TNF inhibitors may have role in scleroderma

[Guest guest]

Jun 25, 2003

TNF inhibitors may have role in scleroderma

Lisbon, Portugal - A multicenter, placebo-controlled trial of a

TNF inhibitor as a primary treatment for scleroderma (systemic

sclerosis) is needed, say Dr Ellman and colleagues from the

University of Chicago and Presbyterian St Luke's Medical Center. They

were reporting positive data from open-label use of etanercept (Enbrel®,

Amgen) in 8 patients at last week's EULAR 2003 meeting [1], having

previously reported beneficial effects from a pilot trial in 10 patients

[2].

" Scleroderma is almost unique among connective-tissue diseases

because of a lack of proven effective disease-modifying medication, " the

group comments. " We think there is a role for TNF blockade in

scleroderma. " The improvement in skin symptoms (as measured by the

Modified Rodnan Skin Score [MRSS]) that they saw with open-label use of

etanercept " was striking and exceeded our expectations, " while temporary

stopping of the drug (because of supply shortages, respiratory

infections, etc) caused perceived worsening of the disease.

Ellman et al reported the original pilot study in 10 patients at

the 2000 meeting of the American College of Rheumatology [2]. These

patients had diffuse scleroderma of less than 5 years' duration and

received etanercept 25 mg subcutaneously twice weekly for 6 months. That

study showed the drug to be safe and possibly effective as a

disease-modifying agent, they commented last week. Skin tightness

improved by 25% in 4 patients, especially in those with the most recent

disease, and no patient had worsening of pulmonary function.

At a poster presentation at EULAR, Ellman et al detailed results

from a further series of 8 patients (1 of whom had been in the original

pilot study and elected to stay on the drug). These patients have now

been taking etanercept for a mean of 29.3 months (range 8 to 59 months).

None of them have had difficulties in administering the drug, the

researchers comment. None of them had serious pulmonary disease to begin

with, and none have had a worsening of pulmonary function. No serious

infections or major side effects have been seen.

One patient stopped taking etanercept because of perceived

inefficacy, but the other 7 felt improvement with treatment and reported

a sense of well-being. No patient has worsened clinically, Ellman et al

said. In all but one patient, the MRSS has " improved remarkably. " Three

patients who started treatment earliest in the course of the disease

(mean 5.7 months) had skin scores decrease from 22.7 to 8.7. Moderately

severe fingertip ulcerations healed in 2 patients.

Initially, most of these patients were also receiving

" disease-modifying agents, " the researchers note, but now 3 patients are

taking only etanercept.

There is a rationale for TNF blockade in scleroderma, Ellman et al

note. Serum levels of TNF are elevated in skin and bronchoalveolar fluid

in patients compared with controls, and in vitro scleroderma fibroblasts

increase production of both interleukins IL-6 and IL-8 after incubation

with TNF. " We think the excess TNF seen in the skin, alveolar fluid, and

serum are contributing to inflammation and progression of the disease, "

they comment.

However, they point out that their group of patients was

self-selected (those that felt improvement staying on the drug) and

small in number; they also had modest lung disease and were taking other

drugs. " And, of course, scleroderma is notoriously difficult to

predict. " Nevertheless, etanercept used early is associated with a

marked improvement in MRSS and in a visual analog scale measuring

disease activity, they comment, and hence a controlled trial is

warranted.

Ellman et al believe " it is unlikely that TNF blockade worsens

scleroderma. " However, they point out a recent article [3] describing

animal work suggesting that it may do so. The work was carried out in a

murine model of scleroderma, in which the presence of a TNF blocker

(TNFRp55) perturbed the matrix metalloproteinases-1 (MMP-1), leading to

accumulation of collagen. The authors speculated that " patients

receiving anti-TNF therapy may be at risk of developing sclerodermalike

symptoms. "

Zosia Chustecka

Cited sources

1. Ellman MH, Mac PA, and Katz RS. Open label use of

etanercept in 8 patients. Ann Rheum Dis 2003; 62(Supp 1):229.

2. Ellman MH, Mac PA, FA. Etanercept as treatment for

diffuse scleroderma: a pilot study. Arthritis Rheum 2000; 43:s392.

3. Murota H, Hamasaki Y, Nakashima T, et al. Disruption of tumor

necrosis factor receptor p55 impairs collagen turnover in experimentally

induced sclerodermic skin fibroblasts. Arthritis Rheum 2003 Apr;

48(4):1117-25.

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