Causes of Rheumatoid Arthritis, Diagnosis

Causes of Rheumatoid Arthritis is a systemic chronic inflammatory disease of unclear etiology that is manifested in by a progressive and destructive polyarthritis in association with serological evidence of autoreactivity. Its diagnosis is based on the classification criteria that involve four parameters: joint involvement, serology (rheumatoid factor and anti-cyclic citrullinated peptide–anti-CCP), levels of acute phase reactants and the duration of the symptoms Aletaha, et al. [1]. This classification simplifies the categorization of the patients with early RA; however, the diagnosis requires highly trained specialists who are able to differentiate early symptoms of RA from other pathologies.

Causes of Rheumatoid Arthritis

Rheumatoid arthritis is a long-term condition that causes pain, swelling and stiffness in the joints. The symptoms usually affect the hands, feet, and wrist.

Causes of Rheumatoid Arthritis

Oral mucosa and RA-related autoimmunity

In recent years, the oral mucosa, specifically the gingiva and periodontal regions, has been studied as a potential site for the origins of RA. In classifiable RA, there is an increased prevalence and severity of periodontitis that has been associated with systemic RA-related autoantibodies [], and in subjects without classified RA, severe periodontitis has also been associated with RA-related autoantibodies []. In addition, Porphyromonas gingivalis (P. ging), a microbe commonly involved in periodontitis, is uniquely found to express a peptidyl arginine deiminase (PAD) enzyme capable of citrullinating human peptides/proteins []. Furthermore, in subjects without classified RA, Mikuls and colleagues identified an association between elevations of antibodies to P. ging and serum RA-related autoantibodies [], and inflamed gingival tissue has been shown to express increased levels of PAD and citrullinated proteins []. Of interest, Harvey and colleagues also identified the presence of local anti-CCP antibodies in gingival crevicular fluid associated with gingivitis. However, despite these intriguing associations, a recent study by Scher and colleagues found that P. ging was associated with the severity of periodontitis but not specifically associated with new-onset RA[]. Rather, they found that Prevotella and Leptotrichia were expanded in new-onset RA, and Anaeroglobus geminatus was associated with RA-related autoantibody positivity.

The lung and RA-related autoimmunity

Another mucosal surface that is a potential originating site of autoimmunity in RA is the lung. This possibility is supported by established data that demonstrate increased RA risk is associated with inhaled exposures such as cigarette smoke [], and a high prevalence of lung disease including airways inflammation has been identified in established RA[]. Furthermore, Demoruelle and colleagues recently identified a higher prevalence of inflammatory airways disease by computed tomographic imaging in arthritis-free subjects (by joint examination and in a subset of subjects, by MRI) with serum RA-related autoantibodies compared to autoantibody negative matched controls []. Importantly, this finding was independent of prior or current cigarette smoking. Additionally, Fischer and colleagues found 80% of anti-CCP positive subjects with chronic lung disease and no joint symptoms had imaging evidence of airways inflammation []; furthermore, in a subset of these subjects that had a lung biopsy, 96% demonstrated histologic evidence of lung inflammation. Importantly, in these 2 studies, 5 subjects developed synovitis classifiable as RA during longitudinal follow-up, and all 5 had evidence of lung inflammation preceding the development of clinically apparent arthritis.

The gut and RA-related autoimmunity

To date, much of the data investigating the gastrointestinal mucosa in RA has focused on the gut microbiome. The gut microbiome is known to influence the development of the innate and adaptive immune system, and may therefore also play a role in the development of autoimmunity []. In murine studies, specific alterations of gut bacteria can enhance or attenuate susceptibility to experimentally-induced arthritis [. In humans, studies have identified differences in the gut microbiota, specifically differences in relative abundance of various microbes, in patients with classifiable RA compared to controls []. However, these studies have been unable to distinguish whether differences in gut microbial communities are a cause of inflammation in RA, the result of an underlying inflammatory environment that selects for the survival of certain microbes, or whether the therapies used in RA are responsible for altering the gut microbial composition. Additional study of subjects prior to the onset of joint inflammation will be informative to understand the relationship between the gastrointestinal microbiome and the development RA.

Pathophysiology of Rheumatoid Arthritis

Causes of Rheumatoid Arthritis

Prominent immunologic abnormalities include immune complexes produced by synovial lining cells and in inflamed blood vessels. Plasma cells produce antibodies (eg, rheumatoid factor [RF], anti-cyclic citrullinated peptide antibody [anti-CCP]) that contribute to these complexes, but destructive arthritis can occur in their absence. Macrophages also migrate to diseased synovium in early disease; increased macrophage-derived lining cells are prominent along with vessel inflammation. Lymphocytes that infiltrate the synovial tissue are primarily CD4+ T cells. Macrophages and lymphocytes produce pro-inflammatory cytokines and chemokines (eg, TNF-α, granulocyte-macrophage-colony-stimulating factor [GM-CSF], various ILs, interferon-γ) in the synovium. The release of inflammatory mediators probably contributes to the systemic and joint manifestations of RA.

Causes of Rheumatoid Arthritis

In chronically affected joints, the normally thin synovium proliferates, thickens, and develops many villous folds. The synovial lining cells produce various materials, including collagenase and stromelysin, which contribute to cartilage destruction, and IL-1 and TNF-α, which stimulate cartilage destruction, osteoclast-mediated bone absorption, synovial inflammation, and prostaglandins (which potentiate inflammation). Fibrin deposition, fibrosis, and necrosis are also present. Hyperplastic synovial tissue (pannus) releases these inflammatory mediators, which erode cartilage, subchondral

Rheumatoid arthritis statistics

  • The Center for Disease Control and Prevention (CDC) estimates that 1.5 million US adults suffer from rheumatoid arthritis.
  • According to The National Health Service (NHS), UK, about 350,000 British people are affected by rheumatoid arthritis.
  • According to the National Rheumatoid Arthritis Society (UK) rheumatoid arthritis affects 0.8% of the UK population.
  • According to The Mayo Clinic, USA, the disease is two to three times more common in women than in men.
  • Although people of any age may be affected, rheumatoid arthritis is much more common after the age of 40. According to the National Rheumatoid Arthritis Society (UK), approximately 12,000 children under 16 years of age have a juvenile form of the disease.

According to the John Hopkins Arthritis Center, USA

  • Approximately 1% to 2% of the world’s population is affected by the disease.
  • Prevalence increases with age, approaching 5% in women over 55 years of age.
  • Annual average incidence is 70 in every 100,000 in the USA.
  • It is 4 times more common in smokers than non-smokers.

Rheumatoid arthritis is much more common that MS (multiple sclerosis) or leukemia. However, awareness of the disease’s effects and severity are more restricted to patients, their caregivers and their relatives because it is not well publicized.

Classification Criteria

What is Rheumatoid Arthritis

In 2010 the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced. The new criterion is not a diagnostic criterion but a classification criterion to identify disease with a high likelihood of developing a chronic form. However, a score of 6 or greater unequivocally classifies a person with a diagnosis of rheumatoid arthritis.

These new classification criteria overruled the “old” ACR criteria of 1987 and are adapted for early RA diagnosis. The “new” classification criteria, jointly published by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) establish a point value between 0 and 10. Four areas are covered in the diagnosis:

Joint involvement, designating the metacarpophalangeal joints, proximal interphalangeal joints, the interphalangeal joint of the thumb, second through fifth metatarsophalangeal joint and wrist as small joints, and shoulders, elbows, hip joints, knees, and ankles as large joints:

  • Involvement of 1 large joint gives 0 points
  • Involvement of 2–10 large joints gives 1 point
  • Involvement of 1–3 small joints (with or without the involvement of large joints) gives 2 points
  • Involvement of 4–10 small joints (with or without the involvement of large joints) gives 3 points
  • Involvement of more than 10 joints (with the involvement of at least 1 small joint) gives 5 points

Serological parameters – including the rheumatoid factor as well as ACPA – “ACPA” stands for “anti-citrullinated protein antibody”:

  • Negative RF and negative ACPA gives 0 points
  • Low-positive RF or low-positive ACPA gives 2 points
  • High-positive RF or high-positive ACPA gives 3 points
  • acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, ESR, or elevated CRP value (c-reactive protein)
  • duration of arthritis: 1 point for symptoms lasting six weeks or longer

Risk Factors

  • The etiology, or cause, of RA is unknown. Many cases are believed to result from an interaction between genetic factors and environmental exposures.
  • Age and sex: The incidence of RA is typically two to three times higher in women than men. The onset of RA, in both women and men, is highest among those in their sixties.
  • Genetics: There is longstanding evidence that specific HLA class II genotypes are associated with increased risk of developing RA. Most attention has been given to the DR4 and DRB1 molecules of the major histocompatibility complex HLA class II genes. The strongest associations have been found between RA and the DRB1*0401 and DRB1*0404 alleles. Other recent investigations indicate that of the more than 30 genes studied, the strongest candidate gene is PTPN22, a gene that has been linked to several autoimmune conditions.

Modifiable: Several modifiable risk factors for RA have been studied including reproductive hormonal exposures, tobacco use, dietary factors, and microbial exposures.

Smoking: Among the modifiable risk factors, smoking is the strongest and most consistent modifiable risk factor for RA. A history of smoking is associated with a modest to moderate (1.3 to 2.4 times) increased risk of RA onset. This relationship between smoking and RA is strongest among people who are ACPA-positive (anti-citrullinated protein/peptide antibodies), a marker of auto-immune activities

Reproductive and Breastfeeding History: Hormones related to reproduction have been studied extensively as potential risk factors for RA.

  • Oral Contraceptives (OC) –  Early studies found that women who had taken OCs had a modest to moderate decrease in risk of RA. However, most recent studies have not found a decreased risk. The estrogen concentration of contemporary OCs is typically 80%-90% lower than the first OCs introduced in the 1960s. This may account for the lack of associations in recent studies.
  • Hormone Replacement Therapy (HRT) – There is mixed evidence of an association between HRT and RA onset.
  • Live Birth History – Most studies have found that women who have never had a live birth have a slight to moderately increased risk of RA.
  • Breastfeeding – Almost all recent population-based studies have found that RA is less common among women who breastfeed.
  • Menstrual History – At least two studies have observed that women with irregular menses or a truncated menstrual history (e.g., early menopause) have an increased risk of RA. Because women with the polycystic ovarian syndrome (PCOS) have an increased risk of RA, the association with an irregular menstrual history may result from PCOS.
  • Early Life Exposures – Early life exposures may alter the risk of developing RA in adulthood.  For example, one study found that maternal smoking doubled the risk of children developing RA as adults. The relationship between birthweight and later onset of RA is inconsistent: one study found no effect while others have found that both low and high birth weight are risk factors. Lower socio-economic status in childhood has been linked to heightened risk of developing RA.
  • Physical Activity – The only study examining the role of physical activity in the development of RA found a dose-response relationship; that is, the risk of RA declined with increasing levels of leisure time physical activity. However, the risk ratios were not statistically significant.
  • Vitamin D: Two studies examining vitamin D as a risk factor for RA onset found no associations.

 Symptoms of Rheumatoid Arthritis

The joints most commonly affected by rheumatoid arthritis are in the hands, wrists, feet, ankles, knees, shoulders, and elbows. The disease typically causes inflammation symmetrically in the body, meaning the same joints are affected on both sides of the body. Symptoms of rheumatoid arthritis may begin suddenly or gradually.

The typical symptoms of rheumatoid arthritis include the following:

  • Warm, swollen joints – It’s common for the same joints to be swollen on both sides of the body, for instance, the fingers of both the right and left hand.
  • Painful joints
  • Stiff joints – After longer periods of rest, and especially in the morning right after you wake up, your joints are stiff. They usually only become more flexible again after an hour or more, or once you have been active for a while.
  • Weakness – Painful, stiff joints often end up not getting as much use, which can cause the muscles to gradually weaken.
  • Exhaustion – Rheumatoid arthritis is an inflammatory disease that affects the entire body. So it often causes tiredness, general physical weakness and occasionally more extreme exhaustion ().
  • Rheumatoid nodules – As the disease progresses, small hard lumps called rheumatoid nodules sometimes develop under the skin. They’re usually not sensitive to pressure or touch.

Rheumatoid arthritis symptoms vary a lot from person to person: It might be that a different joint is affected, or that other symptoms are causing the most trouble.

The following are the most common symptoms of rheumatoid arthritis. However, each individual may experience symptoms differently. Symptoms may include:

  • Inflamed, painful joints
  • Stiff joints
  • Enlarged and/or deformed joints (such as fingers bent toward the little finger and/or swollen wrists)
  • Frozen joints (joints that freeze in one position)
  • Cysts behind the knees that may rupture, causing lower leg swelling and pain
  • Hard nodules (bumps) under the skin near affected joints
  • Low-grade fever
  • Inflamed blood vessels (vasculitis) may occur occasionally, leading to nerve damage and leg sores
  • Inflamed membranes around the lungs (pleurisy), the sac around the heart (pericarditis), or inflammation and scarring of the lungs themselves, that may lead to chest pain, difficulty breathing, and abnormal heart function
  • Swollen lymph nodes
  • Sjögren’s syndrome (dry eyes and mouth)
  • Eye inflammation

If a person has four or more of the following symptoms, he/she may be diagnosed with rheumatoid arthritis:

  • Morning stiffness that lasts longer than one hour for at least six weeks
  • Three or more joints that are inflamed for at least six weeks
  • Presence of arthritis in the hand, wrist, or finger joints for at least six weeks
  • Blood tests that reveal rheumatoid factor
  • X-rays that show characteristic changes in the joints

According to WHo

Symptoms of Rheumatoid Arthritis

Symptoms  of Rheumatoid Arthritis 

Rheumatoid arthritis usually develops gradually, but some people experience a sudden onset of symptoms: one day they are perfectly healthy and the next they are dealing with rheumatoid arthritis.

Symptoms commonly associated with rheumatoid arthritis include:

  • Joint pain, joint swelling, joint stiffness, and warmth around the affected joint
  • Morning stiffness that lasts one or more hours
  • Symmetrical pattern of affected joints, meaning the same joint on both sides of the body is affected (e.g., both knees)
  • Small joints of the hands and feet are characteristically involved, although any joint can be affected
  • Rheumatoid nodules (firm lumps under the skin), found on elbows and hands of about one-fifth of people with rheumatoid arthritis
  • Fatigue and noticeable loss of energy
  • Low-grade fever and sometimes flu-like symptoms
  • Loss of appetite, weight loss, anemia associated with chronic diseases, depression
  • Dry eyes and dry mouth associated with a secondary condition Sjogren’s syndrome
  • Joint deformity and instability from damage to cartilage, tendons, ligaments, and bone
  • Limited range of motion in affected joints
  • Flares and remission of disease activity is characteristic of rheumatoid arthritis
  • Rheumatoid arthritis may have systemic effects (i.e., affect the organs of the body)

No two rheumatoid arthritis cases are exactly the same. There is so much variety among the symptoms that some researchers suspect rheumatoid arthritis is not one disease but rather a several diseases with commonalities.

The symptoms of rheumatoid arthritis may resemble other medical conditions or problems, including acute rheumatic fever, Lyme disease, psoriatic arthritis, gout, osteoarthritis, gonococcal arthritis, and ankylosing spondylitis. Always consult your physician for a diagnosis

Rheumatoid Arthritis Diagnosed

Rheumatoid arthritis can be difficult to diagnose in its early stages for several reasons.

Classification Criteria of diagnosis

In 2010 the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced. The new criterion is not a diagnostic criterion but a classification criterion to identify disease with a high likelihood of developing a chronic form. However, a score of 6 or greater unequivocally classifies a person with a diagnosis of rheumatoid arthritis.

These new classification criteria overruled the “old” ACR criteria of 1987 and are adapted for early RA diagnosis. The “new” classification criteria, jointly published by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) establish a point value between 0 and 10. Four areas are covered in the diagnosis

Joint involvement – designating the metacarpophalangeal joints, proximal interphalangeal joints, the interphalangeal joint of the thumb, second through fifth metatarsophalangeal joint and wrist as small joints, and shoulders, elbows, hip joints, knees, and ankles as large joints:

  • Involvement of 1 large joint gives 0 points
  • Involvement of 2–10 large joints gives 1 point
  • Involvement of 1–3 small joints (with or without the involvement of large joints) gives 2 points
  • Involvement of 4–10 small joints (with or without the involvement of large joints) gives 3 points
  • Involvement of more than 10 joints (with the involvement of at least 1 small joint) gives 5 points

Serological parameters – including the rheumatoid factor as well as ACPA – “ACPA” stands for “anti-citrullinated protein antibody”:

  • Negative RF and negative ACPA gives 0 points
  • Low-positive RF or low-positive ACPA gives 2 points
  • High-positive RF or high-positive ACPA gives 3 points
  • acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, ESR, or elevated CRP value (c-reactive protein)
  • duration of arthritis: 1 point for symptoms lasting six weeks or longer

The new criteria accommodate to the growing understanding of RA and the improvements in diagnosing RA and disease treatment. In the “new” criteria serology and autoimmune diagnostics carry major weight, as ACPA detection is appropriate to diagnose the disease in an early stage before joints destructions occur. Destruction of the joints viewed in radiological images was a significant point of the ACR criteria from 1987. This criterion no longer is regarded to be relevant, as this is just the type of damage that treatment is meant to avoid.

In clinical practice, the following criteria apply

  • two or more swollen joints
  • morning stiffness lasting more than one hour for at least six weeks
  • the detection of rheumatoid factors or autoantibodies against ACPA such as autoantibodies to mutated citrullinated vimentin can confirm the suspicion of RA. A negative autoantibody result does not exclude a diagnosis of RA.

Differential Diagnosis

Several other medical conditions can resemble RA, and usually, need to be distinguished from it at the time of diagnosis

  • Crystal-induced arthritis (gout, and pseudogout) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with an aspiration of joint fluid if in doubt. Redness, asymmetric distribution of affected joints, pain occurs at night and the starting pain is less than an hour with gout.
  • Steroid induces arthritis-  usually, it can involve multiple joint pain during rest or night time.
  • Osteoarthritis – distinguished with X-rays of the affected joints and blood tests, age (mostly older persons), starting painless than an hour, asymmetric distribution of affected joints and pain worsens when using joint for longer periods.
  • Systemic lupus erythematosus (SLE) – distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded DNA)
  • One of the several types of psoriatic arthritis resembles RA – nail changes and skin symptoms distinguish between them
  • Lyme disease – causes erosive arthritis and may closely resemble RA – it may be distinguished by blood test in endemic areas
  • Reactive arthritis (previously Reiter’s disease) – asymmetrically involves heel, sacroiliac joints and large joints of the leg. It is usually associated with urethritis, conjunctivitis, iritis, painless buccal ulcers, and keratoderma blennorrhagica.
  • Axial spondyloarthritis  – (including ankylosing spondylitis) – this involves the spine, although an RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.
  • Hepatitis C – RA-like symmetrical small-joint polyarthritis may occur in the context of this condition. Hepatitis C may also induce Rheumatoid Factor auto-antibodies

Rarer causes that usually behave differently but may cause joint pains

  • Sarcoidosis, amyloidosis, and Whipple’s disease can also resemble RA.
  • Hemochromatosis may cause hand joint arthritis.
  • Acute rheumatic fever can be differentiated from RA by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection. Bacterial arthritis (such as by Streptococcus) is usually asymmetric, while RA usually involves both sides of the body symmetrically.
  • Gonococcal arthritis (another bacterial arthritis) – is also initially migratory and can involve tendons around the wrists and ankles.

Medical history – The doctor begins by asking the patient to describe the symptoms, and when and how the condition started, as well as how the symptoms have changed over time.

  • Physical examination- The doctor will check the patient’s reflexes and general health, including muscle strength. The doctor will also examine bothersome joints and observe the patient’s ability to walk, bend, and carry out activities of daily living. The doctor will also look at the skin for a rash and listen to the chest for signs of inflammation in the lungs.
  • Laboratory tests – A number of lab tests may be useful in confirming a diagnosis of rheumatoid arthritis. Following are some of the more common ones:
  • Rheumatoid factor (RF)- Rheumatoid factor is an antibody that is present eventually in the blood of most people with rheumatoid arthritis. (An antibody is a special protein made by the immune system that normally helps fight foreign substances in the body.) Not all people with rheumatoid arthritis test positive for rheumatoid factor, and some people test positive for rheumatoid factor, yet never develop the disease. Rheumatoid factor also can be positive in some other diseases; however, a positive RF in a person who has symptoms consistent with those of rheumatoid arthritis can be useful in confirming a diagnosis. Furthermore, high levels of rheumatoid factor are associated with more severe rheumatoid arthritis.
  • Anti-CCP antibodies – This blood test detects antibodies to cyclic citrullinated peptide (anti-CCP). This test is positive in most people with rheumatoid arthritis and can even be positive years before rheumatoid arthritis symptoms develop.
  • Others – Other common laboratory tests include a white blood cell count, a blood test for anemia, which is common in rheumatoid arthritis; the erythrocyte sedimentation rate (often called the sed rate), which measures inflammation in the body; and
  • C-reactive protein – another common test for inflammation that is useful both in making a diagnosis and monitoring disease activity and response to anti-inflammatory therapy.
  • Synovial biopsy.
  • CBC,Hb,Widal test ,MT test for tuberculosis
  • IgG, Serum Creatinine
  • Synovial fluid analysis.
  • Erythrocyte Sedimentation Rate – An erythrocyte sedimentation rate (ESR or sed rate) measures how fast red blood cells (erythrocytes) fall to the bottom of a fine glass tube that is filled with the patient’s blood. The higher the sed rate the greater the inflammation.
  • C-Reactive Protein – High levels of C-reactive protein (CRP) are also indicators of active inflammation. Like the ESR, a high result does not indicate what part of the body is inflamed, or what is causing the inflammation.
  • Anti-CCP Antibody –The presence of antibodies to cyclic citrullinated peptides (CCP) can identify RA years before symptoms develop. In combination with the test for rheumatoid factor, the CCP antibody test is the best predictor of which patients will go on to develop severe RA.
  • Tests for Anemia Anemia is a common complication. Blood tests determine the number of red blood cells (hemoglobin and hematocrit) and iron (soluble transferrin receptor and serum ferritin) in the blood.
  • Joint aspiration – Involves a removal of fluid from the swollen bursa to exclude infection or gout as possible causes
  • Biopsy (of nodules tissue) – A procedure in which tissue samples are removed (with a needle or during surgery) from the body for examination under a microscope; to determine if cancer or other abnormal cells are present
  • X rays X rays are used to determine the degree of joint destruction. They are not useful in the early stages of rheumatoid arthritis before bone damage is evident; however, they may be used to rule out other causes of joint pain. They may also be used later to monitor the progression of the disease.
  • MRI-It can be needed in the critical case to diagnosis the internal structure of joints to ensure where osteophyte form or not, tendon, cartilage, ligament, synovial fluid.


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Causes of Rheumatoid Arthritis

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