- Email: [email protected]
Mycophenolate mofetil as a treatment of steroid dependent Cogan's syndrome in childhood
International Journal of Pediatric Otorhinolaryngology 73 (2009) 1477–1479
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case report
Mycophenolate mofetil as a treatment of steroid dependent Cogan’s syndrome in childhood Charlotte Hautefort a,1,*, Natalie Loundon a,1, Marta Montchilova c,1, Sandrine Marlin d,1, Erea Noel Garabedian a,1, Tim Ulinski b,1 a
Service d’ORL, de chirurgie cervico-faciale et d’audiophonologie de l’enfant, Hoˆpital d’Enfants Armand Trousseau, 26 av Dr. Arnold Netter, 75012 Paris, France Service de Ne´phrologie pe´diatrique Hoˆpital d’Enfants Armand Trousseau, 26 av Dr. Arnold Netter, 75012 Paris, France Service d’Ophtalmologie pe´diatrique Hoˆpital d’Enfants Armand Trousseau, 26 av Dr. Arnold Netter, 75012 Paris, France d Service de Ge´ne´tique Hoˆpital d’Enfants Armand Trousseau, 26 av Dr. Arnold Netter, 75012 Paris, France b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 June 2009 Accepted 27 June 2009 Available online 4 August 2009
Cogan’s syndrome is a rare chronic inflammatory disorder which typically associates an ophthalmological and vestibulocochlear involvement, with a risk of systemic symptoms in 50–70% of cases. Autoimmune origin has been consolidated by the recent discoveries of Lunardi as a result of the dysregulation of the response of B and T lymphocytes. We report here a pediatric case of Cogan’s syndrome, with long term follow-up and complete vestibulocochlear and ophthalmologic examination. During the acute phase, early steroids treatment (prednisone 1 mg/kg per day) was effective on ocular lesions and hearing loss. The patient required high steroid doses to maintain remission, suggesting the necessity for steroid sparing immunosuppressive agents. We introduced mycophenolate mofetil (MMF), an immunosuppressive agent mainly used in solid organ transplantation. After steroid withdrawal the patient remained in complete remission on MMF. This is the first report of MMF treatment in Cogan’s syndrome. MMF produces a targeted inhibition of the proliferation of B and T lymphocytes, particularly interesting in Cogan’s syndrome. Low long term toxicity and overall good tolerance make MMF a new treatment option in steroid dependent Cogan’s syndrome. ß 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cogan’s syndrome Mycophenolate mofetil Hearing loss
1. Introduction Cogan’s syndrome, first described in 1945, consists of nonsyphilitic interstitial keratitis and vestibulocochlear dysfunction [1]. More than 100 cases have been reported in the literature. It usually affects young adults, although the age range is from 2.5 to 60 years old [2] with only a handful of cases involving children. Typically, this syndrome is characterized by ophthalmological involvement, which is followed within 2 years [3] by vestibulocochlear dysfunction resembling Meniere’s disease with progression to total hearing loss in 1–3 months without treatment. Atypical forms are described with different ocular diseases which can be uveitis, conjunctivitis, or episcleritis [4]. In addition to the inflammatory lesions of the eye and ear, systemic symptoms are present in 50–70% of cases [5]. Early steroid treatment improves
* Corresponding author. Tel.: +33 (0) 1 44 73 54 17; fax: +33 (0) 1 44 73 61 08. E-mail addresses: [email protected] (C. Hautefort), [email protected] (N. Loundon). 1 Tel.: +33 (0) 1 44 73 54 17; fax: +33 (0) 1 44 73 61 08. 0165-5876/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2009.06.025
long term prognosis [6]. Standard management is oral prednisone at 1–2 mg/kg per day. However, there is considerable risk for steroid associated complications in particular if high doses are required to maintain remission. Some authors have proposed alternative, steroid sparing immunosuppressive agents [6–10]. We report a pediatric case of Cogan’s syndrome requiring long term high dose of oral steroids, which was successfully managed with mycophenolate mofetil (MMF). 2. Clinical case In May 2004, an 11-year-old African girl, with a history of isolated right-sided total deafness occurring suddenly in Burkina Faso, presented with red painful eyes diagnosed as bilateral anterior uveitis. She had no particular familial, perinatal or medial history explaining the previous unilateral sudden deafness. She was initially successfully treated with topical steroids, but as ocular symptoms recurred 1 year later and not totally responded to topical treatment this time, she was admitted to the pediatric department. A complete immunological work-up revealed isolated anti-nuclear antibodies. In August 2005, the patient developed
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C. Hautefort et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 1477–1479
Fig. 3. Left hearing threshold after starting MMF.
Fig. 1. Left hearing threshold at the onset of Cogan’s syndrome before and after steroid treatment.
sudden left-sided hearing loss, mostly on high frequencies (Fig. 1), which responded to prednisone (1 mg/kg per day). The etiologic research was completed at this time, in particular ear tomodensitometry which was normal and vestibular examination which revealed areflexia on the right and hyporeflexia on the left. The genetic assessment eliminated other cause of sudden and progressive deafness and confirmed the diagnosis of Cogan’s syndrome. After 10 days of high prednisone dose, the hearing thresholds on the left hear had returned to subnormal (Fig. 1) with the ongoing treatment, but because of several unsuccessful attempts of tapering systemic steroid dose, prednisone was maintained at a dose of 1 mg/kg per day over the next 2 months (Fig. 2). Dependence to steroid treatment led to a cushingoid appearance, massive weight gain, acne and puberty dysfunction. At this time, a long term steroid sparing immunosuppressive
medication had to be considered. MMF was started at a low dose of 750 mg twice daily (1000 mg/m2 per day) in combination with steroids, which were tapered progressively. In December 2005, audition remained stable until a dose reduction up to 0.5 mg/kg per day of prednisone. However, complete cessation of corticosteroids was not possible and hearing loss deteriorated once again requiring an increase in prednisone dosage to 1 mg/kg per day (Fig. 3). Following this recurrence, MMF dosage was increased to 1000 mg twice daily (1200 mg/m2 per day). The steroid treatment was progressively tapered off until May 2006 without auditory relapse (Fig. 3). The daily use of MMF was well tolerated both clinically (no gastrointestinal symptoms) and biologically (normal blood cell count and biochemistry). At the time of the last follow-up in May 2009, left audition and ophthalmologic examination were normal and side effects related to steroid therapy had resolved (Fig. 3). Laboratory investigations including liver enzymes, IgG level, hemoglobin (12.6 g/dl), platelets (276 000/mL) and white cell count were normal. 3. Discussion
Fig. 2. Left hearing threshold after tapering steroid dose.
The diagnosis of Cogan’s syndrome is based on the clinical description of non-syphilitic interstitial kerarititis followed by vestibuloauditory dysfunction within 2 years. The diagnosis of Cogan’s syndrome is often delayed because of the late appearance of ophthalmological and auditory symptoms. Nevertheless, early diagnosis is important with respect to the prognosis. Although the risk of ophthalmological consequences is low, progression to a profound hearing loss is observed in 50–80% of cases [11]. In our case, diagnosis of Cogan’s syndrome may be discussed because of the particularity of the ocular signs typically interstitial keratitis. Further, uveitis has been previously reported as a part of ‘‘atypical Cogan’s syndrome’’ [3]. The first sign to occur in our case, that is the hearing loss 6 years earlier, had not been documented at this time, but even though the relation with current diagnosis remains hypothetical it is highly probable. The combination of ocular disease, followed by vestibulocochlear dysfunction within 2 years and a response to prednisone strongly supports the diagnosis of Cogan’s syndrome [12,13]. The genetic exploration could also in our case eliminate other cause of sudden deafness. Cogan’s syndrome is supposed to be an immune disease. It has been consolidated by the recent discoveries of Lunardi as a result of the dysregulation of the response of B and T lymphocytes.
C. Hautefort et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 1477–1479
Identification of an antigen, DEP-1/CD148, potentially involved in the etiology of Cogan’s syndrome [14] supports hypothesis that Cogan’s syndrome is an autoimmune condition. In our patient, although there was no evidence of a systemic vasculitis, antinuclear antibodies were nevertheless detected. When hearing loss occurs, early steroid systemic treatment, (typically 1–2 mg/kg per day) reduces the risk of development of profound hearing loss [6,13] and leads to an improvement in 50% of cases as early as the first week [3]—which was the case for our patient. One major problem for patients with Cogan’s syndrome is that despite a rapid and sometimes spectacular initial response to treatment, relapses are frequent when steroids are stopped or during the decrease of dosing. In high doses steroid dependency the use of steroid sparing immunosuppressive agents has been previously proposed [4,7–10] such as methotrexate, cyclophosphamide, cyclosporine and azathioprine. In this autoimmune context immunosuppressive treatment seems to be justified. Of the various immunosuppressors used so far, the best results in adults and children have been reported with single agent methotrexate, or in combination, at a dose of 10 mg/m2 per week [10,7,6,9]. Nevertheless, the immunosuppressive agent may need to be used for several years and sometimes complete cessation of corticosteroids may not be possible. Despite overall good results of low dose methotrexate treatment in Cogan’s syndrome [7–9], liver toxicity has to be considered in particular in long term treatment [15]. To our knowledge, there are no reports of the use of MMF for Cogan’s syndrome. This approach was based on the recent literature on the use of new immunosuppressive agents, which are more specific in their targets and have less side effects and toxicity. MMF has been used as an alternative approach in pediatrics, for example in uveitis [16] associated with systemic lupus erythematosus and idiopathic nephrotic syndrome [17,18] as well as being routinely used in the setting of solid organ transplantation. In those other autoimmune diseases, MMF has shown high efficiency with very few (mainly benign gastrointestinal) adverse effects. Long term data on the use of MMF in solid organ transplantation confirm the favorable benefit–risk ratio [19]. Mycophenolic acid induces a reversible, non-competitive inhibition of inosine monophosphate dehydrogenase (IMPDH), which is a critical enzyme in the pathway for purine nucleotide synthesis. IMPDH catalyses the transformation of inosine monophosphate to guanosine monophosphate, which is an essential substrate for the synthesis of DNA and RNA. There are two routes for purine nucleotide synthesis: the de novo and the rescue pathways. Unlike other cell types, which can use either pathway, B and T lymphocytes cannot use the rescue pathway. According to McCabe and Lunardi, the autoimmune origin of Cogan’s syndrome is the result of the dysregulation of the response of B and T lymphocytes [20,14], and MMF produces a targeted inhibition of the proliferation of those lymphocytes. The main side effects (diarrhea, vomiting and lymphopenia) are relatively rare and reversible after dose reduction. In our patient, MMF allowed the progressive reduction in the dose of corticosteroids and complete and definitive cessation after 5 months. The effective dose of MMF that was used was based on the standard adult dosing schedule. No side effects attributable to MMF were observed. The required duration of treatment remains unknown and must be assessed for each individual case. In other immunological conditions of childhood, where MMF has been used (lupus, nephrotic syndrome), the minimum duration has been 3 years and often treatment has been continued for more than 10 years [17–19]. Since the introduction of MMF in the immunosuppressive regimen in pediatric renal transplantation, steroid-free
1479
immunosuppression seems feasible and well tolerated with a follow-up of more than 12 years [17–19]. Currently, follow-up in our case is 3 years and cessation of MMF is not planned at the moment. Still the exact benefit–risk ratio of methotrexate treatment in comparison with other treatment options such as MMF remains to be examined. 4. Conclusion In Cogan’s syndrome, the auditory and visual outcomes are intimately linked with the early beginning of steroid treatment. Alternative immunosuppressive agent should be considered in case of non-response to steroids or steroid dependence. However, the optimal agent and its dosing remain to be established, the common treatment proposed is methotrexate, which is not always well tolerate. The MMF, an immunosuppressive agent involved in B and T lymphocyte regulation likely to be more specific in Cogan’s pathology, is well known in others autoimmune diseases could be proposed as an alternative treatment because of its good tolerance. Long term studies might help to elucidate which immunosuppressive agent should be used as a first line alternative drug in this syndrome. References [1] D. Cogan, Syndrome of nonsyphilitic interstitial keratitis and vestibuloauditory symptoms, Arch. Ophthamol. 33 (1945) 144–149. [2] S.P. Kundell, H.D. Ochs, Cogan syndrome in childhood, J. Pediatr. 97 (1) (1980 July) 96–98. [3] B.F. Haynes, M.I. Kaiser-Kupfer, P. Mason, A.S. Fauci, Cogan syndrome: studies in thirteen patients, long-term follow-up, and a review of the literature, Medicine (Baltimore) 59 (6) (1980 November) 426–441. [4] S. Balayre, J.-J. Gicquel, M. Mercie, P. Dighiero, Syndrome de Cogan atypique, J. Fr. Ophthamol. 26 (1) (2003) 64–68. [5] S. Van Doornum, G. McColl, M. Walter, I. Jennens, P. Bhathal, I.P. Wicks, Prolonged prodrome, systemic vasculitis, and deafness in Cogan’s syndrome, Ann. Rheum. Dis. 60 (1) (2001 January) 69–71. [6] I.C. Ndiaye, S.J. Rassi, S.R. Wiener-Vacher, Cochleovestibular impairment in pediatric Cogan’s syndrome, Pediatrics 109 (2) (2002 February) E38. [7] B. Richardson, Methotrexate therapy for hearing loss in Cogan’s syndrome, Arthritis Rheum. 37 (10) (1994 October) 1559–1561. [8] L. Riente, E. Taglione, S. Berrettini, Efficacy of methotrexate in Cogan’s syndrome, J. Rheumatol. 23 (10) (1996 October) 1830–1831. [9] Y. Inoue, T. Tomemori, S. Suzuki, T. Arima, M. Tomiita, N. Shimojo, et al., Low-dose oral methotrexate for the management of childhood Cogan’s syndrome: a case report, Clin. Rheumatol. 26 (12) (2007 December) 2201–2203. [10] P. Vinceneux, V. Couloigner, J. Pouchot, D. Bouccara, O. Sterkers, Autoimmune deafness, Presse Med. 28 (34) (1999 November) 1904–1910. [11] E. Pasanisi, V. Vincenti, A. Bacciu, M. Guida, T. Berghenti, A. Barbot, et al., Cochlear implantation and Cogan syndrome, Otol. Neurotol. 24 (4) (2003) 601–604. [12] M. Gluth, K. Baratz, E. Matteson, C. Driscoll, Cogan Syndrome: a retrospective review of 6 patients throughout a half century, Mayo Clin. Proc. 81 (4) (2006 April) 483–488. [13] J. Cundiff, S. Kansal, A. Kumar, D.A. Goldstein, H.H. Tessler, Cogan’s syndrome: a cause of progressive hearing deafness, Am. J. Otolaryngol. 27 (1) (2006 January– February) 68–70. [14] C. Lunardi, C. Bason, M. Leandri, R. Navone, M. Lestani, E. Millo, et al., Autoantibodies to inner ear and endothelial antigens in Cogan’s syndrome, Lancet 360 (9337) (2002 Sep 21) 915–921. [15] J.M. Kremer, G.S. Alarcon, R.W. Lightfoot Jr., R.F. Willkens, D.E. Furst, H.J. Williams, et al., Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology, Arthritis Rheum. 37 (3) (1994 March) 316–328. [16] S. Baltatzis, F. Tufail, E.N. Yu, C.M. Vredeveld, C.S. Foster, Mycophenolate mofetil as an immunomodulatory agent in the treatment of chronic ocular inflammatory disorders, Ophthalmology 110 (5) (2003 May) 1061–1065. [17] A. Paredes, Can mycophenolate mofetil substitute cyclophosphamide treatment of pediatric lupus nephritis? Pediatr. Nephrol. 22 (8) (2007 August) 1077–1082. [18] T. Ulinski, L. Dubourg, M.H. Saı¨d, B. Parchoux, B. Ranchin, P. Cochat, Switch from cyclosporine A to mycophenolate mofetil in nephrotic children, Pediatr. Nephrol. 20 (4) (2005 April) 482–485. [19] S.A. Birkeland, K.E. Larsen, N. Rohr, Pediatric renal transplantation without steroids, Pediatr. Nephrol. 12 (2) (1998 February) 87–92. [20] B.F. McCabe, Autoimmune sensorineural hearing loss, Ann. Otol. Rhinol. Laryngol. 116 (12) (2007 December) 875–879.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case report
Mycophenolate mofetil as a treatment of steroid dependent Cogan’s syndrome in childhood Charlotte Hautefort a,1,*, Natalie Loundon a,1, Marta Montchilova c,1, Sandrine Marlin d,1, Erea Noel Garabedian a,1, Tim Ulinski b,1 a
Service d’ORL, de chirurgie cervico-faciale et d’audiophonologie de l’enfant, Hoˆpital d’Enfants Armand Trousseau, 26 av Dr. Arnold Netter, 75012 Paris, France Service de Ne´phrologie pe´diatrique Hoˆpital d’Enfants Armand Trousseau, 26 av Dr. Arnold Netter, 75012 Paris, France Service d’Ophtalmologie pe´diatrique Hoˆpital d’Enfants Armand Trousseau, 26 av Dr. Arnold Netter, 75012 Paris, France d Service de Ge´ne´tique Hoˆpital d’Enfants Armand Trousseau, 26 av Dr. Arnold Netter, 75012 Paris, France b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 June 2009 Accepted 27 June 2009 Available online 4 August 2009
Cogan’s syndrome is a rare chronic inflammatory disorder which typically associates an ophthalmological and vestibulocochlear involvement, with a risk of systemic symptoms in 50–70% of cases. Autoimmune origin has been consolidated by the recent discoveries of Lunardi as a result of the dysregulation of the response of B and T lymphocytes. We report here a pediatric case of Cogan’s syndrome, with long term follow-up and complete vestibulocochlear and ophthalmologic examination. During the acute phase, early steroids treatment (prednisone 1 mg/kg per day) was effective on ocular lesions and hearing loss. The patient required high steroid doses to maintain remission, suggesting the necessity for steroid sparing immunosuppressive agents. We introduced mycophenolate mofetil (MMF), an immunosuppressive agent mainly used in solid organ transplantation. After steroid withdrawal the patient remained in complete remission on MMF. This is the first report of MMF treatment in Cogan’s syndrome. MMF produces a targeted inhibition of the proliferation of B and T lymphocytes, particularly interesting in Cogan’s syndrome. Low long term toxicity and overall good tolerance make MMF a new treatment option in steroid dependent Cogan’s syndrome. ß 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cogan’s syndrome Mycophenolate mofetil Hearing loss
1. Introduction Cogan’s syndrome, first described in 1945, consists of nonsyphilitic interstitial keratitis and vestibulocochlear dysfunction [1]. More than 100 cases have been reported in the literature. It usually affects young adults, although the age range is from 2.5 to 60 years old [2] with only a handful of cases involving children. Typically, this syndrome is characterized by ophthalmological involvement, which is followed within 2 years [3] by vestibulocochlear dysfunction resembling Meniere’s disease with progression to total hearing loss in 1–3 months without treatment. Atypical forms are described with different ocular diseases which can be uveitis, conjunctivitis, or episcleritis [4]. In addition to the inflammatory lesions of the eye and ear, systemic symptoms are present in 50–70% of cases [5]. Early steroid treatment improves
* Corresponding author. Tel.: +33 (0) 1 44 73 54 17; fax: +33 (0) 1 44 73 61 08. E-mail addresses: [email protected] (C. Hautefort), [email protected] (N. Loundon). 1 Tel.: +33 (0) 1 44 73 54 17; fax: +33 (0) 1 44 73 61 08. 0165-5876/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2009.06.025
long term prognosis [6]. Standard management is oral prednisone at 1–2 mg/kg per day. However, there is considerable risk for steroid associated complications in particular if high doses are required to maintain remission. Some authors have proposed alternative, steroid sparing immunosuppressive agents [6–10]. We report a pediatric case of Cogan’s syndrome requiring long term high dose of oral steroids, which was successfully managed with mycophenolate mofetil (MMF). 2. Clinical case In May 2004, an 11-year-old African girl, with a history of isolated right-sided total deafness occurring suddenly in Burkina Faso, presented with red painful eyes diagnosed as bilateral anterior uveitis. She had no particular familial, perinatal or medial history explaining the previous unilateral sudden deafness. She was initially successfully treated with topical steroids, but as ocular symptoms recurred 1 year later and not totally responded to topical treatment this time, she was admitted to the pediatric department. A complete immunological work-up revealed isolated anti-nuclear antibodies. In August 2005, the patient developed
1478
C. Hautefort et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 1477–1479
Fig. 3. Left hearing threshold after starting MMF.
Fig. 1. Left hearing threshold at the onset of Cogan’s syndrome before and after steroid treatment.
sudden left-sided hearing loss, mostly on high frequencies (Fig. 1), which responded to prednisone (1 mg/kg per day). The etiologic research was completed at this time, in particular ear tomodensitometry which was normal and vestibular examination which revealed areflexia on the right and hyporeflexia on the left. The genetic assessment eliminated other cause of sudden and progressive deafness and confirmed the diagnosis of Cogan’s syndrome. After 10 days of high prednisone dose, the hearing thresholds on the left hear had returned to subnormal (Fig. 1) with the ongoing treatment, but because of several unsuccessful attempts of tapering systemic steroid dose, prednisone was maintained at a dose of 1 mg/kg per day over the next 2 months (Fig. 2). Dependence to steroid treatment led to a cushingoid appearance, massive weight gain, acne and puberty dysfunction. At this time, a long term steroid sparing immunosuppressive
medication had to be considered. MMF was started at a low dose of 750 mg twice daily (1000 mg/m2 per day) in combination with steroids, which were tapered progressively. In December 2005, audition remained stable until a dose reduction up to 0.5 mg/kg per day of prednisone. However, complete cessation of corticosteroids was not possible and hearing loss deteriorated once again requiring an increase in prednisone dosage to 1 mg/kg per day (Fig. 3). Following this recurrence, MMF dosage was increased to 1000 mg twice daily (1200 mg/m2 per day). The steroid treatment was progressively tapered off until May 2006 without auditory relapse (Fig. 3). The daily use of MMF was well tolerated both clinically (no gastrointestinal symptoms) and biologically (normal blood cell count and biochemistry). At the time of the last follow-up in May 2009, left audition and ophthalmologic examination were normal and side effects related to steroid therapy had resolved (Fig. 3). Laboratory investigations including liver enzymes, IgG level, hemoglobin (12.6 g/dl), platelets (276 000/mL) and white cell count were normal. 3. Discussion
Fig. 2. Left hearing threshold after tapering steroid dose.
The diagnosis of Cogan’s syndrome is based on the clinical description of non-syphilitic interstitial kerarititis followed by vestibuloauditory dysfunction within 2 years. The diagnosis of Cogan’s syndrome is often delayed because of the late appearance of ophthalmological and auditory symptoms. Nevertheless, early diagnosis is important with respect to the prognosis. Although the risk of ophthalmological consequences is low, progression to a profound hearing loss is observed in 50–80% of cases [11]. In our case, diagnosis of Cogan’s syndrome may be discussed because of the particularity of the ocular signs typically interstitial keratitis. Further, uveitis has been previously reported as a part of ‘‘atypical Cogan’s syndrome’’ [3]. The first sign to occur in our case, that is the hearing loss 6 years earlier, had not been documented at this time, but even though the relation with current diagnosis remains hypothetical it is highly probable. The combination of ocular disease, followed by vestibulocochlear dysfunction within 2 years and a response to prednisone strongly supports the diagnosis of Cogan’s syndrome [12,13]. The genetic exploration could also in our case eliminate other cause of sudden deafness. Cogan’s syndrome is supposed to be an immune disease. It has been consolidated by the recent discoveries of Lunardi as a result of the dysregulation of the response of B and T lymphocytes.
C. Hautefort et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 1477–1479
Identification of an antigen, DEP-1/CD148, potentially involved in the etiology of Cogan’s syndrome [14] supports hypothesis that Cogan’s syndrome is an autoimmune condition. In our patient, although there was no evidence of a systemic vasculitis, antinuclear antibodies were nevertheless detected. When hearing loss occurs, early steroid systemic treatment, (typically 1–2 mg/kg per day) reduces the risk of development of profound hearing loss [6,13] and leads to an improvement in 50% of cases as early as the first week [3]—which was the case for our patient. One major problem for patients with Cogan’s syndrome is that despite a rapid and sometimes spectacular initial response to treatment, relapses are frequent when steroids are stopped or during the decrease of dosing. In high doses steroid dependency the use of steroid sparing immunosuppressive agents has been previously proposed [4,7–10] such as methotrexate, cyclophosphamide, cyclosporine and azathioprine. In this autoimmune context immunosuppressive treatment seems to be justified. Of the various immunosuppressors used so far, the best results in adults and children have been reported with single agent methotrexate, or in combination, at a dose of 10 mg/m2 per week [10,7,6,9]. Nevertheless, the immunosuppressive agent may need to be used for several years and sometimes complete cessation of corticosteroids may not be possible. Despite overall good results of low dose methotrexate treatment in Cogan’s syndrome [7–9], liver toxicity has to be considered in particular in long term treatment [15]. To our knowledge, there are no reports of the use of MMF for Cogan’s syndrome. This approach was based on the recent literature on the use of new immunosuppressive agents, which are more specific in their targets and have less side effects and toxicity. MMF has been used as an alternative approach in pediatrics, for example in uveitis [16] associated with systemic lupus erythematosus and idiopathic nephrotic syndrome [17,18] as well as being routinely used in the setting of solid organ transplantation. In those other autoimmune diseases, MMF has shown high efficiency with very few (mainly benign gastrointestinal) adverse effects. Long term data on the use of MMF in solid organ transplantation confirm the favorable benefit–risk ratio [19]. Mycophenolic acid induces a reversible, non-competitive inhibition of inosine monophosphate dehydrogenase (IMPDH), which is a critical enzyme in the pathway for purine nucleotide synthesis. IMPDH catalyses the transformation of inosine monophosphate to guanosine monophosphate, which is an essential substrate for the synthesis of DNA and RNA. There are two routes for purine nucleotide synthesis: the de novo and the rescue pathways. Unlike other cell types, which can use either pathway, B and T lymphocytes cannot use the rescue pathway. According to McCabe and Lunardi, the autoimmune origin of Cogan’s syndrome is the result of the dysregulation of the response of B and T lymphocytes [20,14], and MMF produces a targeted inhibition of the proliferation of those lymphocytes. The main side effects (diarrhea, vomiting and lymphopenia) are relatively rare and reversible after dose reduction. In our patient, MMF allowed the progressive reduction in the dose of corticosteroids and complete and definitive cessation after 5 months. The effective dose of MMF that was used was based on the standard adult dosing schedule. No side effects attributable to MMF were observed. The required duration of treatment remains unknown and must be assessed for each individual case. In other immunological conditions of childhood, where MMF has been used (lupus, nephrotic syndrome), the minimum duration has been 3 years and often treatment has been continued for more than 10 years [17–19]. Since the introduction of MMF in the immunosuppressive regimen in pediatric renal transplantation, steroid-free
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immunosuppression seems feasible and well tolerated with a follow-up of more than 12 years [17–19]. Currently, follow-up in our case is 3 years and cessation of MMF is not planned at the moment. Still the exact benefit–risk ratio of methotrexate treatment in comparison with other treatment options such as MMF remains to be examined. 4. Conclusion In Cogan’s syndrome, the auditory and visual outcomes are intimately linked with the early beginning of steroid treatment. Alternative immunosuppressive agent should be considered in case of non-response to steroids or steroid dependence. However, the optimal agent and its dosing remain to be established, the common treatment proposed is methotrexate, which is not always well tolerate. The MMF, an immunosuppressive agent involved in B and T lymphocyte regulation likely to be more specific in Cogan’s pathology, is well known in others autoimmune diseases could be proposed as an alternative treatment because of its good tolerance. Long term studies might help to elucidate which immunosuppressive agent should be used as a first line alternative drug in this syndrome. References [1] D. Cogan, Syndrome of nonsyphilitic interstitial keratitis and vestibuloauditory symptoms, Arch. Ophthamol. 33 (1945) 144–149. [2] S.P. Kundell, H.D. Ochs, Cogan syndrome in childhood, J. Pediatr. 97 (1) (1980 July) 96–98. [3] B.F. Haynes, M.I. Kaiser-Kupfer, P. Mason, A.S. Fauci, Cogan syndrome: studies in thirteen patients, long-term follow-up, and a review of the literature, Medicine (Baltimore) 59 (6) (1980 November) 426–441. [4] S. Balayre, J.-J. Gicquel, M. Mercie, P. Dighiero, Syndrome de Cogan atypique, J. Fr. Ophthamol. 26 (1) (2003) 64–68. [5] S. Van Doornum, G. McColl, M. Walter, I. Jennens, P. Bhathal, I.P. Wicks, Prolonged prodrome, systemic vasculitis, and deafness in Cogan’s syndrome, Ann. Rheum. Dis. 60 (1) (2001 January) 69–71. [6] I.C. Ndiaye, S.J. Rassi, S.R. Wiener-Vacher, Cochleovestibular impairment in pediatric Cogan’s syndrome, Pediatrics 109 (2) (2002 February) E38. [7] B. Richardson, Methotrexate therapy for hearing loss in Cogan’s syndrome, Arthritis Rheum. 37 (10) (1994 October) 1559–1561. [8] L. Riente, E. Taglione, S. Berrettini, Efficacy of methotrexate in Cogan’s syndrome, J. Rheumatol. 23 (10) (1996 October) 1830–1831. [9] Y. Inoue, T. Tomemori, S. Suzuki, T. Arima, M. Tomiita, N. Shimojo, et al., Low-dose oral methotrexate for the management of childhood Cogan’s syndrome: a case report, Clin. Rheumatol. 26 (12) (2007 December) 2201–2203. [10] P. Vinceneux, V. Couloigner, J. Pouchot, D. Bouccara, O. Sterkers, Autoimmune deafness, Presse Med. 28 (34) (1999 November) 1904–1910. [11] E. Pasanisi, V. Vincenti, A. Bacciu, M. Guida, T. Berghenti, A. Barbot, et al., Cochlear implantation and Cogan syndrome, Otol. Neurotol. 24 (4) (2003) 601–604. [12] M. Gluth, K. Baratz, E. Matteson, C. Driscoll, Cogan Syndrome: a retrospective review of 6 patients throughout a half century, Mayo Clin. Proc. 81 (4) (2006 April) 483–488. [13] J. Cundiff, S. Kansal, A. Kumar, D.A. Goldstein, H.H. Tessler, Cogan’s syndrome: a cause of progressive hearing deafness, Am. J. Otolaryngol. 27 (1) (2006 January– February) 68–70. [14] C. Lunardi, C. Bason, M. Leandri, R. Navone, M. Lestani, E. Millo, et al., Autoantibodies to inner ear and endothelial antigens in Cogan’s syndrome, Lancet 360 (9337) (2002 Sep 21) 915–921. [15] J.M. Kremer, G.S. Alarcon, R.W. Lightfoot Jr., R.F. Willkens, D.E. Furst, H.J. Williams, et al., Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology, Arthritis Rheum. 37 (3) (1994 March) 316–328. [16] S. Baltatzis, F. Tufail, E.N. Yu, C.M. Vredeveld, C.S. Foster, Mycophenolate mofetil as an immunomodulatory agent in the treatment of chronic ocular inflammatory disorders, Ophthalmology 110 (5) (2003 May) 1061–1065. [17] A. Paredes, Can mycophenolate mofetil substitute cyclophosphamide treatment of pediatric lupus nephritis? Pediatr. Nephrol. 22 (8) (2007 August) 1077–1082. [18] T. Ulinski, L. Dubourg, M.H. Saı¨d, B. Parchoux, B. Ranchin, P. Cochat, Switch from cyclosporine A to mycophenolate mofetil in nephrotic children, Pediatr. Nephrol. 20 (4) (2005 April) 482–485. [19] S.A. Birkeland, K.E. Larsen, N. Rohr, Pediatric renal transplantation without steroids, Pediatr. Nephrol. 12 (2) (1998 February) 87–92. [20] B.F. McCabe, Autoimmune sensorineural hearing loss, Ann. Otol. Rhinol. Laryngol. 116 (12) (2007 December) 875–879.