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CASE BASED REVIEW
Ahead of print publication  

Hydroxychloroquine-induced auditory toxicity


1 Department of Rheumatology and Clinical Immunology, CMC, Vellore, Tamil Nadu, India
2 Department of Rheumatology, Tomo Riba Institute, Health and Medical Sciences, Papumpare, Arunachal Pradesh, India

Correspondence Address:
Abhishek Patil,
Department of Rheumatology and Clinical Immunology, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_130_19

  Abstract 


A 51-year-old female with mixed connective tissue disease presented with bilateral sensorineural hearing loss. The hearing deficit was gradually progressive over a period of 6 months. On evaluation, no obvious cause for hearing was evident. Due to ototoxic potential of hydroxychloroquine, we decided to stop the drug and observe for improvement. Over time, her hearing loss stabilized, with improvement in audiometric findings. Hydroxychloroquine induced auditory toxicity is rare. Increased awareness and early recognition may minimize damage.

Keywords: Audiogram, cinchonism, deafness, hydroxychloroquine, sensorineural



How to cite this URL:
Patil A, Jerang Y, Mathew J. Hydroxychloroquine-induced auditory toxicity. Indian J Rheumatol [Epub ahead of print] [cited 2020 Apr 5]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=277422




  Introduction Top


Hydroxychloroquine (HCQ) is an antimalarial agent commonly utilized in the management of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and other connective tissue disorders. It has various immunomodulatory properties such as stabilization of lysosomal function, inhibition of Toll-like receptor (TLR9), and downregulation of inflammatory cytokines.[1] The drug is used for prolonged periods in the management of the rheumatic conditions, sometimes lasting over decades. The most common adverse events of HCQ include gastrointestinal (nausea and diarrhea) and dermatologic (pruritis, rash, and hyperpigmentation). However, these are usually mild and rarely result in drug discontinuation. The most well-known and routinely monitored serious adverse effect of HCQ therapy is the ocular toxicity due to retinal pigment epithelial deposition.[2] The American Academy of Ophthalmology and several other societies have clearly defined guidelines for the monitoring of ocular toxicity of HCQ.[3] Although audiovestibular toxicity of HCQ has been reported in the literature, currently, there are no recommendations on the optimal monitoring of the same. Here, we report the case of a middle-aged female who developed auditory toxicity because of HCQ use.


  Case Report Top


Our patient is a 51-year-old female from Arunachal Pradesh, India, who presented with Raynaud's, puffy fingers, and arthritis for 6 years. She had a positive antinuclear antibody (4+ speckled at 1:640 dilution) and high-titer U1RNP antibody (237 [<15]). Thus, she was diagnosed as mixed connective tissue disease (MCTD) and treated with HCQ (400 mg/day) and steroids (40 mg/day of prednisolone with gradual taper to 5 mg/day and maintained) for 1 year. She weighed 74 kg and the cumulative HCQ dose was approximately 140 g. When on therapy, she had complained of tinnitus and gradually worsening hearing loss for 6 months before presentation to our institution. There was no history of vertigo, vomiting, or other features of vestibular system involvement. She was evaluated by an ENT surgeon and labeled as idiopathic mild sensorineural hearing loss (SNHL).

She also had a history of receiving antitubercular therapy (ATT) for an isolated lymph node swelling in the neck for 9 months. However, she had not received streptomycin and ATT was stopped 3 months before the onset of auditory complaints. At presentation to our institution, she had a proteinuria of 800 mg/day and a renal biopsy was done which showed membranous nephropathy. The audiogram obtained at our institute showed a progression of bilateral SNHL with the decrease of about 20 dB in both the ears (compared to initial audiogram obtained 6 months ago) [Table 1] and [Figure 1]. She was further evaluated by the ENT surgeon at our institute. There was no obvious anatomical cause for hearing loss. Her blood sugars and thyroid function tests were normal. On reviewing the medication history, the patient had not been on any medications with the potential for auditory toxicity except for HCQ. Ophthalmological evaluation for HCQ toxicity revealed a mild decrease in the amplitude on multifocal electroretinogram; however, she had a normal spectral-domain ocular coherence tomography and 30-2 visual filed analyzer, thus revealing no specific features of ocular toxicity. We decided to stop the HCQ and observe the patient for improvement. She was also initiated on mycophenolate mofetil and dose of prednisolone was increased to 10 mg/day. Repeat audiogram obtained after discontinuation of the medication showed stabilization of hearing with the improvement in audiogram [Figure 1].
Table 1: Audiogram of the patient at various time points

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Figure 1: Audiogram of the patient (a) at the onset of hearing loss, (b) after 6 months of hydroxychloroquine therapy, and (c) 3 months after stopping the drug

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  Discussion Top


Here, we report a patient with MCTD who developed auditory toxicity due to HCQ. The exact mechanism of HCQ-induced auditory toxicity is unknown. Proposed mechanisms involve the damage to the sensory cells, atrophy of stria vascularis, and loss of nerve fibers.[4] Cinchonism which includes auditory toxicity is a term used to describe a range of symptoms associated with the use of quinine and its derivatives. There is a structural similarity between quinine derivatives and the HCQ and thus the ototoxicity may be expected with HCQ.

Our patient developed SNHL with tinnitus which progressed over a period of 6 months before presentation at our institution. Idiopathic sensory hearing loss affects 5–20/100,000 persons/year.[5] Although idiopathic sudden SNHL is common at this age group, it is typically unilateral.[6] She was not exposed to loud noise over prolonged periods nor she was exposed to a high intensity sound before the onset of hearing impairment. She had no history of head injury around the time of onset of hearing loss. Apart from HCQ, she was not on other medications with known ototoxic potential. MCTD could be associated with hearing loss resulting from pathogenic autoantibodies or immune complex-mediated vasculitis causing damage to inner ear structures.[7] In such cases, the hearing loss is sensorineural and bilateral and develops gradually. The onset of hearing loss after the initiation of high-dose steroids in our patient makes the autoimmune inner ear disease less likely as the underlying etiology. The temporal onset of hearing loss with the use of HCQ and the partial recovery of the deficit after discontinuation of the drug clearly implicate the drug in the auditory defect observed in our patient.

We searched PUBMED using the search terms “Hydroxychloroquine” and “Hearing loss” published and retrieved 17 items. Among these, we chose the case reports and case series which implicated HCQ as the culprit for ototoxicity. The same has been summarized in [Table 2]. In these cases, HCQ was used for various indications such as SLE, RA, and scleroderma. The onset of hearing defect varied from few months to years after the initiation of the drug.[4],[9],[10] The recovery of the hearing impairment after the discontinuation of HCQ has not been uniform. While Seçkin et al.[9] reported the recovery of the hearing impairment after the discontinuation of HCQ, others noted irreversible hearing loss.[10] In an analysis of French pharmacovigilance network between 1986 and 2010, there were 61 cases of audiovestibular symptoms reported in patients treated with antimalarials.[11] However, only in three of these cases, the toxicity was “likely” attributed to HCQ. The median duration to onset of symptoms was approximately 3 months after the initiation of the drug. The key appears to be early recognition and discontinuation of the medication. In a busy outpatient rheumatology setup, the hearing loss of patients may go unnoticed if the physician is not awake to the ototoxic potential of HCQ. Our case highlights the importance of the awareness among the treating physicians of the ototoxicity of HCQ.
Table 2: Reported cases of hydroxychloroquine auditory toxicity

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Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 2015;23:231-69.  Back to cited text no. 1
    
2.
Costedoat-Chalumeau N, Dunogué B, Leroux G, Morel N, Jallouli M, Le Guern V, et al. A critical review of the effects of hydroxychloroquine and chloroquine on the eye. Clin Rev Allergy Immunol 2015;49:317-26.  Back to cited text no. 2
    
3.
Marmor MF, Kellner U, Lai TY, Melles RB. American Academy of Ophthalmology statement recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology 2016;123:1386-94.  Back to cited text no. 3
    
4.
Khalili H, Dastan F, Dehghan Manshadi SA. A case report of hearing loss post use of hydroxychloroquine in a HIV-infected patient. Daru 2014;22:20.  Back to cited text no. 4
    
5.
Byl FM Jr. Sudden hearing loss: Eight years' experience and suggested prognostic table. Laryngoscope 1984;94:647-61.  Back to cited text no. 5
    
6.
Rauch SD. Idiopathic sudden sensorineural hearing loss. N Engl J Med 2008;359:833-40.  Back to cited text no. 6
    
7.
Hajas A, Szodoray P, Barath S, Sipka S, Rezes S, Zeher M, et al. Sensorineural hearing loss in patients with mixed connective tissue disease: Immunological markers and cytokine levels. J Rheumatol 2009;36:1930-6.  Back to cited text no. 7
    
8.
Fernandes MR, Soares DB, Thien CI, Carneiro S. Hydroxychloroquine ototoxicity in a patient with systemic lupus erythematosus. An Bras Dermatol 2018;93:469-70.  Back to cited text no. 8
    
9.
Seçkin U, Ozoran K, Ikinciogullari A, Borman P, Bostan EE. Hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis. Rheumatol Int 2000;19:203-4.  Back to cited text no. 9
    
10.
Johansen PB, Gran JT. Ototoxicity due to hydroxychloroquine: Report of two cases. Clin Exp Rheumatol 1998;16:472-4.  Back to cited text no. 10
    
11.
Jourde-Chiche N, Mancini J, Dagher N, Taugourdeau S, Thomas G, Brunet C, et al. Antimalarial ototoxicity: An underdiagnosed complication? A study of spontaneous reports to the French Pharmacovigilance Network. Ann Rheum Dis 2012;71:1586.  Back to cited text no. 11
    


    Figures

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    Tables

  [Table 1], [Table 2]



 

 
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