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NEW YORK (Reuters Health) Feb 15 - Some patients with systemic
lupus erythematosus (SLE) respond well to treatment with antimalarial
drugs. New research findings suggest that antimalarials reduce
serum levels of the inflammatory cytokine tumor necrosis factor
(TNF)-alpha. Moreover, these drugs are most effective in patients
with high serum levels of TNF-alpha and low levels of interleukin
(IL)-10.
Dr. Ana Suarez and colleagues point out in their report, published
in the February 13th issue of Arthritis Research and Therapy, that
the anti-inflammatory mechanisms of action of the antimalarial
drugs -- hydroxychloroquine, chloroquine, and quinacrine -- are
unknown. They believe that TNF-alpha may be involved.
Dr. Suarez, from University of Oviedo in Spain, and colleagues
therefore measured TNF-alpha in serum samples from 171 SLE patients
and 215 healthy controls.
They found that TNF-alpha levels were similar in controls (19.66
pg/mL) and the 39 treated with antimalarials alone for at least
3 months (16.64 pg/mL), while levels were higher for those who
were untreated or were receiving treatment with NSAIDs, corticosteroids,
or immunosuppressive drugs (60.01-105.34 pg/mL).
The authors note that IL-10 and TNF-alpha "are mutually regulated
and have complex and predominantly opposing roles in systemic inflammatory
responses."
They genotyped polymorphisms at promoter regions of the two cytokines
in 192 SLE patients and 343 controls. High TNF-alpha producers
had the AA or AG genotype at the -308 position, whereas low producers
were of the GG genotype.
For the allele present at the -8,082 position of the IL-10 promoter,
GG genotype was associated with high production and AA or AG with
low production.
Forty patients were long-term users of antimalarial drugs without
requiring other treatment, and 74 also used antimalarials but required
additional treatment with corticosteroids or immunosuppressants.
There was a significant association between carriage of the high
TNF-alpha producer genotype and good response to antimalarial drugs
(odds ratio 2.5, p = 0.024).
When the combined genotypes were analyzed, only the low IL-10/high
TNF-alpha genotype was significantly associated was good response
to antimalarials (odds ratio 3.13, p = 0.005).
The authors suggest that there is a regulatory feedback mechanism
that leads to decreases in TNF-alpha transcription in patients
producing elevated amounts of IL-10. "Thus," they say, "our results
suggest that antimalarial agents require a high rate of TNF-alpha
transcription to achieve the maximal inhibitory effect."
They continue: "Taken in conjunction, these results thus indicate
that determination of TNF-alpha and IL-10 alleles at the onset
of the disease may help identify more suitable candidates for antimalarial
treatment and could be used as a genetic predictor of clinical
outcome."
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