An important topic to understand as you prepare for the Internal Medicine Board or ABIM exam is Rheumatoid Arthritis.
Unlike the similar-sounding disorder osteoarthritis (which was last week’s disease profile), rheumatoid arthritis (RA) is a condition that can wreck havoc beyond the joint spaces. It is an autoimmune, systemic, chronic, and inflammatory process. Because it is an autoimmune disease, a specific antibody will usually be present (stay tuned for the diagnosis section). Antibodies have the ability to disseminate through the bloodstream to different tissues and organs; therefore, making the condition systemic. Although many organs can be harmed by RA, the synovial joints are primarily affected. Being inflammatory in nature, RA can feature morning stiffness lasting longer than 60 minutes, with accompanying swelling, and joints that can be red, warm, and tender to touch. If a synovial fluid analysis is done, the white blood cell count from the synovial fluid will be in the inflammatory range of 5000-50,000 WBC/uL.
Although no known cause exists for RA, many experts believe that antigens trigger an inflammatory response in susceptible individuals. Smoking can increase chances of developing RA. The best known genetic mechanism for the development of RA is the presence of HLA-DRB1 *0401 or HLA-DRB1 *0404. When genetically susceptible individuals have a putative antigen, the synovial macrophages act as antigen presenting cells through HLA-DR to activate T cells. Since RA is primarily a T cell mediated condition, it is very rare to see RA in HIV patients whose T cells can be depleted. B cells release autoantibodies to the putative antigen, secrete pro-inflammatory cytokines, and can also act as antigen presenting cells. Although multiple cytokines are released or involved the pathogenesis of RA, tumor necrosis factor alpha (TNF-alpha) is the most notorious and critical cytokine that initiates and perpetuates the inflammatory cascade in RA. Therefore, TNF-alpha inhibitors play a major role in the management of this condition.
DIAGNOSIS AND CLINICAL FEATURES
As you prepare for the ABIM exam, it is important to understand how a diagnosis of Rheumatoid Arthritis is made.
The diagnosis of RA is both clinical and based on laboratory findings. It is a chronic, symmetrical, poly-articular, systemic condition. Four or more of the following diagnostic criteria are required for the diagnosis of rheumatoid arthritis:
- Morning stiffness greater than one hour
- Swelling of the wrist, MCP, or PIP joints for more than six weeks
- Symmetrical involvement
- Presence of rheumatoid factor (positive in 85% of cases)
- Presence of rheumatoid nodules
- X-ray findings showing marginal bony erosions
DIP joint and the lower back are usually not involved with rheumatoid arthritis. The presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in the blood is very specific (90-95%) for rheumatoid arthritis; therefore, the presence of this antibody enhances the probability that an individual has rheumatoid arthritis. Active disease from the synovium can spread and cause extra-articular manifestations.
These extra-articular manifestations can affect the heart causing constrictive pericarditis or myocarditis.
With lung involvement, pleural effusions, hypersensitivity pneumonitis, or interstitial fibrosis can develop. When pleural effusion occurs because of rheumatoid arthritis, the effusion will be an exudative effusion with glucose levels usually less than 30 mg/dl from the effusion.
Patients can develop anemia of chronic disease. With anemia of chronic disease, we can see normal to low iron levels, decreased TIBC level, and increased ferritin level.
Ulceration of the fingers and toes can occur secondary to vascular involvement, leading to necrosis.
Foot drop or wrist drop can occur because of neuropathy. Patients can also develop carpal tunnel or tarsal tunnel syndrome from RA.
Eye involvement can lead to scleritis or episcleritis.
Skin involvement will cause the most common extra-articular manifestation to occur: rheumatoid nodules.
If renal involvement occurs, it is usually at the late stages of RA. Patients can develop amyloid nephropathy or nephrotic syndrome. When rheumatoid arthritis affects C1-C2 level of the cervical spine, it can lead to atlanto-odontoid subluxation. This subluxation can compress the vertebrobasilar artery system, which leads to syncopal symptoms. With compression of the cervical spinal cord, there can be both motor and sensory compromise. If the lesion is either less than 5 mm or the patient is asymptomatic, treatment is usually not required. However, if the lesion is either greater than or equal to 8 mm or the individual has symptoms, surgical decompression is required for treatment.
Poor prognostic factors for rheumatoid arthritis can best be understood by dividing into three categories: joint involvement, lab findings, and extra-articular manifestations. With joint involvement, progressive synovitis (worsening swelling or inflammation) or joint space loss/erosions on x-ray indicate poor prognostic factors. Lab findings of increased rheumatoid factor, increased ESR (indicating inflammation), and presence of HLA-DR4 indicate poor prognostic factors. Finally, one extra-articular manifestation that predicts poor prognostic factor is also the most common extra-articular manifestation of RA as described above: rheumatoid nodules. Another extra-articular manifestation that predicts poor prognostic factor is ulceration of fingers and toes due to vasculitis.
Management of conditions and diseases is a critical part of the Internal Medicine Board (ABIM) exam.
Management of RA is usually achieved through medications. With mild RA, treatment usually can be initiated with NSAIDS, sulfasalazine, or the anti-malarrial medication hydroxychloroquine. When NSAIDS are used for management of RA, they should be taken with food and/or with proton pump inhibitors to prevent stomach ulcers or gastritis from occurring. Individuals who have allergies to sulfa should not be given sulfasalazine. Those who are being treated with hydroxychloroquine for RA should undergo frequent eye examinations as this medication can cause macular damage, especailly with renal dysfunction.
If patient’s symptoms are not controlled with the above medications, then further treatment is warranted. Moderate to severe rheumatoid arthritis can be managed with methotrexate, leflunomide, or steroids. When methotrexate is used for moderate to severe RA, CBC and liver function tests should be monitored every six-eight weeks to detect early signs of anemia or hepatotoxicity. Also, methotrexate administration should be accompanied by folic acid to prevent folate deficiency. Hypersensitivity pneumonitis and/or pulmonary fibrosis may result from methotrexate use.
Leflunomide is also used to manage moderate to severe RA. Leflunomide is teratogenic and side effects include myelosuppression, hepatotoxicity, rash, diarrhea, and alopecia.
Steroids are used to control the inflammation associated with RA but should be avoided long term because of a bad side-effect profile, including hyperglycemia, hypertension, osteoporosis, and Cushing syndrome.
When these medications do not control the pain associated with RA, then we bring out the “big guns” to help manage RA. As TNF-alpha is a major pro-inflammatory cytokine involved in the pathogenesis of RA. Therefore, TNF-alpha inhibitors can now be used to control very severe symptoms of RA. Before initiating treatment with TNF-alpha inhibitors, a PPD test needs to be done to make sure that a patient does not have pre-existing tuberculosis. Some of the most common TNF-alpha inhibitors that are used are etanercept, infliximab, or adalimumab. If one TNF-alpha inhibitor is not controlling RA symptoms, it should be switched to another TNF-alpha inhibitor, which will usually help control the symptoms. Two or more TNF-alpha inhibitors should NEVER be used concurrently as this combination can compromise the necessary inflammatory response to fight off infections.