According to Creating Issues and Comments from Email:

If an issue key is NOT found in the subject, the in-reply-to header is examined:

• If the email message is found to be a reply to another email message from which an issue was previously created, the body is processed and added as a comment to that issue.
• If the email message is NOT found to be a reply, a new issue is created.

So if a user intends to create a new Issue by hitting Reply and changing the subject, the email is considered a comment and not a new issue by the handler.

Since the way external users send emails can't be controlled, using the In-Reply-To header prevents the creation of legitimate new issues.

Feature Request:
Remove the check or add the possibility to choose the use of In-Reply-To header.