Mesalazine disappoints in ankylosing spondylitis

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Jul 14, 2003

Mesalazine disappoints in ankylosing spondylitis

Amsterdam, the Netherlands - As the gut is thought to play an important

role in the pathogenesis of ankylosing spondylitis (AS), Dutch

researchers set out to determine whether a drug that is commonly used

for inflammatory bowel diseasemesalazine (Salofalk®, Provalis)would

improve the condition.

However the 24-week, open pilot study of 20 people with AS found no

significant improvement in any disease variable among AS patients

except for erythrocyte sedimentation rate (ESR). Even more

disappointing was the fact that 8 patients stopped prematurely due to

adverse gastrointestinal effects and fully 75% experienced such adverse

effects. Dr Irene van der Horst-Bruinsma (Vrije Universiteit Medical

Center, Amsterdam, the Netherlands) and colleagues report their

findings in the July 2003 issue of the Journal of Rheumatology [1].

Mesalazine (also known as 5-aminosalicylic acid, 5-ASA) is a metabolite

of sulfasalazine, released when the parent drug is metabolized in the

large intestine; the other metabolite is sulfapyridine. Sulfasalazine

has been known to have some efficacy in AS, but in inflammatory bowel

disease, it is mesalazine that is the active drug; as it is less toxic

than sulfasalazine and also because the gut is known to be involved in

AS, the Dutch group set out to test whether mesalazine had any effect

in AS. They note that a previous trial comparing sulfasalazine,

mesalazine, and sulfapyridine in AS patients had suggested that the

active moiety was sulfapyridine, but that trial had used a very low

dose of mesalazine (Asacol® [Procter & Gamble Pharmaceuticals] 0.8

g/day). The Dutch group tested a higher dose, up to 4 g/day, of

mesalazine (as Salofalk), in the trial.

Only 60% of patients completed the full study; the 8 who stopped the

medication permanently did so after slightly more than 9 weeks due to

adverse effects consisting of gastrointestinal complaints, especially

diarrhea. Twelve patients completed 24 weeks using a mean dose of

3.2-g/day mesalazine (range 1 g to 4 g/day). An improvement was seen in

ESR, C-reactive protein, and physician's global assessment, but only

the change in ESR (from 29 mm/h on baseline to 25 mm/h at week 24)

reached statistical significance (p=0.03). No change was observed in

any of the other disease activity variables.

" Although we cannot exclude the possibility that a lower dose or a

different formulation of mesalazine might be better tolerated and more

effective, our results suggest that Salofalk has no role in the

treatment of AS, " van der Horst-Bruinsma and colleagues write.

Disappointment, but hope on horizon with biologics

Asked to comment on the study by rheumawire, Dr P Olenginski

(Geisenger Medical School, Danville, PA) says that one of the main

problems in treating AS is that there is currently no therapy shown to

reduce the progression of spinal fusion among patients.

In the past, colon biopsies of AS patients have shown low-grade

inflammation, leading to the belief that some stimulation in the gut is

perhaps driving the arthritis, " so if a drug works locally in the colon

to suppress inflammation, it was thought that we can reduce gut

inflammation and other disease manifestations, " he tells rheumawire.

But it was disappointing that 40% of patients weren't able to tolerate

the mesalazine and dropped out of the new study, he says. " Previously

sulfasalazine has helped with swollen knees and Achilles tendonitis,

but it was disappointing in spinal involvement. "

Currently, AS patients are treated mainly with exercise therapy and

nonsteroidal anti-inflammatory agents (NSAIDs), so the field is ripe

for a novel therapy. Olenginski notes that there is hope now with

biologic agentsthe TNF inhibitors infliximab (Remicade®, Centocor) and

etanercept (Enbrel®, Amgen) have " really been shown to be effective in

AS. "

Infliximab was recently approved for use in AS in Europe, and

etanercept was recommended last month for FDA approval for use in AS by

the FDA Arthritis Advisory Committee, as previously reported on

rheumawire.

Biologics are " are very effective in relieving signs and symptoms of AS

and, we hope, progression of spinal involvement, " Olenginski says, just

as they have been shown to relieve signs and symptoms but also slow

progression of disease in rheumatoid arthritis. However, he adds, " AS

is a much harder disease to monitor because we can't directly feel the

joints the way we can with RA. "

Mann

Source

1. van Demderen JC, van der Horst-Bruinsma IE, Bezemer PD, and Dijkmans

BA. Efficacy and safety of mesalazine (Salofalk) in an open study of 20

patients with ankylosing spondylitis. J Rheumatol 2003; 30:1558-1560.