Discussion:
Azathioprine (AZA) is an immunosuppressant drug that belongs to the
thiopurine class. It is widely used in management of various medical
disorders including inflammatory bowel diseases, autoimmune diseases,
and in preventing organ transplant rejection. (1 - 4)
Azathioprine converts to its active metabolites, mercaptopurine (6-MP)
and thioguanine (6-TGN), by the action of hypoxanthine-guanine
phosphoribosyltransferase (HPRT) and thiopurine methyltransferase (TPMT)
enzymes. (5) The mechanism of action of Azathioprine
involves antagonism of purine metabolism, thus, resulting in the
inhibition of DNA, RNA, and protein synthesis. (1, 2,
5) Its metabolites are incorporated into the replicating DNA & halt
division. AZA metabolites also mediate most of its immunosuppressive and
toxic effects. (5)
One of the major concerns of Azathioprine treatment is the occurrence of
adverse effects which consequently mandates the discontinuation of the
therapy. (6, 7) The reported incidence of the side
effects ranges from 5-30% and those can be dose related (bone marrow
suppression, hepatotoxicity, opportunistic infections & risk of cancer)
or dose independent (idiosyncratic and allergic reactions).(2, 6-7, 10) Dose-dependent side effects often need
decrease of the dose & rarely require discontinuation of AZA. Dose
independent reactions, however, are more common and frequently demand
drug discontinuation. (10-12)
Sialadenitis is inflammation of the salivary gland. Acute sialadenitis
is characterized by sudden pain and enlargement of the affected gland
and chronic sialadenitis, in general, is less likely to be painful and
often characterized by recurrence and abnormally firm gland.
Sialadenitis may be due to obstruction, bacterial/viral infections,
inflammation or drugs. (13)
Drug-induced sialadenitis manifests in several ways, such as xerostomia,
sialorrhea, saliva discoloration, sialolithiasis, and sialadenitis. A
recent review has identified several drugs that may be linked with
salivary gland dysfunction; however, AZA is not included in the list.(14) The etiology of drug-induced salivary dysfunction
is not clearly identified, but it may involve spasm of smooth muscle of
the gland, altered autonomic function interfering the sympathetic
vasoconstrictor effect, anticholinergic effect, or hypersensitivity
reaction. (15)
In our case, the patient was started on Azathioprine for ophthalmopathy,
following failure of the initial therapy, as a steroid sparing agent. 1
week later, patient developed acute sialadenitis involving the
submandibular glands, which resolved upon stopping the medication.
However, when patient was re-challenged with the same medication, he
developed the same symptoms and signs, which supports that his
sialadenitis was drug induced.
Joana da Silva reported a case of acute submandibular sialadenitis in a
Crohn’s disease patient treated with Azathioprine. (8)That patient developed symptoms of submandibular sialadenitis 15 days
after starting Azathioprine, whereas our patient developed in a week
time. However, in both cases, patient responded to discontinuation of
the medication and had recurrence of sialadenitis on the next day of
rechallenge with same drug.
In 2013, Vinayak et al. reported some cases of drug-induced
sialadenitis. (9) Majority were presenting with
bilateral swelling and elevation of inflammatory parameters, and 2 cases
even presenting with fever; a clinical picture similar to our case. Some
of the drugs implicated were oxyphenbutazone, nitrofurantoin,
doxycycline, and enalapril. But there were no cases of Azathioprine
induced sialadenitis reported in this study. As in our case, in most of
the reported cases, the salivary gland swelling subsided after cessation
of the offending drugs, with or without corticosteroid therapy.