Rheumatoid Arthritis?

Rheumatoid arthritis (RA); is an autoimmune disease where the body attacks itself, causing chronic joint inflammation. While it primarily affects joints, it can also cause inflammation oforgans as the disease progresses. People with RA may experience an increase in symptoms –called flares – that can last for days or weeks. They may also have periods of remission where they have few or no symptoms. There is no cure for rheumatoid arthritis, but medications can slow the progression of the disease and ease symptoms

RA affects

between 0.5 and 1% of adults in the developed world with between 5 and 50 per 100,000 people newly developing the condition each year. Onset is most frequent during middle age, but people of

any age can be affected .Constitutional symptoms

Constitutional symptoms including fatigue, low grade fever, malaise, morning stiffness, loss of appetite and loss of weight are common systemic manifestations seen in peoplewith active RA

Arthritis of joints involves inflammation of the synovial membrane. Joints become swollen, tender and warm and stiffness limits their movement. With time, multiple joints are affected almost any deformity depending on which joints are although this is not specific, and the initial presentation and leads to deformity. The fingers may suffer from as arthritis mutilans due to the mutilating nature of the as nociceptive as opposed to neuropathic. as osteoarthritis or “wear-and-tear” arthritis. In arthritis As the pathology progresses the inflammatory activity

caused by mechanical arthritis. flares

an increase in symptoms– that can last for days or weeks. They may also have periods of remission

where they have few or no symptoms.

Synovitis can lead to leads to tendon tethering and erosion

and destruction may be asymmetrical signs of inflammation

of the joint surface, which impairs range of movement of the metacarpophalangeal joint and gives a “Z” appearance or “Z-deformity” consists of hyperextension of particularly early in the morning on waking or following problems of the joints, often referred to prolonged inactivity. Increased stiffness early in the RA typically manifests with signs of inflammation, with tethering of tissue with loss of movement and erosion of the affected joints being swollen, warm, painful and stiff, the interphalangeal

joint, fixed flexion and subluxation.

Causes

There is no evidence that physical and emotional effects or stress could be a trigger for the disease. The many negative findings suggest that either the trigger varies, half of the risk for RA is believed to be genetic. It is strongly associated with the inherited tissue type major

histocompatibility complex (MHC) antigen HLA-DRB1i) genetic ; most specifically the shared epitopealleles, including

(*0401 AND*0404,) and the genes PTPN22 and PADI4 hence family history is an important risk factor.Inheriting the PTPN22 gene has been shown to double

a person’s susceptibility to RA . PADI4 has beenidentified as a major risk factor in people of Asian descent, but not in those of European descent. First-degree relatives prevalence rate is 2–3% (in monozygotic twins is approximately

15–20%).ii)Smoking is the most significant non-genetic risk with RA being up to three times more common in smokers than non-smokers, particularly in men,heavy smokers, and those who are rheumatoid

factor positive. Modest alcohol consumption may

be protective iii)Epidemiological studies have confirmed a potential association between RA and two herpesvirus infection Epstein-Barr virus (EBV) and Human Herpes Virus 6 ,Individuals

iiii) Vitamin D deficiency is more common in people with rheumatoid arthritis than in the general population However, whether vitamin D deficiency is a cause or aconsequence of the disease

Pathophysiology

RA primarily starts as a state of persistent cellular activation leading to autoimmunity and immune complexes in both joints and other, organswhere it manifests. The initial site of disease is the synovial membrane, where swelling and congestion leads to infiltration by immune cells.

The various phases of progression of RA are: Initiation phase, due to non-specific

inflammation._Amplification phase, due to T cell activation_

Chronic inflammatory phase with tissue injury,

due_

to cytokines IL–1, TNF-alpha and IL–6

.Synovial pannus formation

is a characteristic of RA pathology and is caused

by several processes :

(i )the proliferation of resident fibroblast-like synovial cells and synoviocytes; (ii) angiogenesis; (iii) infiltration of macrophages and lymphocytes; and (iv) migration ofpolymorphonuclear cells to the synovial tissue.It has been known for more than 20 yr that cell–cell interactions between synoviocytes, lymphocytes and monocytes lead to production of large amount of collegenase

IL-1 and TNFα play an importantpart in this process and act on endothelial cells, synoviocytes, chondrocytes, or bone-derived cells to produce collagenase, other cytokines (e.g. IL-6), chemokines (e.g. IL-8), or numerous prostanoids

[e.g. prostaglandin E 2 PGE 2 )]] .IL-1—previously referred to by several different

names ,including endogenous pyrogen, lymphocyte-activating factor, mononuclear cell factor and catabolin—exerts many systemic effects on tissuessuch as the brain, liver and muscle. IL-1 is produced by cells in the joint including chondrocytes and bone-lining cells—in-depth immunohistochemistry and in situ hybridization studies have revealed that IL-1 is localized to the synovial pannus in RA, which is in close proximity to cartilage and bone

.At a local level, relatively low concentrations of IL-1 have extraordinary potential to induce cartilage destruction and bone resorption. When equivalent molar

concentrations of IL-1 and TNFα have been

compared,**IL-1 has been found to be more potent at

inducing the production of the tissue-destructiveenzymes known as (matrix metalloproteinases (MMPs) ,It is widely accepted that macrophages are the principle cells producing the prodestructive cytokines IL-1 and TNFα. It is less clear which primary factors control the production of IL-1 and TNFα by

macrophages. At least two major pathways exist:i) the cytokine-dependent pathway—induction of cytokine release by T- or B-lymphocytes, mast cells, or soluble factors (e.g. immune complexes or other cytokines such as TNF) and

(ii)the cytokine-independent pathway by direct contact between the macrophage and activated T-lymphocytes, contact with denatured proteins fromthe matrix and hormonal influences

Two major and separate disease processes are

characteristic of RA :( i ) inflammation and pain and

ii) tissue destruction and lack of tissue repair .

.Cartilage Damage

A hyperplastic synovium is the major contributor to cartilage damage in rheumatoid arthritis. Lossof the normally protective effects of synovium (e.g., reduced expression of lubricin)69 alter the protein-binding characteristics of the cartilage surface, promoting FLS adhesion and invasion. FLS synthesis of MMPs (particularly MMP-1, 3, 8, 13, 14, and 16) promotes disassemblyof the type II collagen network, a process that alters glycosaminoglycan content and water retention and leads directly to biomechanical dysfunction. MMP-14 appears to be the predominant

MMP expressed by FLSs to degrade the collagenous cartilage matrix.70 Other matrix enzymes (e.g., ADAMTS 5) degrade aggrecan and thus further

diminish cartilage integrity..Endogenous enzyme inhibitors, such as TIMPs, failto reverse this destructive cascade. Moreover, articular cartilage itself has limited regenerative potential. Chondrocytes physiologically regulate matrix formation and cleavage: under the influence of synovial cytokines (particularly interleukin-1 and 17A) and reactive nitrogen intermediates, cartilage isprogressively deprived of chondrocytes, which undergo apoptosis. These processes ultimately lead to the destruction of the surface cartilage and the radiographic appearance of joint-space

narrowing.Bone Erosion

Bone erosion occurs rapidly (affecting 80% of patients within 1 year after diagnosis71) and is associated with prolonged, increased inflammation. Synovial cytokines, particularly macrophage colony-stimulating factor and receptoractivator of NF-κB ligand (RANKL), promote osteoclast differentiation and invasion of the periosteal surface adjacent to articular cartilage.TNF-α and interleukin-1, 6, and

potentially amplify osteoclast differentiation

and activation.Moreover, clinical inhibition of TNF-α, interleukin-6, and RANKL retards erosion in rheumatoid arthritis. Notably, blockade of RANKL acts only on bone, with no effect on inflammationor cartilage degradation. Osteoclasts have the acidic enzymatic machinery necessary to destroy mineralized tissues, including mineralized cartilage and subchondral bone; destruction of these tissues leads to deep resorption pits,

which are filled by inflammatory tissue..SYSTEMIC CONSEQUENCES OF RHEUMATOID ARTHRITIS

Rheumatoid arthritis is associated with increasedrates of cardiovascular illness (standardized mortality rate, approximately 1.5), including myocardial infarction, cerebrovascular events, and heart

failure.Traditional risk factors ,

use of glucocorticoids or nonsteroidal antiinflammatory drugs, or shared genetic features. Circulating inflammatory pathways that are implicated include cytokines (interleukin-6 and TNF-α), acute-phase reactants, immune complexes, and altered lipid particles (e.g., serum amyloid A–rich HDL) that increase

endothelial activation and potentially render

atheromatous plaques unstable. Increased levels of acute-phase reactants are an

independent cardiovascular risk factor in the general population. Cytokines also make muscle and adipose tissues insulin-resistant, resulting in an “inflammatory metabolic” syndrome. Moreover, vascular risk is increased early in thecourse of rheumatoid arthritis, perhaps reflecting subclinical inflammation in the

prearticular phase.

Lipid biochemical features are intimately, and reciprocally, linked to inflammation to ensure metabolically efficient host defense. In consequence, active rheumatoid arthritis is associated with reduced serum levels of total, HDL, and LDL cholesterol, which may then be paradoxically elevated by effective therapy.91 Nevertheless, effective therapeutics decrease cardiovascular risk and favorably modify vascularphysiology. Statin drugs also reduce surrogates of vascular risk and inflammatory factors in

patients with rheumatoid arthritis Inflammation in rheumatoid arthritis also affectsthe brain (fatigue and reduced cognitive function), liver (elevated acute-phase response and anemia of chronic disease), lungs (inflammatory and fibrotic disease), exocrine glands (secondary Sjögren's syndrome), muscles (sarcopenia), and bones (osteoporosis). Osteoporosis affects the axial and appendicular skeleton, with only a modest elevation of the acute-phase response or subclinical inflammation,and probably occurs before the onset of articulardisease.96-98 Effective antiinflammatory treatment retards bone loss and suppresses the high rate of systemic bone resorption, as measured with the use of bone-turnover

biomarkers..

The risk of lymphoma is increased among patients with rheumatoid arthritis99 and is strongly associated with inflammatory disease activity; sustained disease activity confers the highest risk.100 Clonal selection of B cells, disturbed immune surveillance due to impaired activity of regulatory T cells, and impaired function of

natural killer cells are postulated mechanisms.

.The higher rates of lung cancer among patients with rheumatoid arthritis than among other persons may be explained in part by the association between smoking and rheumatoid arthritis. However, inflammation increases the risk of lung cancer independently of smoking, perhaps because of the long-known extraarticular effects of rheumatoid arthritis on fibrotic

remodeling of interstitial lung tissue.

Juvenile rheumatoid arthritis#

Juvenile rheumatoid arthritis (JRA) is a term used to describe a common type of arthritis in children. It is a long-term (chronic) disease

resulting in joint pain and swelling.Alternative Names:Juvenile chronic polyarthritis; JRA; Still's disease; Juvenile idiopathic arthritis

It is thought to be an autoimmune illness. This means the body attacks and destroys healthy body

tissue by mistake.#JRA most often develops before age 16. Symptoms

may start as early as 6 months old.There are several types of JRA:

i)Systemic (bodywide) JRA involves joint swelling or pain, fevers, and rash. It is the least common

type.ii)Polyarticular JRA involves many joints. This form of JRA may turn into rheumatoid arthritis. It may

involve five or more large and small joints of

the legs and arms, as well as the jaw and neck.iii)Pauciarticular JRA involves four or less joints, most often the wrists, or knees. It also affects

the eyes.Symptoms of JRA may include:Swollen, red, or warm joint, Limping or problems using a limb

Sudden high fever,Rash (on trunk and extremities)that comes and goes with fever

Stiffness, pain, and limited movement in a joint ,Bodywide symptoms such as pale skin, swollen lymph gland, and “sick” appearance

Diagnosis X-rays and ultrasound images

.of the hands and feet are generally performed in people with a many joints affected. In RA, there may be no changes in the early stages of the disease, or the x ray may demonstrate juxta-articular osteopenia, soft tissue swelling and loss of joint space. As the disease advances, there may be bony erosions and subluxation. Xraysof other joints may be taken if symptoms of pain or swelling occur in those joints.Other medical imaging techniques such as magnetic resonance imaging (MRI) and ultrasound are also used. Therehave been technical advances in ultrasonography

Blood tests

When RA is clinically suspected, testing for the presence of rheumatoid factor (RF, a non-specific

antibody) and(ACPAs) may be required .During the first year of illness, rheumatoid factor is more likely to be negative with some

individuals converting to seropositive status over time the healthy population

Citrulline Antibody Test

Blood tests are usually run to help make a diagnosis of rheumatoid arthritis. These tests check for certain antibodies including anti-cyclic citrullinated peptide antibodies (ACPA), rheumatoid factor (RF), and antinuclear antibodies (ANA), which are present in a majority

of RA patients.Rheumatoid factor (RF) is present in about 75% to80% of RA patients, and a high RF may indicate a more aggressive for of the disease. An advantage of anti-cyclic citrullinated peptide antibody (ACPA) tests is that they can often detect the disease earlier on, and the sooner treatment begins the better patients can manage the disease. The presence of antinuclear antibodies (ANA) is not a definitive diagnosis for RA, but their presence can indicate the doctor that an

autoimmune disorder may be present.

Sedimentation Rate (Sed Rate)

Other blood tests that may be run can help the doctor determine the extent of the inflammation in the joints and elsewhere in the body. The erythrocyte sedimentation rate (ESR, or "sed rate") measures how quickly red blood cells fall to the bottom of a test tube. Usually, the higherthe sed rate, the more inflammation there is in

the body..Another blood test that measures inflammation is the C-reactive protein (CRP) test. If the CRP is high, inflammation levels are usually high as

well, such as during a flare.RA Diagnostic Test: Arthrocentesis

A joint aspiration procedure (arthrocentesis) maybe performed to obtain joint fluid to test in thelaboratory. A sterile needle and syringe drain fluid from the joint, which is then analyzed to detect causes of joint swelling such as arthritis. Removing this joint fluid can also

help relieve joint pain. In some cases, cortisonemay be injected into the joint during the aspiration procedure for more immediate pain

relief..Management

There is no cure for RA, but treatments can improve symptoms and slow the progress of the disease. Diseasemodifying treatment has the best

results when it is started early and aggressively The goals of treatment are to minimize symptoms such as pain and swelling, to prevent bone deformity (for example, bone erosions visible in X-rays), and to maintain day-to-day functioning. This can often be achieved using two main classesof medications: analgesics such as NSAIDs, and

disease-modifying antirheumatic drugs (DMARDs).RA should generally be treated with least one specific anti-rheumatic medication. The use of benzodiazepines (such as diazepam) to treat the pain is not recommended as it does not appear to help and is associated with risks.[ Analgesics, other than NSAIDs, offer lesser, but some benefitwith respect to pain while is not causing the

same level of gastrointestinal irritation]]Disease modifying agents

Disease-modifying antirheumatic drugs (DMARD) arethe primary treatment for RA. They are a diverse collection of drugs, grouped by use and convention They have been found to improve symptoms, decrease joint damage, and improve overall functional abilities. DMARDs should be started early in the disease as they result in disease remission in approximately half of peopleand improved outcomes overall. The following drugs are considered as DMARDs: methotrexate ,hydroxychloroquine, sulfasalazine, leflunomide, TNFalpha inhibitors, abatacept, and anakinra. Rituximab and tocilizumab are monoclonal antibodies and are also DMARDs

Methotrexate is the most important and useful DMARD

and is usually the first treatment ,,Adverse effects should be monitored regularly with toxicity including gastrointestinal hematologic, pulmonary, and hepatic,Side effects such as nausea, vomiting or abdominal pain can be reducedby taking folic acid. The most common undesirableeffect is that it increases liver enzymes in almost 15% of people. It is thus recommended thatthose who consistently demonstrate abnormal levels of liver enzymes or have a history of liver disease or alcohol use undergo liver

biopsies

Biological agents should generally only be used if methotrexate andother conventional agents are not effective aftera trial of three months. These agents used to treat rheumatoid arthritis include: tumor necrosis factor alpha (TNFα) blockers such

asinfliximab ; interleukin 1 blockers such as anakinra, monoclonal antibodies against B cells such as rituximab and tocilizumab, T cell costimulation blocker such as abatacept among others.They are often used in combination with either methotrexate or leflunomide. In those who are well controlled on TNF blockers decreasing the

dose does not appear to affect overall function. Persons should be screened for latent

tuberculosis before starting any TNF blockers therapy to avoid reactivation. TNF blockers and methotrexate appear to have similar effectivenesswhen used alone and better results are obtained when used together. TNF blockers appear to have equivalent effectiveness with etanercept appearing to be the safest

Abatacept appears effective for RA with 20% more people improving with treatment than without but long term safety studies are yet unavailable. There however is a lack of evidence to distinguish between the biologics available for

RA. Issues with the biologics include their high cost and association with infections including tuberculosis

Anti-inflammatory agents

NSAIDs reduce both pain and stiffness in those with RA. Generally they appear to have no effect on people’s long term disease course and thus areno longer first line agents. NSAIDs should be used with caution in those with gastrointestinal,cardiovascular, or kidney problems Use of methotrexate together with NSAIDS is safe , if adequate monitoring is done COX-2 inhibitors, such as celecoxib, and NSAIDs are equally effective.[84] They have a similar gastrointestinal l risk as an NSAIDs plus a proton pump inhibitor. In the elderly there is less gastrointestinal intolerance to celecoxib than to NSAIDs alone, There however an increased risk of myocardial infarction with COX inhibitors. Anti-ulcer medications are not recommended routinely but only in those with high

risk of gastrointestinal problems..Glucocorticoids

can be used in the short term for flareups , while waiting for slow-onset, drugs to take effect.Injection ofglucocorticoids into individual joints is also effective. While long-term use reduces joint damage it also results in osteoporosis and

susceptibility to infections wich is not

recommended.Other Treatments for Rheumatoid Arthritis

While there is no special diet people with rheumatoid arthritis should follow, eating a healthy, balanced diet is always recommended, and

some foods may help ease inflammation..Omega-3 fatty acids found in fish oil may offer anti-inflammatory benefits, so fish such as herring, mackerel, trout, salmon, and tuna may bea part of a healthy diet. If you choose to take fish oil supplements, check with your doctor for

the proper dosage..Extra fiber from fruits, vegetables, and whole grains can result in a lower C-reactive protein (CRP) in the blood. High levels of CRP indicate

inflammation..Many people with RA have low levels of the mineral selenium. This can be found in whole-grain wheat products and shellfish. Consult your doctor before taking selenium supplements for theproper dosage as it can increase your risk for

developing diabetes..

Vitamin D may help lower the risk for RA in women. Eggs, fortified breads and cereals, and low-fat milk contain Vitamin D While some foods can ease inflammation, others may trigger it. Fried foods, grilled meats, margarine, egg yolks,and certain oils may contribute to inflammation and should be eaten in moderation or avoided if

possible.Lifestyle Regular exercise is recommended as bothsafe and useful to maintain muscles strength and overall physical function.It is uncertain if specific dietary measures have an effect. Physical activity is beneficial for persons with

Rheumatoid arthritis complaining of fatigue .

Surgery In early phases of the disease, an arthroscopic or open synovectomy may be performed. It consists of the removal of the inflamed synovia and prevents a quick destructionof the affected joints. Severely affected joints may require joint replacement surgery, such as

kneereplacement. Postoperatively, physiotherapy

is always necessary.

Pregnancy.Methotrexate and leflunomide are teratogenic(harmful to foetus) and not used in pregnancy.It is recommended women of childbearingage should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned. Low dose of prednisolone hydroxychloroquine and sulfasalazine are considered safe in pregnant persons with RA