New Drugs for Treatment of Rheumatoid Arthritis

Pooja Banerjee, M.D.
Scott Vogelgesang, M.D.
University of Iowa Hospitals and Clinics

First Published: Spring 2002
Last Revised: June 2003
Peer Review Status: Internally Peer Reviewed

History: Rheumatoid Arthritis (RA) is a chronic, systemic inflammatory disorder of unrecognized etiology that primarily involves the joints. RA typically affects the small joints of the hand and foot and can lead to deformity and destruction of the joints due to erosion of cartilage and bone. RA occurs worldwide; its prevalence in the developed countries varies between 0.5% and 2%. It affects women two to three times as often as men with peak onset between the ages of 30 and 55 years.

The disease onset is usually insidious (weeks to months), with pain, stiffness, and swelling of multiple joints. Weight loss, low-grade fever, malaise, fatigue, and depression also may be present. Regardless of early asymmetrical involvement, most patients eventually will develop a symmetric inflammatory arthritis.

Elderly patients may first display diffuse myalgias, weight loss, stiffness, and fatigue (similar to polymyalgia rheumatica) and only later develop the typical joint swelling. A small percentage of patients will have an acute onset (days to weeks) of symptoms.

The joints most commonly involved are the metacarpophalangeal, proximal interphalangeal, metatarsophalangeal, and the wrists. Later in the course of the disease, typical deformities can develop, including ulnar deviation of the fingers with subluxation of the affected joints, swan-neck deformities (hyperextension of the proximal and flexion of the distal interphalangeal joints) and boutonnière deformities (fixed flexion of the proximal and hyperextension of the distal interphalangeal joints).

Most patients will have a prolonged course of slowly progressing, destructive disease, with alternating characteristic periods of exacerbation and improvement. A small percentage may enjoy prolonged clinical remissions (bringing the diagnosis of RA into question). A small percentage may suffer a rapidly progressive and destructive course of the disease.

Radiographic evidence of joint damage is common. Early findings include joint space-narrowing from cartilage destruction and osteopenia (loss of bone density) around the affected joints. The majority of patients with RA eventually display radiographic evidence of erosions in the small joints of the hands and feet. In some patients, erosions occur first in the ulnar styloid or metatarsophalangeal joint. It is, thus, worth evaluating both the hands (including the wrists) and the feet radiographically. The number of joint erosions increases over time and correlates with the persistence of inflammation, as evidenced by clinical measures of morning stiffness, synovial swelling, and elevation of ESR and CRP (C-reactive protein).

Active inflammation in the joints of the cervical vertebrae can lead to joint destruction and subluxation, just as in the peripheral joints. Atlantoaxial subluxation is the most common and results usually from laxity (or disruption from erosive disease) of the transverse ligament. Without the posterior stabilization from the transverse ligament, the odontoid process can compress the spinal cord, particularly with neck flexion.

Lateral views taken of the spine cervical region in flexion will demonstrate the subluxation. More than 3 to 4 mm of space between the odontoid process and the posterior arch of the atlas is abnormal. A gap of 8 to 9 mm or more (atlantoaxial subluxation) is associated with an increased frequency of cord compression. Cervical spine radiographs need to be done routinely in the preoperative evaluation of even asymptomatic RA patients, since manipulation of the neck during intubation may lead to neurologic damage.

MRI is invaluable for the assessment of cervical spine disease in RA, because it permits visualization of the cord and any potential compression. Myelopathy from cord compressions may present with pain radiating upwards, peripheral sensory changes, weakness, reflex changes, or slowly progressing spastic quadriparesis. Other signs and symptoms that suggest cervical myelopathy include a sensation of the head falling forward upon flexion of the cervical region, changes in the level of consciousness, "drop" attacks, loss of sphincter control, respiratory dysfunction, dysphagia, vertigo, convulsions, hemiplegia, dysarthria and nystagmus, and peripheral paresthesias without evidence of peripheral nerve disease or compression. Suspected myelopathy requires immediate attention and possibly intervention. Unfortunately, soft cervical collars do not adequately stabilize the affected region. A definitive therapy is the surgical stabilization of the cervical vertebrae.

Standard therapy of patients with RA includes prednisone, hydroxychloroquine, sulfasalazine, and methotrexate, either as single agents or in combination. Methotrexate has been a very popular agent in the United States. It is relatively strong and, although it has the potential for significant toxicity, is generally well tolerated. Usual doses are 15-20 mg taken weekly either orally or injected subcutaneously. Common side effects include oral ulcers, headache, nausea, and diarrhea. Monthly blood counts (monitoring potential cytopenias) as well as AST and albumin determinations (monitoring potential liver toxicity) and creatinine determinations are required. Although hypersensitivity pneumonitis can be a serious complication, it is unusual. Leflunomide has been used in Europe for transplant immunosuppression prior to its approval in the United States. Although studies vary, it is likely as effective as methotrexate, with liver toxicity as a major adverse event.

New facts: Active synovitis and joint destruction cause a high degree of economic loss and morbidity and are associated with early mortality. There is mounting evidence that currently available Disease Modifying Anti-Rheumatic Drugs (DMARD) and anti-cytokine agents can control synovitis and may slow or even stop radiographic progression. The treatment goals are to control the signs and symptoms, restore the physical function, and prevent (or halt) the development of joint damage. With refractory disease, the treatment goals are to relieve pain, improve joint motion, limit functional loss, and incur a minimum of adverse effects.

Recently, several new agents have been approved by the FDA for the treatment of patients with RA, including etanercept, infliximab, adalimumab, and anakinra. These new medications represent a more targeted approach to RA, directed against specific components of the inflammatory process. Cytokines--particularly Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1)--play a major role in perpetuating the inflammation that causes joint destruction in RA.

Etanercept is a soluble TNF receptor, which binds the circulating TNF and makes it biologically inactive. It is effective in controlling the symptoms of RA and appears to slow the rate of radiographic progression of joint damage. It is injected twice weekly in a dose of 25 mg per injection. Side effects include injection-site erythema and flu-like symptoms.

Infliximab is an antibody directed against TNF. Because it is a chimeric antibody that combines mouse proteins with human proteins, there is concern that an RA patient may develop antibodies to the mouse protein that could render infliximab ineffective. The FDA recommends infliximab be used in combination with methotrexate to suppress such antibody formation. Infliximab is given by intravenous infusion every other month. Common side effects include infusion reactions and flu-like symptoms.

Adalimumab is also an antibody directed against TNF. It is different from infliximab because it has no mouse proteins, only human proteins. It is injected subcutaneously twice monthly. Common side effects include injection site reactions and flu-like symptoms.

Anakinra is a recombinant, non-glycosylated form of the human IL-1 receptor antagonist. It blocks the biologic activity of IL-1 through competitive inhibition of the IL-1 receptor, which is expressed in a wide variety of tissues and organs.

Practice: Etanercept, infliximab, adalimumab, and anakinra are exciting, new therapeutic options for the treatment of RA that are used by rheumatologists at UI Hospitals and Clinics. These agents appear to be very effective; however, their long-term safety is still unknown. As with any new drug, additional adverse effects are being recognized as infliximab, etanercept, and adalimumab are put into wider use.

All three agents have been associated with infections and should be used with caution in patients predisposed to infection, experiencing an acute infection, or having recurrent infections. There have been recent reports of reactivation of tuberculosis, especially with infliximab. Accordingly, a PPD should be checked prior to initiation of therapy or placed for those who are already using these therapies.

Etanercept has been associated with rare cases of pancytopenia, including aplastic anemia. Antagonists of TNF have also been associated with demyelinating illnesses (e.g., multiple sclerosis, myelitis, optic neuritis).

Consequently, these agents are reserved for RA patients who have persistent disease despite more traditional therapy. Rheumatoid arthritis remains a chronic destructive disease; however, the expanding repertoire of therapeutics allows most of those afflicted to enjoy a full life.

Revised criteria for the classification of RA: (Arnett FC, et al. Arthritis Rheum 31:315-324, 1988)

1. Morning stiffness for at least one hour before maximal improvement and present for at least 6 weeks.
2. Simultaneous swelling of three or more joint areas observed by a physician, for at least six weeks.
3. At least one area swollen in wrist, metacarpophalangeal, or proximal interphalangeal joints, for at least six weeks.
4. Simultaneous bilateral involvement of proximal interphalangeal, metacarpophalangeal, or
5. metatarsophalangeal joints is acceptable without absolute symmetry.
6. Subcutaneous nodules over bony prominences, or extensor surfaces, or in juxta-articular regions.
7. Demonstration of abnormal amounts of serum Rheumatoid factor by any method for which the result has been positive in less than 5% of normal control subjects.
8. Radiographic changes typical of RA on posteroanterior hand and wrist radiographs, which include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joint.

Note: Four of the seven criteria are required.

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