Pathophysiology of Arthritis

Pathophysiology


Joint abnormalities in rheumatoid arthritis
Rheumatoid arthritis is an auotimmune disease, the cause for which is still unknown. It is a systemic (whole body) disorder principally affecting synovial joints.
Chemical mediators (Cytokines) give rise to inflammation of joint synovium. Constitutional symptoms such as fever, malaise, loss of appetite and weight loss are also due to cytokines released in to the blood stream. Blood vessel inflammation (vasculitis) affecting many other organ systems can give rise to systemic complications.
As with most autoimmune disease, it is important to distinguish between the cause(s) that trigger the inflammatory process, and those that permit it to persist and progress.
It has long been suspected that certain infections could be triggers for this disease. The "mistaken identity" theory suggests that an infection triggers an immune response, leaving behind antibodies that should be specific to that organism. The antibodies are not sufficiently specific, though, and set off an immune attack against part of the host. Because the normal host molecule "looks like" a molecule on the offending organism that triggered the initial immune reaction - this phenomenon is called molecular mimicry. Some infectious organisms suspected of triggering rheumatoid arthritis include Mycoplasma, Erysipelothrix, parvovirus B19 and rubella, but these associations have never been supported in epidemiological studies. Nor has convincing evidence been presented for other types of triggers such as food allergies. There is also no clear evidence that physical and emotional effects, stress and improper diet could be a trigger for the disease. The many negative findings suggest that either the trigger varies, or that it might in fact be a chance event, as suggested by Edwards et al [12].
Epidemiological studies have confirmed a potential association between RA and two herpesvirus infections: Epstein-Barr virus (EBV) and Human Herpes Virus 6 (HHV-6). [13] Individuals with RA are more likely to exhibit an abnormal immune response to the Epstein-Barr virus. [14] [15] The allele HLA-DRB1*0404 is associated with low frequencies of T cells specific for the EBV glycoprotein 110 and predisposes one to develop RA. [16]
The factors that allow the inflammation, once initiated, to become permanent and chronic, are much more clearly understood. The genetic association with HLA-DR4 is believed to play a major role in this, as well as the newly discovered associations with the gene PTPN22 and with two additional genes [17], all involved in regulating immune responses. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for rheumatoid arthritis, namely cigarette smoking [18] Other environmental factors also appear to modulate the risk of acquiring RA, and hormonal factors in the individual may explain some features of the disease, such as the higher occurrence in women, the not-infrequent onset after child-birth, and the (slight) modulation of disease risk by hormonal medications.
Autoimmune diseases require that the affected individual have a defect in the ability to distinguish foreign molecules from the body's own. There are markers on many cells that confer this self-identifying feature. However, some classes of markers allow for RA to happen. 90% of individuals with RA have the cluster of markers known as the HLA-DR4/DR1 cluster, whereas only 40% of unaffected controls do. Thus, in theory, RA requires susceptibility to the disease through genetic endowment with specific markers and an infectious event that triggers an autoimmune response.
Once triggered, B lymphocytes produce immunoglobins, and rheumatoid factors of the IgG and IgM classes that are deposited in the tissue, this subsequently leads to the activation of the serum complement cascade and the recruitment of the phagocytic arm of the immune response, which further exacerbates the inflammation of the synovium, leading to edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Early and intermediate molecular mediators of inflammation include tumor necrosis factor alpha (TNF-α), interleukins IL-1, IL-6, IL-8 and IL-15, transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor. Synovial macrophages and dendritic cells further function as antigen presenting cells by expressing MHC class II molecules, leading to an established local immune reaction in the tissue. The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining (pannus) with extensive angiogenesis and production of enzymes that cause tissue damage. Modern pharmacological treatments of RA target these mediators. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.
Pathophysiology
RA is a chronic, progressive, and disabling disease. Despite intensive research, the cause of RA remains unknown. The pathogenesis of this disease is likely multifactorial, involving autoimmunity and genetic factors; infectious agents also are suspected of having a role. Further details are provided below.
Genetic factors: Family studies reveal that RA has a genetic component; human leukocyte antigen (HLA) is an important genetic factor, and the risk for RA is thought to be associated with a sequence of amino acids within the genetic code of certain individuals.
Autoimmunity: Macrophage-derived cytokines appear to be involved in the induction and perpetuation of the chronic inflammatory processes of the joints seen in RA. High titers of serum rheumatoid factors, or autoantibodies to the Fc portion of the immunoglobulin G (IgG) molecules, are associated with more severe joint disease and with extra-articular manifestations.
Infectious agents: Viral infections such as rubella, Ross River virus, and parvovirus are associated with the development of acute polyarthritis; Chlamydia pneumoniae has been detected in some individuals with RA. However, cause or connection has not been demonstrated(1).
Although the precise mechanism of bone and cartilage destruction in RA is not completely understood, the cytokines IL-1 and TNF-alpha play an important role. These cytokines:
Are abundant in inflamed joints and promote the influx of inflammatory neutrophils and monocytes into the joints
Stimulate cells in the inflamed synovium to produce proteolytic enzymes, including collagenase and stromelysin, that can degrade tissue
Cause systemic manifestations such as malaise and fatigue
Thus, although the initial cause of RA remains unknown, the maintenance and propagation of the disease appear to be related to immunologically mediated inflammatory processes. Hence, interfering with key steps in the inflammatory process would be expected to provide symptomatic relief and to slow disease progression.
Signs and symptoms
Signs and symptoms
While rheumatoid arthritis primarily affects joints, problems involving all other organs of the body are known to occur. Extra-articular ("outside the joints") manifestations occur in about 15% of individuals with rheumatoid arthritis.[3] It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications commonly used to treat it - for example, lung fibrosis from methotrexate, or osteoporosis from corticosteroids.
[edit] Joints
The arthritis of rheumatoid arthritis is due to synovitis, which is inflammation of the synovial membrane that covers the joint. Joints become red, swollen, tender and warm, and stiffness prevents their use. By definition, RA 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. Eventually, synovitis leads to erosion of the joint surface, causing deformity and loss of function.[1]
Inflammation in the joints manifests itself as a soft, "doughy" swelling, causing pain and tenderness to palpation and movement, a sensation of localised warmth, and restricted movement. Increased stiffness upon waking is often a prominent feature and may last for more than an hour. These signs help distinguish rheumatoid from non-inflammatory diseases of the joints such as osteoarthritis (sometimes referred to as the "wear-and-tear" of the joints). In RA, the joints are usually affected in a fairly symmetrical fashion although the initial presentation may be asymmetrical.


Hands affected by RA
As the pathology progresses the inflammatory activity leads to erosion and destruction of the joint surface, which impairs their range of movement and leads to deformity. The fingers are typically deviated towards the little finger (ulnar deviation) and can assume unnatural shapes. Common deformities in rheumatoid arthritis are the Boutonniere deformity (Hyperflexion at the proximal interphalangeal joint with hyperextension at the distal interphalangeal joint), swan neck deformity (Hyperextension at the proximal interphalangeal joint, hyperflexion at the distal interphalangeal joint). The thumb may develop a "Z-Thumb" deformity with fixed flexion and subluxation at the metacarpophalangeal joint, and hyperextension at the IP joint.
[edit] Skin
The rheumatoid nodule is the cutaneous (strictly speaking subcutaneous) feature most characteristic of rheumatoid arthritis. The initial pathologic process in nodule formation is unknown but is thought to be related to small-vessel inflammation. The mature lesion is defined by an area of central necrosis surrounded by palisading macrophages and fibroblasts and a cuff of cellular connective tissue and chronic inflammatory cells. 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 titer and severe erosive arthritis. Rarely, they can occur in internal organs.
Several forms of vasculitis are also cutaneous manifestations associated with 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. (This rash is also otherwise associated with the antiphospholipid-antibody syndrome, a hypercoagulable state linked to antiphospholipid antibodies and characterized by recurrent vascular thrombosis and second trimester miscarriages.)
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).
[edit] 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.
[edit] Kidneys
Renal amyloidosis can occur as a consequence of chronic inflammation. [4] Rheumatoid vasculitis is a rare cause of glomerular disease in the kidney. Treatment with Penicillamine and gold salts are recognized causes of membranous nephropathy.
[edit] Heart and blood vessels
Possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis. The risk of cardiovascular, specifically myocardial infarction (heart attack) or congestive heart failure are greater in individuals with RA. Over 1/3 of deaths of people with RA are directly attributable to cardiovascular death.
[edit] Other
Ocular
Keratoconjunctivitis sicca (dry eyes), scleritis, episcleritis and scleromalacia.
Gastrointestinal and Hematological
Felty syndrome, anemia
Neurological
Peripheral neuropathy and mononeuritis multiplex may occur. The most common problem is carpal tunnel syndrome due to compression of the median nerve by swelling around the wrist. Atlanto-axial subluxation can occur, owing to erosion of the odontoid process and or/transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. Clumisiness is initially experienced, but without due care this can progress to quadriplegia.
Vasculitis
Vasculitis in rheumatoid arthritis is common. It typically presents as vasculitic nailfold infarcts.
Osteoporosis
Osteoporosis classically occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines.
Lymphoma
The incidence of lymphoma is increased in RA as it is in most autoimmune conditions.



Histopatho

There are two popular theories regarding the pathogenesis of rheumatoid arthritis (RA). The first holds that the T cell, through interaction with an - as yet unidentified - antigen, is the primary cell responsible for initiating the disease as well as for driving the chronic inflammatory process. This theory is based upon the known association of RA with class II major histocompatability antigens, the large number of CD4+ T cells and skewed T cell receptor gene usage in the RA synovium. The second theory holds that, while T cells may be important in initiating the disease, chronic inflammation is self-perpetuated by macrophages and fibroblasts in a T-cell independent manner. This theory is based upon the relative absence of activated T cells phenotypes in chronic RA and the preponderance of activated macrophage and fibroblast phenotypesSynovium The synovium, in normal joints, is a thin delicate lining that serves several important functions.
The synovium serves as an important source of nutrients for cartilage since cartilage itself is avascular. In addition, synovial cells synthesize joint lubricants such as hyaluronic acid, as well as collagens and fibronectin that constitute the structural framework of the synovial interstitium.
1. Synovial lining or intimal layer: Normally, this layer is only 1-3 cells thick.
normal synovial lining
In RA, this lining is greatly hypertrophied (8-10 cells thick). Primary cell populations in this layer are fibroblasts and macrophages.
2. Subintimal area of synovium: This is where the synovial blood vessels are located; this area normally has very few cells. In RA, however, the subintimal area is heavily infiltrated with inflammatory cells, including T and B lymphocytes, macrophages and mast cells. The intense cellular infiltrate is accompanied by new blood vessel growth (angiogenesis).
In RA, the hypertrophied synovium (also called pannus) invades and erodes contiguous bone and cartilage. As such, it can be thought of as a tumor-like tissue, although mitotic figures are rare and, of course, metastasis does not occur.
1. CartilageComposed primarily of type II collagen and proteoglycans, this is normally a very resilient tissue that absorbs considerable impact and stress. In RA, its integrity, resilience and water content are all impaired. This appears to be due to elaboration of proteolytic enzymes (collagenase, stromelysin) both by synovial lining cells and by chondrocytes themselves. Polymorphonuclear leukocytes in the synovial fluid may also contribute to this degradative processBoneComposed primarily of type I collagen, invading synovium causes erosion of contiguous bone via release of prostaglandins and proteases by synovial cells and, possibly, by osteoclastsSynovial Cavity Synovial Cavity Normally only a "potential" space with 1-2ml of highly viscous (due to hyaluronic acid) fluid with few cells. In RA, large collections of fluid ("effusions") occur which are, in effect, filtrates of plasma (and, therefore, exudative - i.e., high protein content). The synovial fluid is highly inflammatory. However, unlike the rheumatoid synovial tissue that is infiltrated with lymphocytes and macrophages but not neutrophils, the predominant cell in the synovial fluid is the neutrophil
2. Pathophysiology: Order of changes
1. Synovial Macrophage and fibroblast activation
2. Cytokine production (interleukin, TNF)
3. Lymphoctes infiltrate perivascular areas
4. Synovial thickening (Pannus formation and spread)
5. Neovascularization
6. Local micro-Vasculitis
7. Chondrocyte, Osteoclast, CD4+ Helper activity
8. Endothelial proliferation
9. Joint space narrowing
10. Cytokine release (resulting in fever, Anemia)