Symptoms

Signs and symptoms of rheumatism may include:

• Tender

• Warm and swollen joints

• Joint stiffness that's usually worse within the mornings and after inactivity

• Fatigue, fever and loss of appetite

Early rheumatism tends to affect your smaller joints first particularly the joints that attach your fingers to your hands and your toes to your feet. As the disease progresses, symptoms often spread to the wrists, knees, ankles, elbows, hips and shoulders. In most cases, symptoms occur within the same joints on either side of your body [1,2].

About 40% of individuals who have arthritis also experience signs and symptoms that do not involve the joints. Areas which will be affected include [3]:

• Skin

• Eyes

• Lungs

• Heart

• Kidneys

• Salivary glands

• Nerve tissue

• Bone marrow

• Blood vessels

Rheumatoid arthritis signs and symptoms may vary in severity and should even come and go. Periods of increased disease activity, called flares, alternate with periods of relative remission when the swelling and pain fade or disappear. Over time, atrophic arthritis can cause joints to deform and shift out of place [4].

Causes

Rheumatoid arthritis is a disease. Normally, your system helps protect your body from infection and disease. In rheumatism, your system attacks healthy tissue in your joints. It also can cause medical problems along with your heart, lungs, nerves, eyes and skin. Doctors do not know what starts this process, although a genetic component appears likely. While your genes don't actually cause autoimmune disease, they'll cause you to more likely to react to environmental factors like infection with certain viruses and bacteria which will trigger the disease [5].

Risk Factors

Factors that will increase your risk of rheumatism include:

• Your Sex: Women are more likely than men to develop autoimmune disorder

• Age: Autoimmune disorder can occur at any age, but it most ordinarily begins in time of life

• Family History: If a member of your family has arthritis, you will have an increased risk of the disease

• Smoking: Cigarette smoking increases your risk of developing atrophic arthritis, particularly if you've got a genetic predisposition for developing the disease. Smoking also appears to be related to greater disease severity

• Excess Weight: Those who are overweight appear to be at a somewhat higher risk of developing rheumatism

Pathogenesis of Arthritis

Pathogenesis of RA evoke cytokines that control a large type of inflammatory process in rheumatoid joints, where the imbalance between pro and anti-inflammatory cytokine activities induces autoimmunity and chronic inflammation causing joint damage (Figure 1). T cells proliferate as a cascade of system release activates B cells and macrophages, thereby inducing cytokines like TNF-α and IL-6. The inflammatory response invoked thanks to the onset of RA ends up in joint destruction and extra-articular complications causing infections, lymphomas, disorder and osteoporosis which will last over a period of time [6].

Figure 1: Compaarison between (A) Normal and (B) Rheumatoid Arthritis Joints

Cytokines play a significant role thanks to its destructive effects on bones and articular cartilage, which offer the rationale for current RA treatment including the usage of monoclonal antibodies against TNF-α, IL-1β, and IL-6. As a proinflammatory cytokine, TNF-α regulates inflammatory responses during RA conditions. Although no treatment can promise complete recovery of RA, it can address problems referring to joint pain, inflammation and also the damage caused to articular structures (Figure 2).

Management of arthritic condition involves an interdisciplinary approach that involves physiotherapy modalities related to medical management. During the past 10 years there are major advances within the treatment of RA, starting from the aggressive use of disease modifying anti-rheumatic drugs to immune therapies targeting cells specific to RA immunopathogenesis (Figure 3).

NSAIDs, COX-2, and Rheumatism

Historically considered a first-line treatment option for RA, NSAID drugs (NSAIDs) are replaced by conventional and biological DMARDs that provide joint protective effects. Though effective at relieving pain and inflammation related to RA, chronic use of NSAIDs may end up in cardiovascular and Gastrointestinal (GI) toxicities like acute coronary syndrome or stomach ulcers. COX-2 inhibitors like rofecoxib and celecoxib were developed so as to potentially prevent adverse GI side effects, continue the anti-inflammatory properties, and supply additional pain relief.

In the late 90s and early 2000s, NSAID therapies for treating arthritis were limited and lacked effectiveness. Therefore, initially there wasn't a robust competitive NSAID market. However, the approval of Merck’s selective COX2 inhibitor rofecoxib (Vioxx) for RA in 1999 drove rapid industry wide innovation and cause the discharge of Pfizer’s celecoxib in 2000. Both were shown to be effective in treating joint pain related to Osteoarthritis (OA) and RA and proved to cut back GI toxicity. While initially these products didn't directly compete with one another, when rofecoxib was pulled from the market citing stroke and other cardiovascular risk concerns, celecoxib initially took an enormous hit in sales. Despite this, celecoxib was ultimately ready to expand to the US market. While COX inhibitors play a character in RA treatment regimens, they play a bigger role within the treatment of OA [7].

Figure 2: Symptoms Associated with Rheumatoid Arithritis

Cytokines in RA

Origins of Cytokine Response: CD4 T cells are known to play a key role within the pathogenesis of RA. Yet, it remains unknown how arthritis-causing T cells initiate disease. Early events that cause autoimmunity in RA before late manifestations of disease-specific immune dysregulation, like overt joint inflammation, are currently not well-studied [8].

However, it's believed that within the early pre-clinical phase of RA, there's a genetic component plus an environmental trigger before the onset of detectable systemic autoimmunity as reviewed by Deane and Holers [9].

The strongest genetic association is with the MHC class II allele, HLA-DR4, supporting a task for antigen-presentation in disease. Polymorphisms within the HLA-DR4 allele may end up in altered antigen binding to the MHC class II molecules present on the membranes of Antigen Presenting Cell (APC). This ends up in altered presentation of self-antigens to CD4 T cells leading to their inappropriate activation and differentiation [10].

Once these T cells, a subset of which likely recognize an intra-articular antigen, and other inflammatory immune cells enter the synovial microenvironment, arthritis is triggered. Environmental factors including smoking, stress, and hormonal changes (such as menopause) can trigger and enhance these genetic risk factors, though the precise mechanism is unclear.

Manifestations (Related to Autoimmune Disease)

The main manifestations of RA are categorized into three which include bone, airway and circulatory system. Firstly, bones are affected both locally and systemically. Local factors that stimulate osteoclasts lead to increased bone resorption and these osteoclasts were released from inflammatory and fibroblastic pannus cells.

Secondly, the manifestations of RA with reference to systema respiratorium include cricoarytenoid arthritis, pulmonary fibrosis and little airway disease, typically seen as bronchiolitis with obstructive abnormalities in lung functions.

Lung disease is more predominant in RA patients especially in male seropositive smokers.

Treatments for Autoimmune Disease

Figure 4.

Figure 3: Pathogenesis of Rheumatoid Arthritis

Figure 4: Treatment Approaches for Rheumatoid Arthritis

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