Blocking Tumor Necrosis Factor Offers Hope in Rheumatoid Arthritis

Blocking Tumor Necrosis Factor Offers Hope in Rheumatoid Arthritis

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Jan- Feb 00	Rank Last Period Nov- Dec 99
1	S. Hulley, et al., "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women," JAMA-J. Amer. Med. Assoc., 280(7):605-13, 19 August 1998. [U. Calif. San Francisco; Johns Hopkins U., Baltimore, MD; Wake Forest U. Sch. Med., Winston-Salem, NC; Wyeth-Ayerst Res., Radnor, PA] *110ME	43	3
2	L. Hansson, et al., "Effects of intensive blood-pressure- lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial," The Lancet, 351(9118):1755-62, 13 June 1998. [10 institutions worldwide] *ZU444	42	4
3	F.J. Palella, et al., "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection," New Engl. J. Med., 338(13):853-60, 26 March 1998. [5 U.S. institutions] *ZD284	37	2
4	B. Fisher, et al., "Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study," J. Natl. Cancer Inst., 90(18):1371-88, 16 September 1998. [10 U.S. and Canadian institutions] *120NT	33	1
5	F.O. Nestle, et al., "Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells," Nature Medicine, 4(3):328-32, March 1998. [U. Zurich Med. Sch., Switzerland; U. Heidelberg, Germany; U. Munstervon, Munster, Germany] *ZN163	23	5
6	J.R. Downs, et al., "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS," JAMA-J. Amer. Med. Assoc., 279(20):1615-22, 27 May 1998. [7 U.S. institutions] *ZP489	23	†
7	B.D. Trapp, et al., "Axonal transection in the lesions of multiple sclerosis," New Engl. J. Med., 338(5):278-85, 29 January 1998. [Cleveland Clinic Fdn., OH; Haukeland Hosp., Bergen, Norway] *YT963	23	7
8	J.G. McHutchinson, et al., "Interferon alpha-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C," New Engl. J. Med., 339(21):1485-92, 19 November 1998. [8 U.S. institutions] *139VT	20	†
9	S.A. Rosenberg, et al., "Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma," Nature Medicine, 4(3):321-7, March 1998. [NCI, NIH, Bethesda, MD] *ZN163	19	†
10	I. Goldstein, et al., "Oral sildenafil in the treatment of erectile dysfunction," New Engl. J. Med., 338(20):1397-1404, 14 May 1998. [6 U.S. institutions] *ZM667	18	9

SOURCE: ISI's Hot Papers Database. Read the full legend.

inherited from my family-physician father-in-law medical texts used when he was a young doctor, and find it salutary to dip into them from time to time, especially when some breakthrough is hinted at. "For patients with rheumatoid arthritis, a new era in treatment has begun"–this from an editorial in the New England Journal of Medicine of March 16, 2000, by Dr. David S. Pisetsky (see New Engl. J. Med., 342:810-1, 2000) had me reaching for the shelves. Therein I found the expected mix of optimism and ignorance. Crippling pain and deformity "with little or no prospect of relief" was entirely the wrong picture of a disease probably caused by "a low-grade infection," opined one physician in 1937. Even 12 years earlier another had declared the outlook "not so hopeless as was once thought" though he had to admit that the "suggestive therapeutics of hope and confidence are more valuable than drugs."

Since then we have a range of useful drugs, including non-steroidal antiinflammatory agents, steroids, gold compounds, and methotrexate. Pisetsky's new era refers to treatments in an entirely different class, stemming from rheumatoid-arthritis research on the involvement of tumor necrosis factor (TNF), a cytokine that medicine finds difficult to classify as good or bad in rheumatoid arthritis. Two agents have come to prominence recently.

Etanercept is a soluble receptor for TNF alfa and beta (lymphotoxin) while infliximab is an antibody to TNF alfa. The Pisetesky editorial was pegged on a study of etanercept in juvenile rheumatoid arthritis, published in the same issue of NEJM, far too recently yet to have much of a citation impact. An earlier study in adults whose disease remained active despite methotrexate therapy, is just beginning to attract attention (see M.E. Weinblatt, et al., "A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate," New Engl. J. Med., 340(4):253-9, 28 January 1999; currently ranked #12, with 17 citations this period). The same is true of a similar clinical trial of the monoclonal antibody infliximab (see R. Maini, et al., "Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial," Lancet, 354(9194):1932-9, 1999; with 3 citations to date).

The American College of Rheumatology has stipulated that a 20% improvement in disease activity at 24 weeks indicates improvement, and in the NEJM clinical trial, in patients still taking their methotrexate , improvement was recorded in 71% of those on etanercept but in only 27% of those randomized to placebo.

There was no significant toxicity with etanercept, including no development of antibodies, and antibodies may be a problem with infliximab if not given with methotrexate. These products are genetically engineered, and predicting antibody problems is not straightforward, but infliximab is chimeral (human and mouse) while etanercept is made by fusing two TNF receptors with part of the human immunoglobulin IgG1. The editorial accompanying paper #12 in 1999 also refers to a "new era." One outstanding question is how these agents fare when no methotrexate accompanies them.

Mr. David W. Sharp, MA (Cambridge) is Deputy Editor of The Lancet, London, U.K.