Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and affects more than 2 million Americans. The diagnosis is not easy to make in many instances. There are more than 100 different kinds of arthritis. Most of them involve inflammation. When a patient goes to a rheumatologist to get a diagnosis, there is a process of elimination in order to arrive at the proper diagnosis. This process of elimination is called “differential diagnosis.”
Differential diagnosis can be a difficult undertaking because so many forms of arthritis, particularly inflammatory forms of arthritis look alike. Generally it is helpful to divide the differential diagnosis of rheumatoid arthritis into two groups. The first group are the non-infectious diseases to consider and the second group are the infection-related conditions.
Since the discussion is rather long I have chosen to divide the article into two parts.
The following is a partial list of forms of inflammatory arthritis that can be seen and must be considered when evaluating a patient with inflammatory symptoms of arthritis and are not infection related.
RA is an autoimmune chronic inflammatory disease, primarily involving the peripheral joints (hands, wrists, elbows, shoulders, hips, knees, ankles, and feet). It can also affect non joint structures such as the lung, eye, skin, and cardiovascular system.
RA may start slowly with nonspecific symptoms, including fatigue, malaise (feeling “blah”), appetite loss, low-grade fever, weight loss, and vague joint pains, or it may have an explosive onset with inflammation involving multiple joints. The joint symptoms usually occur bilaterally- both sides of the body equally involved- and symmetric. Erosions- damage to the joint- can be seen with x-ray. In about 80% of cases, elevated levels of rheumatoid factor (RF) or anti-cyclic citrullinated antibodies (anti-CCP) are present in the blood. There appears to be a correlation between the presence of anti-CCP antibodies and erosions.
Juvenile rheumatoid arthritis (JRA) occurs in children under the age of 16. Three forms of JRA exist, including oligoarticular (1-4 joints), polyarticular (more than 4 joints), and systemic-onset or Still’s disease. The latter condition is associated with systemic symptoms — including fever and rash in addition to joint disease.
Polyarticular JRA has similar characteristics to adult RA. It causes about 30% of cases of JRA. Most children with polyarticular JRA are negative for RF and their prognosis is usually good.
Approximately 20% of polyarticular JRA patients have elevated RF, and these patients are at risk for chronic, progressive joint damage.
Eye involvement in the form of inflammation- called uveitis- is a common finding in oligoarticular JRA, especially in patients who are positive for anti-nuclear antibody (ANA), a blood test that is often used to screen for autoimmune disease. Uveitis may not cause symptoms so careful screening should be performed in these patients.
SLE is an inflammatory, chronic, autoimmune disorder that can involve the skin, joints, kidneys, central nervous system, and blood vessel walls. Patients may present with 1 or more of the following: butterfly-shaped rash on the face, affecting the cheeks; rash on other parts of the body; sensitivity to sunlight; mouth sores; joint inflammation; fluid around the lungs, heart, or other organs; kidney abnormalities; low white blood cell count, low red blood cell count, or low platelet count; nerve or brain inflammation; positive results of a blood test for ANA; positive results of a blood test for antibodies to double-stranded DNA or other antibodies.
Patients with lupus can have significant inflammatory arthritis. As a result, lupus can be difficult to distinguish from RA, especially if other features of lupus are not present. Clues that favor a diagnosis of RA over lupus in a patient presenting with arthritis affecting multiple joints include lack of lupus features, erosions (joint damage) seen on x-rays, and elevations of RF and anti-CCP antibodies.
Polymyositis (PM) and dermatomyositis (DM) are types of inflammatory muscle disease. These conditions typically present with bilateral (both sides involved) large muscle weakness. In the case of DM, rash is present. Diagnosis consists of finding the following: elevation of muscle enzyme levels in the blood [the two enzymes that are measured are creatine kinase (CPK) and aldolase], signs and symptoms, electromyograph (EMG)- an electrical test- alteration, and a positive muscle biopsy.
In addition, in many cases abnormal antibodies specific for inflammatory muscle disease can be elevated.
In both PM and DM, inflammatory arthritis can be present and can look like RA. Both inflammatory muscle disease and RA can affect the lungs. In RA, muscle function will usually be normal. Also, in PM and DM, erosive joint disease is unlikely. RF and anti-CCP antibodies are typically elevated in RA but not PM or DM.
SAs — psoriatic arthritis, reactive arthritis, ankylosing spondylitis, and enteropathic arthritis — are a category of diseases that cause systemic inflammation, and preferentially attack parts of the spine and other joints where tendons attach to bones. They also can cause pain and stiffness in the neck, upper and lower back, tendonitis, bursitis, heel pain, and fatigue. They are termed “seronegative” types of arthritis. The term ‘seronegative’ means that testing for rheumatoid factor is negative. Symptoms of adult SAs include:
o Back and/or joint pain;
o Morning stiffness;
o Tenderness near bones;
o Sores on the skin;
o Inflammation of the joints on both sides of the body;
o Skin or mouth ulcers;
o Rash on the bottom of the feet; and
o Eye inflammation.
Occasionally, arthritis similar to that seen in RA can be present. Careful history and physical examination can often distinguish between these conditions, especially if an obvious disease that is promoting inflammation is present (psoriasis, inflammatory bowel disease, etc.). In addition, RA rarely affects the DIP joints- the last row of finger joints. If these joints are involved with inflammatory arthritis, the diagnosis of an SA is possible. (Note of caution: a condition known as inflammatory erosive nodal osteoarthritis can also affect the DIP joints). RF and anti-CCP antibodies are negative in SAs, although, rarely, in cases of psoriatic arthritis there may be elevations of RF and anti-CCP antibodies.
Gout is caused by deposits of monosodium urate (uric acid) crystals into a joint. Gouty arthritis is acute in onset, very painful, with signs of significant inflammation on exam (red, warm, swollen joints). Gout can affect almost any joint in the body, but typically affects cooler areas including the toes, feet, ankles, knees, and hands. Diagnosis is made by drawing fluid from an inflamed joint and analyzing the fluid. Demonstrating monosodium urate crystals in the joint fluid is diagnostic, although finding elevated serum levels of uric acid can also be helpful.
In most cases, gout is an acute single joint disease that is easy to distinguish from RA. However, in some cases, chronic erosive joint inflammation where multiple joints are involved can develop. And, in cases where tophi (deposits of uric acid) are present, it can be difficult to distinguish from erosive RA. However, crystal analysis of joints or tophi and blood tests should be helpful in distinguishing gout from RA.
Calcium pyrophosphate deposition disease (CPPD), also known as pseudogout, is a disease is caused by deposits of calcium pyrophosphate dihydrate crystals in a joint. The presence of these crystals in the joints leads to significant inflammation. Establishing the diagnosis includes using:
o Detailed medical history;
o Withdrawing fluid from a joint to check for crystals;
o Joint x-rays to show crystals deposition in the cartilage (chondrocalcinosis); and
o Blood tests to rule out other diseases (e.g., RA or osteoarthritis).
In most cases, CPPD arthritis presents with single joint inflammation. In some cases, CPPD disease can present with chronic symmetric multiple joint erosive arthritis similar to RA. RA and CPPD disease can usually be told apart by joint aspiration demonstrating calcium pyrophosphate crystals, and by blood tests, including RF and anti-CCP antibodies, which are usually negative in CCPD arthritis. A complicating feature is that RA and CPPD can coexist!
Sarcoidosis is an inflammatory joint disorder. The majority of patients with this disease have lung disease, with eye and skin disease being the next most frequent signs of disease. Although the diagnosis of sarcoidosis can be made on clinical and x-ray presentation alone, sometimes the use of tissue biopsy with the demonstration of “noncaseating granulomas” is necessary for diagnosis.
Arthritis is present in 15% of patients with sarcoidosis, and in rare cases can be the only sign of disease. In acute sarcoid arthritis, joint disease is usually of rapid onset. It is symmetric involving the ankles, although knees, wrists, and hands can be involved. In most cases of acute disease, lung and skin disease are also present. Chronic sarcoid arthritis can be difficult to distinguish from RA. Although RA-specific blood tests, such as RF and anti-CCP antibodies, can be helpful in distinguishing RA from sarcoidosis, in some cases a biopsy of joint tissue may be required for diagnosis.
Polymyalgia Rheumatica (PMR) is a disease that leads to inflammation of tendons, muscles, ligaments, and tissues around the joints. It presents with large muscle pain, aching, morning stiffness, fatigue, and in some cases, fever. It can be associated with temporal arteritis (TA), also known as giant-cell arteritis, which is a related but more serious condition in which inflammation of large blood vessels can lead to blindness and aneurysms. Also, a peculiar syndrome where use of the arms and legs leads to cramping because of insufficient blood flow (limb claudication) can occur. PMR is diagnosed when the clinical picture is present along with elevated markers of inflammation (ESR and/or CRP). If temporal arteritis is suspected (headache, vision changes, limb claudication), biopsy of a temporal artery may be necessary to demonstrate inflammation of blood vessels.
PMR and TA can present with symmetric inflammatory arthritis similar to RA. These diseases can usually be distinguished by blood testing. In addition, headaches, vision changes, and large muscle pain are uncommon in RA, and if these are present, PMR and/or TA should be considered.
In part 2 of this article, I will discuss infectious diseases that need to be considered in the differential diagnosis of rheumatoid arthritis. When RA is suspected, it is critical to consult with an expert rheumatologist.