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.