Objective: To review the published literature on the use of thalidomide in rheumatoid arthritis (RA). Data Sources: A MEDLINE search was performed in May 1999 of articles published in English since 1965. Additional references were identified from the references of these articles, plus a review of Micromedex. Search terms included thalidomide, tumor necrosis factor, arthritis, and rheumatoid arthritis. Study Selection: A total of 18 publications were reviewed. Those reporting overlapping results were identified, and only the most recent publication was used. Data Extraction: Publications were reviewed for information pertaining to the use of thalidomide in RA, or for information that described mechanisms for thalidomide’s action in RA. Data Synthesis: Use of thalidomide has been associated with improvement in signs and symptoms of RA in animal models and in two open clinical trials. The pharmacologic mechanism for this activity remains to be elucidated. Significant side effects, including the risk of teratogenicity, limit the drug’s use in the general population. Conclusion: Thalidomide’s side effect profile may preclude its widespread use in RA, and no randomized, controlled trials are available to support its efficacy. However, analogs of thalidomide show potential as a new class of drugs to treat RA. Key Words: Rheumatoid Arthritis, Thalidomide, Tumor Necrosis Factor Abbreviations: RA = rheumatoid arthritis; TNFa = tumor necrosis factor alpha; NSAID = nonsteroidal anti-inflammatory drug; DMARD = disease-modifying antirheumatic drug; ENL = erythema nodosum leprosum; ESR = erythrocyte sedimentation rate; AIDS = acquired immunodeficiency syndrome. Consult Pharm 1999;14:875-8.

Rheumatoid arthritis (RA) is the most common chronic inflammatory rheumatic disease affecting approximately 2% of the world population, including about 2.5 million Americans. The diagnosis of RA is usually made between ages 35 and 50; however, 20% of patients are diagnosed after age 60. The disease is three times more common in women, and women generally experience the disease more severely than men. After age 60, the relative prevalence in men and women is approximately equal.^1,2

RA is characterized by inflammation of the joints, with the most common joints affected being the small joints of the hands, wrist, and feet, although larger joints may also be involved. The classic symptoms of early-onset RA include swelling, erythema, stiffness, warmth, and pain of the joints. As RA progresses, joint deformities and disfiguration may occur, leading to functional decline. Approximately 50% of patients suffering from RA cannot function in their jobs within 10 years after disease onset.^1,2

Diagnosis of RA is based on the presence of at least four of the seven criteria defined by the American Rheumatism Association in 1987: morning stiffness, swelling in three or more joints, bilateral involvement, rheumatoid nodules, presence of rheumatoid factor in serum, and bone erosion or decalcification in involved joints.³ The first four symptoms, when present, need to exist for at least four weeks to qualify for diagnosis.

The cause of RA is currently unknown. Recent evidence suggests T-cell involvement, particularly because large amounts of T-cell cytokines have been found in synovial fluid and adjacent membranes. In addition to T-cell involvement, the destructive activity of RA is associated with the formation of inflamed synovial tissue (pannus) and production of monokines, such as tumor necrosis factor a (TNFa), interleukin-1, and metalloproteinases. These abnormalities lead to bone and cartilage destruction, which results in loss of joint function.^4,5

Numerous drugs and other therapies have been used to treat and slow progression of the disease, but currently there is no cure. Traditional treatment of RA includes both nonpharmacologic and pharmacologic modalities. The goal of therapy is to alleviate pain, maintain function for activities of daily living and work, slow progression of disease, and improve and maintain quality of life. Nonpharmacologic treatment includes rest and exercise. Adequate rest helps decrease the systemic inflammatory response by alleviating undo stress on the joint and allowing time for joint repair. Exercise helps to maintain strength and mobility of the joints. A good balance between rest and exercise is essential and must be tailored to a patient’s individual pain tolerance, endurance level, and physical capacity.^1,2,6

Pharmacologic therapy of RA often involves combinations of drugs for the majority of patients. Patients with mild disease may initially be prescribed only nonsteroidal anti-inflammatory drugs (NSAIDs). With moderate-to-severe presentation or progression of the disease, disease-modifying antirheumatic drugs (DMARDs) and/or corticosteroids are usually added. DMARDs include methotrexate, gold, azathioprin, hydroxychloroquine, penicillamine, sulfasalazine, and leflunomided. DMARDs have been successfully used for slowing the progression of RA, but they are associated with both long- and short-term side effects. If RA continues to progress after treatment with these agents, patients are considered refractory. No therapeutic regimen has been shown to halt the progressive loss of joint structure and function. The search for such a regimen continues, and many agents are undergoing clinical trials. Recently, interest has grown in treating RA with biological response modifiers, such as the new drug etanercept.^1,5,6

Role of Thalidomide

Thalidomide’s mechanism of action as an immunomodulator has yet to be elucidated. Complicating factors for determining the drug’s mechanism include its chemical characteristics, metabolism, and potential for more than one mechanism of action. Thalidomide exists as two enantiomers, the relative activity of which has not been adequately defined. Racemization of the drug occurs in different mediums and at different rates, resulting in variable activity under different experimental conditions. There are no studies available that adequately describe the metabolism of thalidomide in humans. In animal studies, the drug appears to be hydrolyzed to several metabolites, some of which appear to have immunomodulatory activity of their own.⁷ Thus, it will need to be demonstrated whether actions seen in an animal model reflect activity in humans or other animal models. Finally, several potential mechanisms for thalidomide’s immunologic activity have been identified. Most recent studies have focused on the drug’s ability to selectively inhibit TNFa production.⁸ Other studies have focused on prevention of angiogenesis, which promotes inflammation and pannus formation. While some studies support these activities of thalidomide or its analogs in animal models of RA^9,10, other studies suggest efficacy by different mechanisms.^11,12 Results of these studies plus encouraging results from studies in other autoimmune diseases have evoked interest in investigating thalidomide’s potential benefit for patients with RA.

Clinical Experience in RA

Huizinga et al.¹⁴ later conducted a study of 12 patients who had RA for a mean duration of 10.1 + 5.4 years. The objective was to assess the toxicity and efficacy of combined pentoxyfylline, which also blocks TNFa production, and thalidomide therapy for patients with active RA. Patients were enrolled in the study if they met the following inclusion criteria for active RA (defined as six or more swollen joints and at least two of the following): more than nine joints that are painful on motion or tender on pressure, morning stiffness less than 45 minutes, ESR less than 28 mm during the first hour. Patients were excluded if they had a history of peripheral neuropathy, gastrointestinal ulcer, severe constipation, or vertigo; were women of childbearing age; or had a change in antirheumatic treatment during the preceding three months. Patients received pentoxyfylline (400 mg three times a day) and thalidomide (100 mg once a day) for 12 weeks. During the 12-week study period, existing drug treatment was continued, which consisted of NSAIDs and DMARDs, and two patients received corticosteroids. Patients were assessed at weeks 4, 8 and 12 for number of swollen joints, tender joints, and joints with restricted motion and grip strength and physician-patient overall assessment. Patient’s TNFa and interleukin production levels were also evaluated using whole-blood stimulation assay.

All patients experienced side effects from the study treatment, and three withdrew as a result. Patients experienced dry mouth (33% before treatment, 100% after treatment), constipation (33% before, 77% after), drowsiness (33% before, 77% after), edema (44% before, 66% after), and dizziness (11% before, 33% after). The treatment did decrease TNFa production capacity by half, compared with baseline values (analysis of variance P < 0.03), but had no effect on interleukin production. Nine patients completed the study, five of whom met the American College of Rheumatology 20% response criteria after 12 weeks of treatment. Huizinga et al. concluded that the risk of adverse events outweighs the limited efficacy of the combined therapy with pentoxyfylline and thalidomide for patients with active RA.

Safety Concerns

Current Status

Teratogenicity is not the only adverse outcome seen with thalidomide. Virtually all patients receiving the drug reported side effects such as drowsiness, constipation, erythema, edema, and neuropathy. Thalidomide was first marketed as a sedative/hypnotic agent structurally related to barbiturates, which accounts for its high incidence of drowsiness. Patients who experience extreme drowsiness may need to decrease the dose or discontinue the use of the drug. Administration of thalidomide at bedtime helps minimize daytime drowsiness. Patients who experience constipation should be started on a bowel regimen plan and make diet modifications. Some patients may need to discontinue the drug for 24–48 hours to have a bowel movement and then reinitiate therapy. If a patient experiences neuropathic symptoms such as tingling or numbness of the hands and feet, thalidomide should be discontinued. Continued therapy with thalidomide has resulted in irreversible peripheral neuropathy.¹⁵

Conclusions

References
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