By Wayne Veysey | Chief Correspondent
The midfielder has suffered a recurrence of his long-running ankle problems and is considered unlikely to even make the substitute's bench for the Emirates Stadium showdown.
Goal understands that the latest damage is to Wilshere's right ankle, which he had surgery on during the summer, and Arsenal are ready to give him a breather in order not to aggravate the joint.
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The England star's likely absence is a major blow to the Premier League leaders ahead of a match that is regarded as a litmus test of their title credentials.
With Mathieu Flamini (groin) and Serge Gnabry (ankle) already ruled out and Theo Walcott, Lukas Podolski, Alex Oxlade-Chamberlain and Abou Diaby still unavailable, manager Arsene Wenger is left with few selection dilemmas.
Goal understands that Wenger will make seven changes to the Arsenal team that were beaten 2-0 by Chelsea in the Capital One Cup in midweek, although this amounts to only one change to the starting X1 against Crystal Palace seven days ago, a game the Gunners won 2-0.
Wojciech Szczesny, Bacary Sagna, Per Mertesacker, Kieran Gibbs, Mikel Arteta, Mesut Ozil and Olivier Giroud, who were all rested on Tuesday, are expected to re-join Laurent Koscielny, Aaron Ramsey, Santi Cazorla and Tomas Rosicky in the team.
Wenger admitted eight days ago that he is trying "to be a bit more cautious" with Wilshere, whose short career has been blighted by problems to his ankles, particularly his right one, and this latest setback will be alarming to Arsenal and England supporters.
The 21-year-old has made 20 appearances for club and country this season but his form has been fitful, despite him scoring what Wenger described as one of the outstanding goals of his Arsenal reign against Norwich last month.
Wilshere was a second-half sub against Palace last weekend after limping off against Borussia Dortmund three days earlier with ankle pain. However, he played the full 90 minutes against Chelsea in midweek.