Open Trial of Methotrexate as Treatment for Autoimmune Hearing Loss

Transcription

1 ARTHRITIS CARE & RESEARCH 45: , 2001 ORIGINAL ARTICLE Open Trial of Methotrexate as Treatment for Autoimmune Hearing Loss ERIC L. MATTESON, 1 DAVID A. FABRY, 2 GEORGE W. FACER, 2 CHARLES W. BEATTY, 2 COLIN L. W. DRISCOLL, 2 SCOTT E. STROME, 2 AND THOMAS J. MCDONALD 2 Objective. To assess the efficacy of low-dose methotrexate (MTX) administered for the treatment of autoimmune hearing loss. Methods. This was a prospective, 12-month, open-label study of 17 patients with refractory autoimmune hearing loss. All patients had ongoing episodic worsening of hearing in one or both ears prior to enrollment despite traditional medical therapy. The MTX dose was mg/week. Hearing loss and vertigo were evaluated at baseline and at completion of the study. Hearing improvement was defined as an improvement in pure tone threshold (PT) average of >10 db or an increase in speech discrimination (SD) of >15%; worsening was defined as a decrease of >10 db in PT or a decrease of >15% in SD in at least one ear. Results. MTX was well tolerated. Among patients with Meniere s disease, 5 of 9 had improvement or resolution of vertigo. Equilibrium improved in all 3 patients with Cogan s syndrome and improved in 2 out of 3 patients with idiopathic hearing loss and this symptom. According to the parameters defined above, hearing improved in 11 patients (65%), was unchanged in 4 patients (23%), and worsened in 2 patients (12%). Conclusion. Long-term low-dose MTX therapy may be a useful therapy for at least some patients who have hearing loss with a presumptively autoimmune-mediated component that is refractory to traditional therapies. KEY WORDS. Autoimmune hearing loss; Cogan s syndrome; Meniere s disease; Methotrexate. INTRODUCTION Autoimmune inner ear disease is a clinical syndrome of uncertain pathogenesis. It is often associated with rapidly progressive hearing loss that, especially early in the disease course, may be unilateral but is most commonly bilateral, presenting as sudden deafness or rapidly progressive sensorineural hearing loss (1,2). The hearing loss may be associated with vestibular symptoms. Autoimmunity has been proposed as the pathogenesis of sudden sensorineural hearing loss, although the mechanism of disease is poorly understood. Clinically, sudden sensorineural hearing loss has been seen in association with other autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel 1 Eric L. Matteson, MD, MPH, Division of Rheumatology, Mayo Clinic and Foundation, Rochester, Minnesota; 2 David A. Fabry, PhD, George W. Facer, MD, Charles W. Beatty, MD, Colin L. W. Driscoll, MD, Scott E. Strome, MD, and Thomas J. McDonald, MD, Department of Otorhinolaryngology, Mayo Clinic and Foundation, Rochester, Minnesota. Address correspondence to Eric L. Matteson, MD, MPH, Mayo Clinic and Mayo Graduate School of Medicine, 200 1st Street SW, Rochester, MN Submitted for publication April 29, 2000; accepted in revised form December 6, disease, and polyarteritis nodosa (1,3 5). Cogan s syndrome is accepted as an autoimmune disease, and it is likely that at least some cases of Meniere s disease, especially when bilateral, are autoimmune in nature (6 9). Circulating autoantibodies against inner ear antigens have been reported, as have viral antigens in the endolymph, although the sensitivity, specificity, and role of these antibodies in the disease process are poorly defined (10 14). The improvement in hearing following corticosteroid and immunosuppressive therapy as well as plasmapheresis further suggests an autoimmune response as the etiology of the hearing loss in these conditions (3,8,15). It has been suggested that a nonspecific reactant, heat shock protein (HSP) 70, may be predictive of corticosteroid responsiveness (16). It has also been suggested that disturbance of microcirculation in the inner ear by thrombosis associated with antiphospholipid antibodies may lead to sudden deafness (2,17,18). High doses of corticosteroids, often in doses of gm/day, may be useful in the initial management of autoimmune-mediated sensorineural hearing loss. Unfortunately, improvement in hearing is rarely sustained, and unacceptable side effects from the corticosteroid therapy soon follow. To improve the outcome of autoimmune inner ear disease, the use of cytotoxic therapy with cyclo- 2001, American College of Rheumatology Published by Wiley-Liss, Inc.

2 Arthritis Care & Research MTX for Autoimmune Hearing Loss 147 phosphamide has been proposed (10,15). Although some success has been reported with this therapy in slowing or arresting the hearing loss, cyclophosphamide use is associated with significant toxicities, including increased risk of infection, malignancy, and death (19). Another chemotherapeutic agent, methotrexate (MTX), has been successfully used in low doses for the management of a number of autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, and Wegener s granulomatosis, with favorable experience from a standpoint of both efficacy and toxicity (20). Based on this experience, MTX has also been employed as treatment for autoimmune inner ear diseases, including some cases of Meniere s disease and Cogan s syndrome (21,22). We conducted a 1-year prospective study of low-dose MTX to evaluate the long-term efficacy of this therapy in the management of autoimmune hearing loss. PATIENTS AND METHODS Patients. This was an open-label prospective study of oral MTX for the treatment of refractory autoimmune hearing loss with a planned duration of 12 months. Patients were eligible for enrollment based on the following criteria: (a) presence of unilateral or bilateral progressive sensorineural hearing loss, symptoms of bilateral Meniere s disease, or sensorineural hearing loss associated with Cogan s syndrome and (b) a positive response (in hearing) to prednisone (1 mg/kg/day). Over a period of 36 months, 17 patients were enrolled. All patients had ongoing episodic and/or progressive worsening of hearing in one or both ears prior to enrollment despite traditional medical therapy. These therapies included the use of low-salt diet, diuretics, and vestibular suppressants in patients with Meniere s disease, as well as oral corticosteroids. No patients had received chemotherapeutic agents for treatment of hearing loss prior to enrollment. Prior to initiation of the study drug, MTX, 25 patients were given a challenge of oral prednisone at an initial dose of 1 mg/kg/day, tapering off over 3 weeks. Of these, 18 had partial improvement in hearing in at least one ear; 17 patients gave informed consent and were enrolled into the trial. Treatment. Oral MTX was administered at an initial dose of 7.5 mg per week, increasing to 25.0 mg per week over the ensuing 4 to 8 weeks. Laboratory evaluation including a complete blood count and liver enzyme testing was performed every 4 to 8 weeks to assess for MTX toxicity. To minimize the potential toxicity, folic acid was prescribed for each patient at a dose of 1 mg per day. Assessment of clinical disease activity. Patients returned to clinic every 3 months for general health assessment and evaluation of hearing and vertigo. Formal audiometric evaluation was performed prior to the oral prednisone challenge (pretreatment), at baseline (following the prednisone challenge, and at the time treatment with MTX was begun), and at completion of the study (month 12). In addition, patients were asked for a subjective assessment of hearing and, if applicable, of disequilibrium or vertigo (improved, worse, or unchanged). Data analysis. Improvement in hearing was defined as an improvement in pure tone audiometric threshold (PT, at 0.5, 1.0, 2.0, 3.0 khz) average of 10 db or an increase in speech discrimination (SD) of 15%, and worsening was defined as a decrease of 10 db in PT or a decrease of 15% in SD in at least one ear. These parameters of outcome were selected based on the likelihood of finding true differences in hearing based on test retest performance characteristics of audiometry (23,24). Data from all enrolled patients were considered, including 2 patients who did not complete MTX therapy for the full 12 months of the study. The parameters of improvement were assessed by audiometry obtained at baseline and at the completion of the study. We chose this statistically conservative approach to avoid possibly overestimating the treatment effect of MTX, which could occur if the response of patients to the initial, pretreatment prednisone challenge were compared with the audiogram done at study termination. RESULTS Patient characteristics. A total of 17 patients (7 women, 10 men) were enrolled into this study. The mean age at enrollment was 48.8 years (range 19.9 to 71.1 years). Patients had had hearing loss for an average of 4.7 years (range 3 months to 14.8 years). Hearing loss was due to Meniere s disease in 9 patients, was due to Cogan s syndrome in 3, and was idiopathic in 5. There were 7 patients who had ever smoked; none were smokers at enrollment. Hearing loss was bilateral in 14 patients, including 5 patients who were functionally deaf in one ear at enrollment (3 with Meniere s disease, 1 with Cogan s syndrome, 1 with idiopathic hearing loss). Prior to enrollment, all patients had ongoing episodic worsening of hearing in one or both ears despite traditional medical therapy, including corticosteroids in all patients and diuretic therapy in patients with Meniere s disease. Disequilibrium or vertigo was present in 15 of the 17 patients at baseline. Prior to enrollment into the study, a total of 25 patients received a challenge of oral prednisone at an initial dose of 1 mg/kg/day, tapering off over 3 weeks. All 17 patients enrolled into the study had at least partial improvement of hearing as defined above in at least one ear. At baseline, 4 patients (1 with idiopathic hearing loss, 3 with Cogan s syndrome) were on chronic daily prednisone therapy, which was continued through and following the taper of the prednisone challenge. The baseline prednisone dose was further adjusted in these patients during the active treatment period with MTX according to clinical symptoms. Baseline laboratory assessment included negative or normal complete blood count, serum aspartate aminotransferase, Westergren sedimentation rate, syphilis serology, rheumatoid factor, and antinuclear antibody. Perinu-

3 148 Matteson et al Vol. 45, No. 2, April 2001 Table 1. Summary of therapeutic efficacy of low-dose methotrexate for autoimmune hearing loss in 17 patients at 1 year of followup Outcome Improved* Unchanged Worse Global audiometric assessment of hearing (n ) Meniere s disease (n 9) Cogan s syndrome (n 3) Idiopathic autoimmune hearing loss (n 5) Pure tone threshold, at least 1 ear Speech discrimination, at least 1 ear Patient assessment of hearing (n 17) Meniere s disease (n 9) Cogan s syndrome (n 3) Idiopathic autoimmune hearing loss (n 5) Vertigo (subjective assessment of patients who experienced vertigo, n 15) Meniere s disease (n 9) Cogan s syndrome (n 3) Idiopathic autoimmune hearing loss (n 3) * According to the study criteria, improvement in pure tone average by 10 db or in speech discrimination by 15% in at least one ear. Pure tone threshold 10 db from baseline; speech discrimination 15% from baseline. Worsening in pure tone threshold 10 db from baseline or in speech discrimination 15% from baseline. clear antineutrophilic cytoplasmic antibody was present in 2 patients; cytoplasmic antineutrophilic cytoplasmic antibody was negative in all. Antiphospholipid IgM antibodies were present in low titer (1:4 to 1:64) in 3 patients (2 with Meniere s, 1 with idiopathic disease) and were negative in the other patients. Serum protein electrophoresis revealed a slight polyclonal increase in gamma immunoglobulin in 1 patient and was otherwise negative in the remaining patients. HSP 70 was not available to us as a clinical test and was not measured. Computerized tomography (5 patients) or magnetic resonance imaging (12 patients) of the brain was nondiagnostic in all patients. Clinical efficacy. During the course of 1 year of followup on MTX therapy, improvement in hearing as defined in the Methods section (change in PT threshold average of 10 db or increase in SD of 15% in at least one ear) was seen in 11 of 17 patients (65%), while hearing was worse in 2 patients (12%) and was unchanged in 4 patients (23%). Improvement in PT in one ear was seen in 9 of 17 patients (53%), and SD was improved in at least one ear in 5 of 17 patients (29%). In 2 patients the SD improved in both ears, and no patients had improvement in PT in both ears. However, both PT and SD were improved in at least one ear in only 4 of 17 patients (23%), and no patient had improvement in both PT and SD in both ears. Table 1 contains a summary of these results. For clarity, the responses by diagnosis are displayed separately and together. Patients were asked to keep a diary of the occurrence and severity of hearing fluctuation during the course of the study. Using this information, and their overall impression of their hearing, all were asked to give their subjective assessment of their hearing at completion of the 12-month study. Only 6 of the 17 patients (35%) felt that their hearing had actually improved by the end of the study. Both at month 3 and at month 6, 8 of the 17 felt that their hearing was improved; by month 9, 5 of 17 thought that their hearing was better. There was discordance between patient assessment and audiometric assessment of hearing, as the PT results (hearing improved, unchanged, or worse) agreed with the patient assessment in only 8 of 17 cases, and SD agreed with patient assessment in 5 of 17 cases. Hearing remained stable or improved subjectively and by audiometric criteria in all patients with Cogan s syndrome (Table 1). In these patients, the average prednisone dose at enrollment was 28 mg/day; at completion of the study the average dose was 12 mg/day, and 1 of the 3 patients discontinued steroids completely while maintaining stable hearing. None of the patients with Cogan s syndrome had active ocular or systemic disease at enrollment, and none of these patients developed these disease manifestations during the study. All patients also kept a diary to assess the frequency and severity of disequilibrium or vertigo during the study. At baseline, this symptom was experienced to some degree by 15 patients. Improvement in disequilibrium or vertigo (reduced number and/or severity of episodes) was noted by 10 of the 15 patients, including 3 of 3 with Cogan s syndrome, 5 of 9 with Meniere s disease, and 2 of the 3 patients with idiopathic autoimmune hearing loss. Toxicity. MTX therapy was well tolerated. Low-grade elevation of serum aspartate aminotransferase occurred in 1 patient, necessitating reduction in the weekly MTX dose from 17.5 to 12.5 mg. Two patients discontinued MTX prematurely, patient 5 at week 36 and patient 9 at week 28, because of their concern about possible side effects in view

4 Arthritis Care & Research MTX for Autoimmune Hearing Loss 149 of their perception of lack of therapeutic efficacy. Both of these patients are included in the analysis of the results. DISCUSSION Autoimmune inner ear disease is an uncommon condition, the etiology of which is uncertain. Response to treatment, usually with corticosteroids and/or immunosuppressive drugs, is uncertain, and many if not most patients eventually develop some degree of permanent hearing loss. The present study examined the 1-year outcome of patients with autoimmune hearing loss treated with lowdose oral MTX at doses commonly used in the treatment of another immune-mediated disorder, rheumatoid arthritis. To ascertain whether the therapy could be beneficial in the studied patients, we first administered a short course of prednisone, enrolling patients who had improvement following the corticosteroid challenge. At the outset of the study, success was defined as improvement in audiometric parameters of PT average by 10 db or of SD by 15% in at least one ear. These parameters were chosen because they represent true differences in hearing based on test retest audiometrics (23,24). According to the audiometric criteria, improvement was seen in 11 of 17 treated patients. It is encouraging that PT improved in at least one ear in 9 of 17 patients, while SD improved in 7 of 17 patients. However, improvement in both PT and SD in at least one ear occurred in only 4 of 11 patients. It could not be expected that both PT and SD would improve in both ears in all patients, as 5 patients were functionally deaf in one ear at study outset; nevertheless, no patient had improvement in both of these parameters in both ears. The view of the patients revealed a rather different picture. By patient assessment, only 6 of 17 patients felt that their hearing had improved during the study. This discordance to the audiometric findings is of considerable clinical importance, as the final arbiter of success of a therapy must be the favorable outcome in the opinion of the patient who must take the medication and cope with the side effects. Despite apparent improvement in audiometric parameters, 2 patients discontinued the drug prior to completion of the 52-week study, as they did not feel that their hearing had improved and did not wish to have the expense, inconvenience, and potential side effects of MTX therapy. However, in poststudy followup, 7 of the 17 patients, including the 3 with Cogan s syndrome, continue to take MTX and have had essentially stable hearing by audiometric and subjective assessment for 2 years since study initiation. Although it is not the primary outcome of interest, by the end of the 12-month followup, disequilibrium or vertigo was improved in 10 of the 15 patients entering the study with this symptom. The assessment of this symptom was entirely patient-derived in this study, and formal testing was not included as a parameter of outcome. Whether this improvement is a true treatment effect, represents the natural course of the symptom and the accommodation of the patient to it, or is a placebo effect remains unknown. This study was of an exploratory nature and has all of the shortcomings of an open-label trial. The outcome may simply reflect the usual course of autoimmune hearing loss rather than the result of treatment. While 11 of 17 patients were improved by audiometric criteria, only 6 of 17 patients felt improved, suggesting that the audiometric parameters chosen were clinically inadequate in defining success. However, only 2 of 17 had worsening of hearing by either audiometric or subjective criteria, including 1 patient with idiopathic disease who continued on corticosteroid therapy for 8 months of the trial. Whether the improvement or stabilized symptoms are due to the prednisone treatment or to the MTX therapy remains uncertain. A randomized, controlled trial would be required to establish the role of MTX in the treatment of this disease. Future studies may need to require an even larger degree of improvement in audiometric parameters than was employed in this study, including perhaps improvement in both ears, and perhaps a different method for patient-derived assessment. We believe that the patient assessment must be a cornerstone for any claims of success in any study, because it is the patient who must finally decide whether the treatment is of value. Patients with Cogan s syndrome appeared to do the best and were most willing to continue with MTX therapy after completion of the trial. The daily prednisone dose could be reduced by 50% during the course of the study, and 1 patient with Cogan s syndrome discontinued prednisone altogether without worsening of hearing, a factor that contributed to patient satisfaction. The number of patients was too small to permit meaningful conclusions about the ultimate role of MTX as adjuvant therapy for Cogan s syndrome, but this and other reports suggest that it may be superior to corticosteroid therapy alone (15,25). All 3 patients with Cogan s syndrome continued taking prednisone throughout the study, as did 1 patient with idiopathic autoimmune hearing loss who had worsened hearing over the course of the 1-year followup and requested continuation of prednisone therapy. If these patients with Cogan s syndrome are excluded, 8 of 14 (57%) of patients were improved by audiometric criteria, and 5 of 14 (36%) were subjectively improved. Understanding of the efficacy of long-term benefits of brief courses of corticosteroids or long-term therapies for autoimmune hearing loss is limited by the lack of knowledge about the natural history of these entities. Untreated, the hearing loss may progress in most patients, even to deafness in a substantial number (1,25). Comparative treatment studies are not available, although short-term responses to corticosteroids and chemotherapeutic agents including cyclophosphamide and azathioprine have been reported in some series (1,26). Three syndromes of autoimmune hearing loss, possibly with differing pathoetiologies, were examined in this study. Patients were enrolled based on the diagnosis and on improvement in audiometric parameters following a challenge of prednisone given prior to initiation of therapy with MTX. Future studies should examine these entities separately. MTX may offer an additional generally well tolerated and durable therapeutic option for the treatment of some patients with autoimmune hearing loss. Further random-

5 150 Matteson et al Vol. 45, No. 2, April 2001 ized, controlled trials of this therapy should be considered for this indication. Improved understanding of the pathogenesis and natural history of these disorders will also greatly contribute to improved therapies. REFERENCES 1. McCabe BF. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol 1979;88: Toubi E, Ben-David J, Kessel A, Podoshin L, Golan TD. Autoimmune aberration in sudden sensorineural hearing loss: association with anticardiolipin antibodies. Lupus 1997;6: Veldman JE, Roord JJ, O Connor AF, Shea JJ. Autoimmunity and inner ear disorder: an immune complex mediated sensorineural hearing loss. Laryngoscope 1984;94: Summers RW, Harker L. Ulcerative colitis and sensorineural hearing loss: is there a relationship? J Clin Gastroenterol 1982; 4: Andonopoulos AP, Naxakis S, Goumas P, Lygatsikas C. Sensorineural hearing disorders in systemic lupus erythematosus: a controlled study. Clin Exp Rheumatol 1995;13: Shea JJ. Autoimmune sensorineural hearing loss as an aggravating factor in Meniere s disease. Presented at: Barany Society Meeting; June, 1982; Basel, Switzerland. 7. Hughes GB, Kinney SE, Barna BP, Calabrese LH. Autoimmune reactivity in Meniere s disease: a preliminary report. Laryngoscope 1983;93: Hughes GB, Kinney SE, Barna BP. Autoimmune reactivity in Cogan s syndrome: a preliminary report. Otolaryngol Head Neck Surg 1983;91: Haynes BF, Pikus A, Kaiser-Kupfer M, Fauci AS. Successful treatment of sudden hearing loss in Cogan s syndrome with corticosteroids. Arthritis Rheum 1981;24: Hughes GB, Kinney SE, Barna BP, Calabrese LH. Practical versus theoretical management of autoimmune inner ear disease. Laryngoscope 1984;94: Alleman AM, Dornhoffer JL, Arenberg IK, Walker PD. Demonstration of autoantibodies to the endolymphatic sac in Meniere s disease. Laryngoscope 1997;107: Shin S-O, Billings PB, Keithley EM, Harris JP. Comparison of anti-heat shock protein 70 (Anti-hsp70) and anti-68-kda inner ear protein in the sera of patients with Meniere s disease. Laryngoscope 1997;107: Gottschlich S, Billings PB, Keithley EM, Weisman MH, Harris JP. Assessment of serum antibodies in patients with rapidly progressive sensorineural hearing loss and Meniere s disease. Laryngoscope 1995;105: Kumagami H. Detection of viral antigen in the endolymphatic sac. Eur Arch Otorhinolaryngol 1996;253: McCabe BF. Autoimmune inner ear disease: therapy. Am J Otol 1989;10: Hirose K, Wener MH, Duckert LG. Utility of laboratory testing in autoimmune inner ear disease. Laryngoscope 1999;109: Casoli P, Tumiati B. Cogan s syndrome: a new possible complication of antiphospholipid antibodies? Clin Rheumatol 1995;14: Naarendorp M, Spiera H. Sudden sensorineural hearing loss in patients with systemic lupus erythematosus or lupus-like syndromes and antiphospholipid antibodies. J Rheumatol 1998;25: Clements PJ. Alkylating agents. In: Dixon J, Furst DE, editors. Second line agents in the treatment of rheumatic diseases. New York: Marcel Dekker; p Songsiridey N, Furst DE. Methotrexate: the rapidly acting drug. Clin Rheumatol 1990;4: Kilpatrick JK, Sismanis AM, Spencer RF, Wise CM, Michaelides EM. Low dose methotrexate for the treatment of bilateral Meniere s disease. Presented at: 131st annual meeting, American Otological Society; May 9 10, 1998; Palm Beach, FL. 22. Richardson B. Methotrexate therapy for hearing loss in Cogan s syndrome. Arthritis Rheum 1994;37: Thornton AR, Raffin MJM. Speech discrimination scores modeled as a binomial variable. J Speech Hear Res 1978;21: Raffin MJM, Thornton AR. Confidence levels for differences between speech-discrimination scores: a research note. J Speech Hear Res 1980;23: Vollertsen RS, McDonald TJ, Young BR, Banks PM, Stenson AW, Ilstrup DM. Cogan s syndrome: 18 cases and a review of the literature. Mayo Clin Proc 1986;61: Saracaydin A, Katircioglu S, Katircioglu S, Karatay MC. Azathioprine in combination with steroids in the treatment of autoimmune inner-ear disease. J Int Med Res 1993;21:192 6.