CLINICAL COMMENTARY

Raising expectations for arthritis treatment

Biologic response modifiers are making remission possible

Marc D. Cohen, MD

VOL 116 / NO 5 / NOVEMBER 2004 / POSTGRADUATE MEDICINE

Dr Cohen is a consultant for Amgen Inc, Wyeth, Centocor, Inc, Abbott Laboratories, Tap Pharmaceuticals Inc, Merck & Co, Inc, and Pfizer Inc. He discloses no unlabeled uses of any product mentioned in this article.

Cohen MD. Raising expectations for arthritis treatment: biologic response modifiers are making remission possible. Postgrad Med 2004;116(5):41-50

As the two preceding articles in this symposium explain, the traditional approach to rheumatoid arthritis and the spondyloarthropathies has been dramatically revised in the last decade. The clinical objectives of treatment have evolved to a point where disease remission is no longer considered an unattainable ideal.

This evolution is due, in part, to the introduction of biologic response modifiers. The impressive efficacy of these agents has prompted new therapeutic end points for the clinical, radiographic, and functional components of rheumatoid arthritis and spondyloarthropathy. A variety of end points have been considered, including reductions in counts of swollen and tender joints that meet American College of Rheumatology (ACR) criteria for 20%, 50%, or 70% response; changes in radiographic assessment of erosions and joint space narrowing as measured by total Sharp score assessments; and improvements in Health Assessment Questionnaire scores. All of these end points are potentially improved with aggressive treatments, and newer, more sensitive end points may be necessary in the near future. The availability of effective, safe, and durable treatments has forced reevaluation of how physicians approach therapy for patients with these diseases.

Conventionally, initial treatment of rheumatoid arthritis uses nonsteroidal anti-inflammatory drugs (NSAIDs) and traditional disease-modifying antirheumatic drugs (DMARDs) to minimize pain and inflammation, common early symptoms of the disease. However, NSAIDs do not prevent the disease progression that can lead to structural joint damage, and they are notorious for producing gastrointestinal and other side effects. Traditional DMARDs may delay disease progression, but they are slow to become effective, may lose efficacy with time, and are often associated with potentially serious toxic effects.

A substantial proportion of patients with rheumatoid arthritis either fail to respond adequately to traditional DMARDs or experience significant toxicity, which limits long-term use of these drugs. Use of tumor necrosis factor (TNF) inhibitors to block or bind to TNF results in a relative improvement in safety and efficacy over NSAIDs and traditional DMARDs. These newer drugs have been shown to dramatically improve clinical symptoms and laboratory manifestations of inflammation, slow or halt radiographic progression of the disease, and improve health-related quality-of-life variables.

Evolving therapy
Treatment of rheumatoid arthritis has evolved rapidly in the last decade. Early and aggressive use of traditional DMARDs and study of the newer biologic response modifiers have clearly shown improved patient outcomes and slowing of radiographic progression of joint damage.

This radiographic slowing is of particular significance, because radiographic progression occurs early in the disease and correlates with functional decline. Joint erosions can be detected by magnetic resonance imaging in 45% of patients within 4 months of disease onset (1). Up to 93% of patients have some degree of radiographic damage within 2 years of disease onset (2). Disease progression is thought to be more rapid during the first year of rheumatoid arthritis than during the second and third years (3).

These observations have led to the suggestion that the optimal window for aggressive treatment is during the early years of the disease. Further research findings support this conclusion. For example, in the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial (4), patients with early rheumatoid arthritis received either sulfasalazine monotherapy or brief and aggressive treatment with sulfasalazine plus step-down treatment with prednisolone (which was discontinued after 28 weeks) and methotrexate (which was discontinued after 40 weeks), followed by maintenance therapy with sulfasalazine alone. After 5 years, the group that received the aggressive multi-drug regimen early in the disease course showed a 35% lower rate of radiographic progression, as assessed by total Sharp scores, than the group that received sulfasalazine monotherapy (5.6 points versus 8.6 points, P=.03).

The Tight Control for Rheumatoid Arthritis (TICORA) study (5) demonstrated that aggressive treatment resulted in significantly better functional outcomes than routine care. In this trial, patients with rheumatoid arthritis of less than 5 years' duration received either routine outpatient care or aggressive and intensive outpatient care with traditional DMARDs. After 18 months, patients receiving aggressive therapy had greater improvements in disease activity scores than patients undergoing routine care (mean improvement, about 3.5 points versus 2 points, P<.001).

Mean scores on the disability index portion of the Health Assessment Questionnaire improved by 0.97 point from baseline in patients receiving aggressive therapy compared to 0.47 point in patients receiving routine care (P<.05) (5). Total Sharp scores increased by only 4.5 points in patients receiving aggressive therapy compared to 8.5 points in the routine-care group (P<.005).

Role of anti-TNF-alpha agents
Several studies have evaluated the effects of anti-TNF-alpha agents on the signs and symptoms of rheumatoid arthritis. They have shown that in more than 50% of subjects, an ACR 20 response (ie, a clinical response of 20% or more but less than 50%) was obtained within a few weeks of initiating treatment with infliximab, etanercept, or adalimumab (6-8). Such response levels were reached in the following weeks in 60% of patients studied and were maintained for more than 5 years in several ongoing trials (6-8).

Furthermore, these and other studies (6-9) have shown that treatment with infliximab plus methotrexate or adalimumab plus methotrexate virtually halted radiographic progression of joint damage. Patients treated with these drug regimens demonstrated minimal increases from baseline in total Sharp scores. These increases were significantly lower than those observed in patients treated with methotrexate alone (P<.001).

With respect to disability and quality of life, another study (10) showed statistically significant and clinically important improvements in fatigue, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale, after treatment with adalimumab plus methotrexate compared with methotrexate alone.

Benefits of early treatment
Use of anti-TNF agents early in the course of rheumatoid arthritis is more effective than use of these agents in advanced disease. The Active Controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) (11) compared the effects of infliximab plus methotrexate with those of methotrexate alone in patients with early rheumatoid arthritis (mean duration of disease, 7 months). At 54 weeks, the percentage of patients achieving an ACR response was significantly higher with infliximab plus methotrexate than with methotrexate alone (P<.03). Furthermore, the mean increase in the total Sharp score from baseline was significantly lower in patients receiving infliximab plus methotrexate than in those receiving methotrexate alone (P<.001).

Similarly, another study (7) compared the effects of etanercept in patients with early rheumatoid arthritis and patients with established disease. Improvements in Health Assessment Questionnaire scores accrued rapidly in both patient subgroups during the first 3 months of treatment, and these improvements were maintained for 3 years.

Approaches to later-stage rheumatoid arthritis
A recent study (12) evaluated anti-TNF therapy in patients with rheumatoid arthritis (mean duration of disease, 6.3 to 6.8 years) who were considered to have moderate rheumatoid arthritis on the basis of disease activity. The response rates of patients treated with etanercept plus methotrexate over 52 weeks were significantly higher than those of patients treated with methotrexate alone or etanercept alone (P<.01).

Moreover, the mean total Sharp score decreased by 0.5 point with use of etanercept plus methotrexate, which was significantly better than the increase of 0.5 point in patients treated with etanercept alone and the increase of 2.8 points in those treated with methotrexate alone (P<.01). This study also demonstrated that twice as many patients were able to achieve a remission, defined by a disease activity score of less than 1.6, when treated with etanercept plus methotrexate than when treated with either drug alone.

Thus, studies demonstrate that aggressive treatment with a combination of an anti-TNF agent and methotrexate yields substantial improvements, even in patients with rheumatoid arthritis whose disease duration is beyond that considered "early." Although early initiation may be ideal, aggressive treatment may never be too late and should be considered in all patients with ongoing, active rheumatoid arthritis.

Anti-TNF agents have a reasonable toxicity profile. Serious adverse events related to use of these drugs are relatively uncommon. A purified protein derivative (tuberculin) skin test before treatment with an anti-TNF agent can significantly reduce the risk of tuberculosis in patients with rheumatoid arthritis. Anti-TNF agents do not appear to increase the risk of malignancies in these patients, but long-term observational studies are under way to further assess this risk.

New therapeutic strategies for the spondyloarthropathies
The underlying pathophysiologic processes involved in rheumatoid arthritis, psoriatic arthritis, psoriasis, and spondyloarthropathies such as ankylosing spondylitis have similarities, and TNF likely plays a key role in all of these conditions. Research is showing that anti-TNF therapy can be highly effective in these conditions.

TNF overexpression in psoriasis, psoriatic arthritis, and ankylosing spondylitis has led to new therapeutic strategies with anti-TNF agents. Etanercept has been approved by the US Food and Drug Administration for treatment of these three conditions. Clinical trials are completed or are being conducted with other anti-TNF agents, particularly infliximab and adalimumab (13-15).

The results of clinical trials of anti-TNF agents for treatment of psoriatic arthritis are impressive. For example, ACR 20 response rates, as well as score improvements on the disability index of the Health Assessment Questionnaire, the Psoriatic Arthritis Response Criteria, and the Psoriasis Area in Severity Index, were significantly better in patients with psoriatic arthritis treated with etanercept than in patients receiving placebo (16). Radiographic assessments made after the original 6-month clinical trial and after an additional 6 months of open-label treatment demonstrated that patients who received etanercept experienced no progression of joint damage when contrasted with patients who initially received placebo (17). Skin responses are also impressive.

Similar trials in ankylosing spondylitis have demonstrated significant improvements in clinical indexes in patients treated with anti-TNF agents compared with those receiving placebo (18-20).

Further studies are required to determine which patients respond to a particular treatment. Hopefully, improvements in diagnostic and prognostic testing for these diseases will help physicians make definitive diagnoses earlier than currently possible, eventually leading to even earlier initiation of aggressive treatment.

Conclusion
New aggressive treatments have revolutionized the therapeutic strategies available for rheumatoid arthritis and the spondyloarthropathies, and significant improvements in outcomes are already possible. Best practice now requires early diagnosis and treatment and, whenever possible, referral to a rheumatologist for diagnostic confirmation and initiation of therapy with DMARDs.

Interaction between primary care physicians and rheumatologists is increasingly important to promote early, aggressive treatment, to change treatment on the basis of the patient's response to therapy, and to appropriately monitor and minimize toxicity. Expectations for successful treatment are high--justifiably higher than ever before--and future developments in diagnostic and therapeutic opportunities hold much promise.

References

1. McQueen FM, Stewart N, Crabbe J, et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis 1998;57(6):350-6
2. Fuchs HA, Kaye JJ, Callahan LF, et al. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol 1989;16(5):585-91
3. van der Heijde DM, van Leeuwen MA, van Riel PL, et al. Radiographic progression on radiographs of hands and feet during the first 3 years of rheumatoid arthritis measured according to Sharp's method (van der Heijde modification). J Rheumatol 1995;22(9):1792-6
4. Landewe RB, Boers M, Verhoeven AC, et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002;46(2):347-56
5. Porter DR, Grigor C, Stirling A, et al. A randomised controlled trial of a strategy of tight control of disease activity in rheumatoid arthritis--outcome over 18 months. (Abstr 515) Arthritis Rheum 2003;48(Suppl):S232
6. Breedveld FC, Rau R, van Riel PL, et al. Sustained efficacy over 5 years with adalimumab (Humira) in patients with active rheumatoid arthritis. (Abstr 198) Arthritis Rheum 2003;48(Suppl):S118
7. Kremer JM, Weinblatt ME, Fleischmann RM, et al. Etanercept (Enbrel) added to background methotrexate in rheumatoid arthritis: continued observations. (Abstr 1421) Arthritis Rheum 2002;46(Suppl):S531
8. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Eng J Med 2000;343(22):1594-602
9. Lipsky P, van der Heijde D, St Clair W, et al. 102-week clinical and radiologic results from the ATTRACT trial: a 2-year, randomized, controlled phase 3 trial of infliximab (Remicade) in patients with active rheumatoid arthritis despite methotrexate. (Abstr 1216) Arthritis Rheum 2000;43(Suppl):S269
10. Chartash E, Vasey F, Yount S, et al. Adalimumab improves fatigue in patients with active rheumatoid arthritis. (Abstr SAT0225) Ann Rheum Dis 2003;62(Suppl):349
11. Smolen JS, Emery P, Bathon J, et al. Treatment of early rheumatoid arthritis with infliximab plus methotrexate or methotrexate alone: preliminary results of the ASPIRE trial. (Abstr OP0001) Presented at the Annual European Congress of Rheumatology, Jun 2003, Lisbon
12. Klareskog L, van der Heijde D, de Jager JP, et al; TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363(9410):675-81
13. Antoni C, Kavanaugh A, Kirkham B, et al. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT). (Abstr 985) Arthritis Rheum 2002;46(Suppl):S381
14. Chaudhari U, Romano P, Mulcahy LD, et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001;357(9271):1842-7
15. Chen DM, Gordon K, Leonardi C, et al. Adalimumab efficacy and safety in patients with moderate to severe chronic plaque psoriasis: preliminary findings from a 12-week dose-ranging trial. J Am Acad Dermatol 2004;50(3 Pt 2):Pl
16. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50(7):2264-72
17. Ory P, Sharp JT, Salonen D, et al. Etanercept (Enbrel) inhibits radiographic progression in patients with psoriatic arthritis. (Abstr 442) Arthritis Rheum 2002;46(Suppl):S196
18. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359(9313):1187-93
19. Davis JC Jr, van der Heijde D, Braun J, et al; Enbrel Ankylosing Spondylitis Study Group. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 2003;48(11):3230-6
20. Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 2002;346(18):1349-56

Dr Cohen, coordinator of this symposium, is professor of medicine; chair, division of rheumatology; chair, department of hospital medicine; associate chair, department of internal medicine; and director, internal medicine residency program, Mayo Clinic, Jacksonville, Florida. Correspondence: Marc D. Cohen, MD, Division of Rheumatology, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL 32224. E-mail: cohen.marc@mayo.edu.

Symposium Index

• DAMAGE CONTROL IN RHEUMATOID ARTHRITIS: Hard-hitting, early treatment is crucial to curbing joint destruction. By Sakeba N. Issa, MD, Eric M. Ruderman, MD
• TREATMENT UPDATE ON SPONDYLOARTHROPATHY: From NSAIDs and DMARDs to anti-TNF-alpha agents. By Allen P. Anandarajah, MD, Christopher T. Ritchlin, MD
• Clinical Commentary. RAISING EXPECTATIONS FOR ARTHRITIS TREATMENT: Biologic response modifiers are making remission possible. By Marc D. Cohen, MD

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