own tissues. The
environmental agent is thought by many to be an infective organism.
This in fact is identified in certain subsets of the spondyloarthropathies, and these subsets are called REACTIVE arthropathies. The organisms include
Chlamydia - usually from urogenital source. Streptococcus - from airway / respiratory / skin infection, source. Yersinia, Campylobacter, Salmonella, Shigella - from bowel source. Klebsiella - from bowel source.
About 10% of patients do not have a preceding symptomatic infection. Inflammation of joints, entheses, axial skeleton, skin, mucous membranes, gastrointestinal tract, and eyes may occur. Results for HLA-B27 are positive in 65%-96% of patients (average, 75%) with reactive arthritis. The likelihood of developing ReA is increased 50-fold in patients who are HLA-B27–positive, but this syndrome can also occur in patients who are HLA-B27 negative.
The mechanism of the interaction of the inciting organism with the host (often HLA-B27–positive) leading to the development of reactive arthritis is not known. It is unclear if microbial antigens cross-react with self-proteins, stimulating (molecular mimicry) and perpetuating a Th2-cell–mediated autoimmune response. Chronic and joint damage have been associated with a Th2 cytokine profile that leads to decreased bacterial clearance.
Synovial fluid cultures are negative for enteric organisms or Chlamydia species. However, a systemic and intrasynovial immune response to the organisms has been found with intra-articular antibody and bacterial reactive T cells. Furthermore, bacterial antigen has been found in the joints. Thus, the elements for an immune-mediated synovitis are present.
Molecular evidence of bacterial DNA (by polymerase chain reaction [PCR]) in synovial fluids has been found only in Chlamydia -related reactive arthritis, and one placebo-controlled trial of a tetracycline derivative (ie, lymecycline) showed a reduction in the duration of acute Chlamydia -related, but not enteric-related, reactive arthritis. This suggests that persistent infection may play a role, at least in some cases of chlamydial reactive arthritis. In a more recent trial, the combination of doxycycline and rifampin was superior to doxycycline alone in reducing morning stiffness and swollen and tender joints in patients with undifferentiated spondyloarthropathy.
The Toll-like receptors (TLRs) recognize different extracellular antigens as part of the innate immune system. TLR-4 recognizes gram-negative lipopolysaccharide (LPS). Studies in mice and humans showed abnormalities in antigen presentation due to down-regulation of TLR-4 costimulatory receptors in patients with reactive arthritis. More recent studies implicated TLR-2 polymorphism associated with acute reactive arthritis; however, its role is still disputed.
The role of HLA-B27 in this scenario remains to be defined but, as discussed elsewhere (Ankylosing Spondylitis and Undifferentiated Spondyloarthropathies), molecular mimicry, presentation of pathogenic peptides, and an altered host response to the bacteria are all possible.
ReA, including classic Reiter syndrome, can occur in patients infected with HIV or who have AIDS. This is likely because both conditions can be sexually acquired rather than ReA being triggered by HIV. The course of ReA in these patients tends to be severe, with a generalized rash that resembles psoriasis, profound arthritis, and frank AIDS. The frequency of HLA-B27 is the same of that associated with non–AIDS-related reactive arthritis in a similar demographic group. This association points out the likely importance of CD8+ cytotoxic T cells compared to CD4+ helper T cells in the pathogenesis of ReA.
According to the etiology:
• postenterokolitic (recovering from Yersinia, Salmonella, Campylobacter, or shigella infection);
• urogenital (Chlamidia trachomatis).
• acute (up to 6 months)
• subacute (up to 12 months)
• chronic (longer than 12 months)
• recurrent (with the development of the joint attack after remission lasting at least 6 months.)
According to the degree of activity:
• low (I);
• Average (II);
• High (III);
• remission (0);
According to the degree of functional impairment of the joints (FNS):
• I - professional ability retained;
• II - professional ability is lost;
• III - is an ability for self-care.
A- Acute symptoms
Most commonly present with oligoarthritis but also can present with polyarthritis or monoarthritis
ü Frequently involved
§ Sacroiliac joints
§ Lumbar spine
ü Occasionally involved
§ Thoracic spine (usually seen in chronic ReA)
§ Cervical spine (usually seen in chronic ReA)
§ Cartilagenous joints (symphysis pubis; sternoclavicular and costosternal joints)
ü Frequently involved
§ Large joints of the lower extremities (especially knees)
C. Dactylitis (sausage digit): Very specific for a spondyloarthropathy
ü Hallmark feature
ü Transitional zone where collagenous structures, such as tendons and ligaments, insert into bone
ü Inflammation causes collagen fibers to undergo metaplasia forming fibrous bone
Chronic enthesitis leads to radiographic findings
ü Plantar or Achilles spurs
ü Nonmarginal syndesmophytes
ü Syndesmoses of the sacroiliac joints
ü Oral ulcers (generally painless)
ü Sterile dysuria (occurs with both postvenereal and postdysentery forms)
ü Keratoderma blenorrhagicum
§ Pustular or plaque-like rash on the soles or palms
§ Grossly and histologically indistguishable from pustular psoriasis
ü Also can involve nails (onycholysis, subungual keratosis, or nail pits), scalp, extremities
ü Circinate balanitis
§ Erythema or plaque-like lesions on the shaft or glans of penis
ü Conjunctivitis: typically during acute stages only
ü Anterior uveitis (iritis): often recurrent
ü Rarely described: scleritis, pars planitis, iridocyclitis, and others
ü Pericarditis (uncommon)
B- Chronic symptoms (>6 months)
ü Sacroiliac joints
ü Lumbar spine
ü Thoracic spine
ü Cervical spine
B. Cartilagenous joints (symphysis pubis; sternoclavicular joints)
C. Peripheral: Large joints of the lower extremities (especially knees)
D. Dactylitis (sausage digit): Very specific for a spondyloarthropathy
A. Chronic inflammation can cause collagen fibers to undergo metaplasia forming fibrous bone
B. Chronic enthesitis leads to radiographic findings
ü Plantar/Achilles spurs
ü Nonmarginal syndesmophytes
ü Syndesmoses of the sacroiliac joints
ü Sterile dysuria
ü Keratoderma blennorrhagicum
ü Circinate balanitis
ü Anterior uveitis (iritis): often recurrent
ü Rarely described: scleritis, pars planitis, iridocyclitis, and others
ü Aortic regurgitation
ü Valvular pathologies
ReA usually develops 2-4 weeks after a genitourinary or gastrointestinal infection. Recent evidence indicates that a preceding respiratory infection with Chlamydia pneumoniae may also trigger the disease. About 10% of patients do not have a preceding symptomatic infection.
in men, and vaginal discharge and/or cervicitis in women are other possible manifestations.
The onset of ReA is usually acute and characterized by malaise, fatigue, and fever. An asymmetrical, predominately lower-extremity, oligoarthritis is the major presenting symptom. Low-back pain occurs in 50% of patients. Heel pain is common because of enthesopathies at the Achilles or plantar aponeurosis insertion on the calcaneus. The complete Reiter triad of urethritis, conjunctivitis, and arthritis may occur.
This figure shows the areas of the body that reactive arthritis might affect.
Enthesitis — The enthesis is the site of insertion of ligaments, tendons, joint capsule, or fascia to bone; enthesitis (or enthesopathy), the term for inflammation around the enthesis, can occur in patients with reactive arthritis and other forms of spondyloarthritis. Swelling at the heels is among the most characteristic symptom of enthesitis. Common sites of heel involvement are at the insertions of the Achilles tendon and of the plantar fascia on the calcaneus. Pain, swelling, and local tenderness are suggestive clinical features.
Clinical Manifestations* of Reactive Arthritis
*--Patients may have one, more than one or all of these manifestations.
The onset is typically acute, with the simultaneous development of urethritis, conjunctivitis (in about 50%) and an inflammatory oligoarthritis affecting the large or small joints of the lower limbs, 1-3 weeks following sexual exposure or an attack of dysentery. There may be considerable systemic disturbance with fever, weight loss and vasomotor changes in the feet.
Often the onset is insidious and many patients present with monoarthritis of a knee or an asymmetrical inflammatory arthritis of some interphalangeal joints. Symptoms and signs of urethritis or conjunctivitis may have been minimal or forgotten. In such patients heel pain, Achilles tendonitis or plantar fasciitis are a valuable clue, while the presence of circinate balanitis or the rash of keratoderma blennorrhagica can establish the diagnosis, even in the absence of the classical triad and without an overt history of sexual promiscuity or dysentery. The skin lesions vary from faint macules, vesicles and pustules on the hands and feet to marked hyperkeratosis with plaque-like lesions spreading to the scalp and trunk. These may be associated with severe nail dystrophy and massive subungual hyperkeratosis. Ocular involvement is usually limited to mild bilateral conjunctivitis which subsides spontaneously within a month. Acute iritis occurs at the outset in 10% of patients. It is distinguished from simple conjunctivitis by injection of the ciliary vessels around the cornea, by a constricted, irregular or unreactive pupil and by cells in the anterior chamber on slit lamp examination. Unlike the conjunctivitis, it requires urgent treatment. Chronic iritis may lead to glaucoma and blindness.
The urethritis is usually associated with minor dysuria and a clear sterile discharge. Sometimes it is asymptomatic and detected only by finding mucoid threads in the first voided specimen of early morning urine. Occasionally there may be severe dysuria, haematuria and suprapubic discomfort from an associated acute haemorrhagic cystitis and prostatitis.
Joints, axial skeleton, enthuses:
The arthritis is usually self-limiting, with spontaneous remission of symptoms within 2-3 months of onset. There is, however, a recurrence rate of about 15% per annum, not necessarily related to further overt exposure to infection. Low back pain and stiffness from sacroiliitis are common and 15-20% of patients develop spondylitis. Wrists, fingers, and other joints are affected less often. People with reactive arthritis commonly develop tendinitis. In many with reactive arthritis, this results in ankle pain or Achilles tendinitis. Some with reactive arthritis also develop heel spurs, which are bony growths in the heel that may cause chronic foot pain. Approximately half of people with reactive arthritis report low-back and buttock pain.
Reactive arthritis also can cause spondylitis or sacroiliitis. People with reactive arthritis who have the HLA-B27 gene are even more likely to develop spondylitis and/or sacroiliitis.
Syndrome now considered consisting of:
4) Mucocutaneous lesions
However, not all patients will exhibit all of these features.
Usually follows infection with Yersina, Salmonella, Campylobacter (gastrointestinal infections) and Chlamydia (genitourinary infection). A heightened immune reaction then occurs to the triggering infection --> increase in IgG/IgA antibodies and an enhanced antigen specific proliferation of synovial fluid lymphocytes.
Skin and nails
· Keratoderma blennorrhagica on the palms and soles is indistinguishable from pustular psoriasis and is highly suggestive of chronic ReA.
· Erythema nodosum may develop but is uncommon.
· Nails can become thickened and crumble, resembling mycotic infection or psoriatic onychodystrophy, but nail pitting is not observed.
· Circinate balanitis may also develop.
· Conjunctivitis is part of the classic triad of Reiter syndrome and can occur before or at the onset of arthritis.
Diagnosis revealed that the rash on the bottom of this individual’s feet, known as keratoderma blennorrhagica, was due to Reiter's syndrome'
Patients with florid Reiter's syndrome can develop scaly and sometimes pustular changes on the hands and feet which resemble severe psoriasis. This is keratoderma blenorrhagica.
· Involved fingers and toes that often swell, causing the so-called "sausage digits."
Swollen "sausage" toe:
· Fingernails and toenails which may become thickened and crumble as if infected by fungus.
· Fever and chills.
· Inflammation of the eye (conjunctivitis, uveitis or iritis) that can cause redness, pain, sensitivity to light and skewed vision.
· Enthesopathy - inflammation where the tendon attaches to the bone.
· Inflammation and pain in the lower back or pelvic area.
· Cystitis, which is an inflammation of the bladder or urinary tract, causing frequent urination and a burning sensation when urinating.
· Genital sores appearing on the shaft of the penis or scrotum, or in women, on the external areas of the genitals. These are usually blisters that break open and crust over. Although they heal without scarring, these blisters can be a source of great anxiety in those with ReA.
Urogenital symptoms may be primary or postdysenteric:
Superficial oral ulcers (30-60%):
The diagnosis of ReA still remains a problem,
because the preceding bacterial infection is often asymptomatic, and
identification of the triggering bacterium is difficult at the time when arthritis occurs. No good criteria for
the diagnosis of ReA are available. Two sets of diagnostic criteria are
currently used, the first established by the
Modified ACR criteria for reactive arthritis
1. Arthritis for longer than 1 month with uveitis or cervicitis
2. Arthritis for longer than 1 month and other urethritis or cervicitis or bilateral
4. Episode of arthritis and conjunctivitis
5. Episode of arthritis of more than 1 month, urethritis, and conjunctivitis
and the second developed atthe Third International Workshop on Reactive Arthritis in 1996 (socalled European criteria):
Third International Workshop diagnostic criteria for reactive arthritis –1996
ü Predominantly lower limb, asymmetric oligoarthritis
ü Evidence of preceding infection
ü Diarrhea or urethritis in the prior 4 weeks
ü No evidence of infection
ü Other causes of monoarthritis or oligoarthritis excluded
According to the ACR criteria for thedefinite diagnosis ofReA, the evidence
of peripheral arthritis with urethritis or cervicitis need to be confirmed, but laboratory confirmation is not necessary. According to the European criteria a typical pattern of clinical presentation of spondyloarthropaties plus the evidence of gastrointestinal or urogenital infection in the preceding 4 weeks must be found. These criteria are not precise and need to be revised. The best diagnostic results are focused on both laboratory and clinical settings. The diagnostic approach to Chlamydia trachomatis‑, Yersinia‑, and Salmonella‑induced ReA has also been worked out.
Documentation of specific bacterial infection:
· Cervical or urethral swab may be performed. Look for Chlamydia in every case of reactive arthritis, preferably by direct florescent antibody, enzyme immunoassay, or DNA probe for ribosomal RNA. Serology is useful in some cases; however, culture techniques are unreliable, causative agents are only indentified in 58% of cases with urogenital symptoms, and there is a high positive rate in control populations (people without reactive arthritis).
· Obtaining stool cultures even when bowel symptoms are in apparent or mild may help direct treatment; however, cultures are often negative by the time of presentation.
· Arthrocentesis and fluid analysis are often needed to rule out an infectious process, especially in monoarticular arthritis with constitutional symptoms. Polymerase chain reaction (PCR) has been used to detect Chlamydia andYersinia antigenic DNA in synovial fluid, but, again, there is a high prevalence in the control population and results have proven highly variable between institutions. Interestingly, using synovial fluid PCR, bacterial antigenic material has been detected in up to 50% of patients previously diagnosed with undifferentiated spondyloarthropathy
· Neutrophilic leukocytosis
· Elevated C-reactive protein or C3 and C4 (nonspecific)
· Erythrocyte sedimentation rate (ESR) - Usually elevated during acute phase of disease
· Antistreptolysin- O (ASO) or anti-DNase B, if poststreptococcal infection is suspected
· HIV and tuberculosis (TB) testing may be warranted, depending on treatment modality. Certain therapies are contraindicated in these populations.
· Echocardiography may reveal carditis or valvular dysfunction in patients with poststreptococcal reactive arthritis.
Plain radiography can find:
· Asymmetric, oligoarticular, and more common in the lower extremities pattern of joint involvement
· Juxta-articular osteoporosis in acute episodes of arthritis - Erosions have indistinct margins and are surrounded by periosteal new bone and periostitis. Examples are shown in the radiographs below.
Lateral radiograph of the foot reveals a calcaneal spur and enthesitis.
Radiograph of both hands shows small erosive changes in both first metacarpal heads associated with minimal subluxation. Bone density is normal.
· Spinal pattern - Unilateral or bilateral sacroiliitis, nonmarginal syndesmophytes, which are asymmetric, paravertebral, bulky, discontinuous, comma-shaped ossifications involving the lower thoracic and upper lumbar vertebrae; these are shown in the radiographs below
Image in 40-year-old man with nonmarginal syndesmophytes predominantly in the lower thoracic and upper lumbar spine.
Ø Test results for rheumatoid factor and antinuclear antibody are negative. (Test results usually are not available during the ED evaluation.)
Ø HLA-B27 may be useful when extra-articular features are not present. The presence of antigen correlates with axial disease, carditis, and uveitis. (Test results usually are not available during the ED evaluation.)
Ø Consider referral for HIV and TB testing in patients presenting with history, symptoms, or findings suggesting increased risk for the disease.
Ø Ultrasonography may reveal enthesitis, as periosteal reaction and tendinosis, more accurately that physical examination.
Ø It has been shown that positron emission tomography scanning allows recognition of enthesitis in the early stage of reactive arthritis, before detection by other modalities.
Ø Synovial fluid: Macrophages with vacuoles filled with nuclear debris and whole leukocytes may be found but are nonspecific.
Ø Synovial biopsy: Nonspecific inflammatory changes; infectious antigens have been found in synovium; immunohistochemistry, polymerase chain reaction, and molecular hybridization may become more useful. (Procedure usually is not performed during the ED evaluation.)
Therapeutic management of ReA
A. Patient education
B. Management of extraarticular manifestations: use of topical corticosteroids, mydriatic agents, cycloplegics
C. Physical therapy
D. Occupational therapy
A. Acute presentation
ü NSAIDs: COX-1 and COX-2 inhibitors
ü Antibiotics: tetracycline, erythromycin, ciprofloxacin
B. Chronic or refractory presentation
ü Second-line or DMARDs: sulfasalazine, methotrexate, cyclosporine, gold salts, leflunomide, 6-mercaptopurine, levamisole, bromocriptine
ü Biological agents: infliximab, etanercept, adalimumab, thalidomide
Treatment of extra-articular manifestations
Cutaneous and mucosal involvement
Carcinate balanitis and psoriatic‑like lesions should be treated with topical steroids and keratolytic agents. More severe skin lesions respond well to methotrexate or retinoids.Carcinate balanitis should be treated for one week with weak steroid in cream, e.g. hydrocortisone. Oral lesions resolve spontaneously and require no treatment.
Eye lesions, especially uveitis, should be managed with ophthalmologic advise.
It is recommended to use topical or intravitreal steroids with mydriatics. Inpatients who are unresponsive to topical therapy systemic corticosteroids should be administrated.
Treatment of arthritis
Nonfarmacological treatment and physiotherapy
Exercises may help improve joint functions, but patients should avoid too much exercises, especially of the infected joints. Physiotherapy and kinesiotherapy are an essential component of the treatment.
Non‑steroidal anti‑inflammatory drugs (NSAIDs) usually provide effective
relief of pain (particularly at nights) and morning stiffness. They should be used early, at full doses. The individual response to the different NSAIDs varies, and no individual NSAIDs is recommended.
Corticosteroids. The systemic use of corticosteroids is not indicated, except for short courses (no more than 2–4 months) incase of severe unresponsive peripheral joint symptoms or progressive atrioventricular conduction abnormalities. In many cases those of intra‑articular steroid injections (septic arthritis must be excluded before) gives prompt relief, but it should be limited to one joint at every one visit.
Disease modifying antirheumatic drugs (DMARDs). Only 25% of patients respond to NSAIDs therapy. Second‑line therapy with DMARDs should be considered for those patients who demonstrate persistent symptoms (more than 3 months), and who have not responded completely to NSAIDs. Sulfasalazine therapy (2 g/day) is effective in treating ReA even for patients with 10 years of disease duration. Sulfasalazine is effective mainly in peripheral disease and has little or no effect on spinal disease. Methotrexate can be used with good effects, also in patients with spinal involvement. It may prevent radiological progression ofperipheral‑, and spinal‑joint destruction. Azathioprine is effective in treating peripheral arthritis when given at a dose of 1 to 2 mg/kg. The efficacy of other
DMARDs has not been confirmed in controlled clinical trials.
Anti‑TNF α therapy in ReA remains controversial, and clinical practice is based on a small series of cases. In persistent infection there is also a concern about reactivation of the triggering infection in patients with ReA.
Antibiotics Antibiotic treatment is indicated only if the infection is well established, and mainly for those with Chlamydia infection. However, some studies of small group of patients showed the benefit of using ciprofloxacin in ReA triggered by different kinds of bacteria. A double‑blind study with ciprofloxacin (500mg twice a day for 3 months) in chronic ReA showed a favorable effect on the duration of the arthritis and decreasing morning stiffness during a 6‑month follow‑up.
1. Davidson’s Principles and practice of medicine (21st revised ed.) / by Colledge N.R., Walker B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.
3. Merck Manual of Diagnosis and Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 2011.
4. Web -sites:
B - Additional:
1. Clinical Rheumatology (The Clinical Medicine Series) 12 edition/ Pacific Primary Care Software PC/ M.D., C. G. Weber.- 2011.- 526 p.
2. Kelley's Textbook of Rheumatology, 9th Revised edition / Firestein, Gary S.; Budd, Ralph C.; Gabriel, Sherine E.; O'Dell, James R.; McInnes, Iain B.-2012.- 2292 p.
3. Rheumatoid Arthritis/ Smolen, Josef S.; Kalden, Joachim R.; Maini, Ravinder N. -2012. - 424 p.