Inflammation is a key feature of RA associated with pain and swelling of joints and conditions that affect many different tissues and organ systems in the body, from of the heart and blood vessels to the lungs and eyes.


Which joints are affected by RA-related inflammation?

Inflammation of joints in RA typically occurs in a symmetrical fashion, in other words, joints on both sides of the body will be affected. The earliest joints to be affected by inflammation in RA are usually the hands (including wrists) and feet. The elbow may also be affected early in the course of the disease and is the site most frequently affected by RA nodules. The shoulder is a common site for RA-related inflammation. However, this joint tends to be affected in later stages of the disease.

RA affects larger joints in the lower body, the knees and hips, and the ankles, in later stages of the disease. Inflammation of the hips may be difficult to detect by physical examination alone because of the location of the joint. However, chronic inflammation over time will result in joint destruction, with a significant impact on mobility. Inflammation in the knee and ankle should be readily apparent from swelling and stiffness that affect mobility.

Inflammation may affect the joints of the cervical spine, making it difficult to move your head and causing stiffness in the neck. Additionally, the larynx joint (also called the cricoarytenoid joint) may become inflamed, resulting in hoarseness in the voice.


How does inflammation affect the joints?

In RA, inflammation is triggered by an autoimmune process, in which immune cells, principally white blood cells (leukocytes), including B and T lymphocytes (B- and T-cells, for short), neutrophils, monocytes, dendritic cells, and macrophages, multiply in the joint cavity, where they release a wide range of inflammatory mediators (eg. cytokines, enzymes, leukotrienes, prostaglandins).

As cells and chemicals of the immune system multiply in the synovial fluid that fills the joint space, the fluid normally clear with a consistency like egg yoke, becomes cloudy and increases in volume. The synovial lining on the inside of the joint becomes inflamed and swollen. With continued exposure to inflammation, thickening of the synovial lining, and pannus formation, the joint space decreases over time.

With chronic inflammation, cartilage within the joint erodes and the bony structure of the joint may become deformed. Additionally, chronic inflammation can affect the soft tissues surrounding the joints, resulting in deterioration of muscles, tendons, and ligaments. Degradation of the connective tissue around the joints can result in the loss of proper joint alignment and may eventually lead to deformity.


When does RA-related inflammation occur?

With RA, inflammation can occur at any time. Although RA is considered a chronic disease, which means that it is long-lasting and persistent, it typically does not progress on an even or predictable course. Most patients with RA experience periods when the disease worsens beyond normal day-to-day variations, and is more active. These periods of worsening disease are called flares, during which inflammation and associated symptoms (swelling, pain, stiffness, extra-articular manifestations) may be more severe.1


Does RA-related inflammation affect the body beyond the joints?

Inflammation that occurs with RA affects not just the joints, but organs and tissues throughout the body.

RA nodules. Although we do not understand precisely why nodules occur with RA, we think that they form in response to inflammation and are associated with the action of immune cells called helper T cells.2,3 They typically develop under the skin (subcutaneously) in areas subject to pressure including the elbows, finger joints, wrist, hip, lower back, and Achilles tendon. However, they can also occur internally in the tissue of the heart and lung. RA nodules are found in about 7% of patients at the time of initial diagnosis and affect about 30% of patients at some point during the disease.2

Lungs. Abnormal airway function occurs commonly with RA, affecting up to 38% of patients. RA is associated with a variety of conditions involving inflammation of the lungs and related tissues, including pleuritis, pulmonary fibrosis, and interstitial lung disease (types of bronchiolitis and pneumonia). In these conditions, inflammation can result in difficulty breathing and pain in the chest.2,4

Pleuritis, which can be caused by autoimmune disorders including systemic lupus erythematosus, as well as RA, is an inflammation of the lining of the cavity or pleura surrounding the lungs. Every time the lungs expand during inhalation, they rub against the inflamed pleura causing sharp pain.2

Pulmonary fibrosis is the formation of fibrous tissue inside the lungs that appears on x-ray as scarring. The formation of scar tissue interferes with the ability of the lung to expand normally upon inhalation and can lead to chest discomfort, shortness of breath, fatigue, weakness, and a chronic cough.2,4

An estimated 6% of patients with RA develop some form of interstitial lung disease, a range of conditions that affect the space and tissues surrounding the air sacs (alveoli) in the lungs. Interstitial lung disease associated with RA typically includes interstitial pneumonias and bronchiolitis, as well as damage to alveoli.2,4

Blood vessels. Vasculitis or inflammation of the blood vessels is a form of systemic inflammation that can sometimes affect patients with RA. This complication is rare, but can affect blood vessels throughout the body, resulting in a number of effects including ulcers in the legs and a rash on the skin caused by bleeding from small blood vessels.2

Heart. Pericarditis, or inflammation of the membrane that encloses the heart, is the most common type of RA-related inflammation that affects the heart. Symptoms of pericarditis include acute chest pain and difficulty breathing.2

Nerves. Inflammation in RA may affect nerve function and result in tingling or numbness.2

Eyes and mouth. RA-related inflammation can also affect the eyes and mouth and is frequently associated with a condition called secondary Sjögren’s syndrome, an autoimmune disease in which inflammation affects the glands that produce tears and saliva resulting in a decrease in the production of tears (this condition is also called keratoconjunctivitis sicca) and/or saliva (this condition is called xerostomia). Additionally, RA inflammation can lead to episcleritis, a condition affecting the white part of the eye and causing pain, light sensitivity, and tearing .2


How is RA-related inflammation treated?

There are a variety of medications used to control RA-related inflammation. The major groups include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (also called corticosteroids), and disease-modifying anti-rheumatic drugs (DMARDs), a group which includes newer biologics treatments.

NSAIDs, both over-the-counter (aspirin, ibuprofen, naproxen) and prescription, are used to control minor inflammation associated with RA. The selective NSAID Celebrex (celecoxib) is less likely to cause side effects, including gastrointestinal effects, than less selective NSAIDs. NSAIDs must be taken continually and for a period of several weeks before their effectiveness can be judged and two different NSAIDs should not be taken together. Additionally, NSAIDs are not effective at reducing RA-related damage to joints and other tissues.5

Glucocorticoids (also called corticosteroids or just steroids) are commonly used to control inflammation. Specific glucocorticoids include prednisone and prednisolone. They may be taken orally, injected into a vein, or injected into an affected joint. While these drugs are effective at controlling inflammation, they do not slow or prevent structural damage to joints and related structures. However, they may be given to achieve control of acute inflammation concurrently with DMARDs, which have been shown to slow or prevent damage to joints.5

Traditional disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, sulfasalazine, and hydroxychloroquine are effective at reducing inflammation, as well as slowing or preventing damage to joints. Traditional DMARDs, such as methotrexate, tend to work slowly. Therefore, they are often taken with glucocorticoids to control acute inflammation that occurs with RA disease flares.5 The newer biologics are also considered DMARDs.

Newer biologic treatments, including TNF-inhibitors such as etanercept (Enbrel), adalimumab (Humira), and other immunomodulators, have been shown to be effective in controlling RA symptoms including inflammation. The drugs are considered DMARDs because, like older treatments such as methotrexate, they modify the course of RA and are effective at slowing or preventing joint damage. Biologics are often used in patients who do not fully respond to treatment with traditional DMARDs. These agents can also be used together with traditional DMARDs and glucocorticoids to control inflammation and prevent joint damage. Unlike traditional DMARDs, which may take a month to achieve full effect, newer biologics tend to work more quickly, achieving full effect in some cases within two weeks.5

view references
1. Bartlett SJ, Hewlett S, Bingham CO, et al. Identifying core domains to assess flare in rheumatoid arthritis: an OMERACT international patient and provider combined Delphi consensus. Ann Rheumatic Dis 2012;71:1855-60. 2. Turesson C, Matteson EL. Clinical features of rheumatoid arthritis: extra-articular manifestations. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatoid Arthritis. Philadelphia, Penn: Mosby Elsevier; 2009:62-67. 3. García-Patos V. Rheumatoid Nodule. Semin Cut Med Surg 2007;26:100-7. 4. Nannini C, Ryu JH, Matteson EL. Lung disease in rheumatoid arthritis. Curr Opin Rheumatol 2008;20:340-6. 5. Venables PJW. Patient information: Rheumatoid arthritis treatments (beyond the basics). In: O'Dell JR, Greene JM, eds. UptoDate. Wolters Kluwer Health. Accessed at: 2013.further reading
Paget SA, Lockshin MD, Loebl S. Rheumatoid Arthritis Handbook. New York, NY: John Wiley and Sons, Inc; 2002. Fox B, Taylor N, Yazdany J. Arthritis for Dummies. Hoboken, NJ: Wiley Publishing, Inc; 2004. Emery P. Pocket Reference to Early Rheumatoid Arthritis. London: Springer Healthcare Ltd; 2011.
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