- Email: [email protected]
Cogan syndrome: Characteristics, outcome and treatment in a French nationwide retrospective study and literature review
Accepted Manuscript Cogan syndrome: Characteristics, outcome and treatment in a French nationwide retrospective study and literature review
Charlotte Durtette, Eric Hachulla, Matthieu Resche-Rigon, Thomas Papo, Thierry Zénone, Bertrand Lioger, Christophe Deligny, Marc Lambert, Cédric Landron, Jacques Pouchot, Jean Emmanuel Kahn, Christian Lavigne, Benoit De Wazieres, Robin Dhote, Guillaume Gondran, Edouard Pertuiset, Thomas Quemeneur, Mohamed Hamidou, Pascal Sève, Thomas Le Gallou, Anne Grasland, Pierre-Yves Hatron, Olivier Fain, Arsène Mekinian, CRI, on the behalf of SNFMI PII: DOI: Reference:
S1568-9972(17)30255-0 doi:10.1016/j.autrev.2017.10.005 AUTREV 2072
To appear in: Received date: Accepted date:
7 August 2017 14 August 2017
Please cite this article as: Charlotte Durtette, Eric Hachulla, Matthieu Resche-Rigon, Thomas Papo, Thierry Zénone, Bertrand Lioger, Christophe Deligny, Marc Lambert, Cédric Landron, Jacques Pouchot, Jean Emmanuel Kahn, Christian Lavigne, Benoit De Wazieres, Robin Dhote, Guillaume Gondran, Edouard Pertuiset, Thomas Quemeneur, Mohamed Hamidou, Pascal Sève, Thomas Le Gallou, Anne Grasland, Pierre-Yves Hatron, Olivier Fain, Arsène Mekinian, CRI, on the behalf of SNFMI , Cogan syndrome: Characteristics, outcome and treatment in a French nationwide retrospective study and literature review. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Autrev(2017), doi:10.1016/j.autrev.2017.10.005
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ACCEPTED MANUSCRIPT Cogan syndrome: characteristics, outcome and treatment in a French nationwide retrospective study and literature review Charlotte Durtette1, Eric Hachulla2, Matthieu Resche-Rigon3, Thomas Papo4, Thierry Zénone5, Bertrand Lioger6, Christophe Deligny7, Marc Lambert2, Cédric Landron8, Jacques Pouchot9, Jean Emmanuel Kahn10, Christian Lavigne11, Benoit De Wazieres12, Robin Dhote13, Guillaume Gondran14, Edouard Pertuiset15, Thomas Quemeneur16, Mohamed Hamidou17,
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Pascal Sève18, Thomas Le Gallou19, Anne Grasland20, Pierre-Yves Hatron2, Olivier Fain1,
AP-HP, Hôpital Saint-Antoine, service de médecine interne and Inflammation-
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Arsène Mekinian1, on the behalf of SNFMI and CRI.
University Paris 06, F-75012, Paris, France 2
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Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC
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Service de Médecine Interne et Immunologie Clinique, CHU Lille, Centre national de
référence maladies systémiques et auto-immunes rares, Université de Lille, 59037 Lille cedex, France3AP-HP, Hôpital Saint-Louis, service de Biostatistiques, UPMC Univ Paris 07, F-
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75011, Paris, France
AP-HP, service de médecine interne, Hôpital Bichat-Claude Bernard, Paris, France
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Service de médecine interne, CH Valence, Valence, France
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Service de médecine interne, CHU Tours, Université de Tours, Tours, France
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Service de médecine interne, CHU Martinique, Fort de France, France
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Service de médecine interne, CHU Poitiers, Poitiers, France
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Service de Médecine Interne, Hôpital européen Georges-Pompidou, Assistance Publique
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Hôpitaux de Paris - APHP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France 10
Service de médecine interne, Hôpital Foch, 92150 Suresnes, Université Versailles Saint
Quentin en Yvelines, France 11
Service de médecine interne et Maladies vasculaires, Centre de compétence de Maladies
rares, CHU Angers, Université Angers, 49000 Angers, France
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Service de médecine interne et Maladies vasculaires, Centre de compétence de Maladies
rares, CHU Angers, Université Angers, 49000 Angers, France 12
Service de médecine interne, CHU Nîmes, Nîmes, France.
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Service de médecine interne, Université Paris 13, AP-HP, Avicenne, 93000, Bobigny,
France. Service de médecine interne, CHU Limoges, Limoges, France.
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Service de Rhumatologie, Centre Hospitalier René Dubos, Pontoise
Service de médecine interne et de néphrologie, Hôpital de Valenciennes, Valenciennes,
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France.
Hôpital Hôtel Dieu, service de médecine interne, Université de Nantes, Nantes, France
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Service de médecine interne, Hôpital de la Croix-Rousse, Université de Lyon, Lyon, France AP-HP, service de médecine interne, Hôpital Louis Mourier, Colombes, France
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Original research article
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Correspondence and reprint requests to: Arsene Mekinian, MD, AP-HP, Hôpital Saint Antoine, service de medicine interne and
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Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75012, Paris, France, Phone: + (33) 1 49282387 Fax: + (33) 149282652. E-mail: [email protected]
Running title: Infliximab for Cogan syndrome
Word count: abstract (250), manuscript (), figures (4), tables (2). Key words : Cogan’s syndrome; treatment, infliximab, outcome Conflicts of interest and funding: none.
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ACCEPTED MANUSCRIPT Abstract Background Cogan syndrome is mainly treated with corticosteroids. We aimed to determine the place of DMARDs and biologic-targeted treatments. Patients and Methods
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We conducted a French nationwide retrospective study of patients with Cogan syndrome (n=40) and a literature review of cases (n=22) and analyzed the efficacy of disease-modifying
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anti-rheumatic drugs (DMARDs) and tumor necrosis factor α (TNF-α) antagonists.
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Results
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We included 62 patients (31 females) investigated (median age 37 years [range 2-76]. At diagnosis, 61 patients (98%) had vestibulo-auditory symptoms, particularly bilateral hearing loss in 41% and deafness in 31%. Ocular signs were present in 57 patients (92%), with
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interstitial keratitis in 31 (51%). The first-line treatment consisted of steroids alone (n=43; 70%) or associated with other immunosuppressive drugs (n=18; 30%). Overall, 13/43 (30%) and 4/18 (22%) patients with steroids alone and with associated immunosuppressive drugs,
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respectively (p=0.8), showed vestibulo-auditory response; 32/39 (82%) and 15/19 (79%)
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ocular response; and 23/28 (82%) and 10/14 (71%) general response. In all, 61 patients had used a total of 126 lines of treatment, consisting of steroids alone (n=51 lines), steroids with DMARDs (n=65) and infliximab (n=10). Vestibulo-auditory response was significantly more
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frequent with infliximab than DMARDs or steroids alone (80% vs 39% and 35%, respectively), whereas ocular, systemic and acute-phase reactant response rates were similar.
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Infliximab was the only significant predictor of vestibulo-auditory improvement (odds ratio 20.7 [95% confidence interval 1.65; 260], p=0.019). Conclusion
Infliximab could lead to vestibulo-auditory response in DMARDS and steroid-refractory Cogan syndrome, but prospective studies are necessary.
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ACCEPTED MANUSCRIPT Key messages Vestibulo-auditory response was similar with DMARDs and steroids alone. Infliximab could lead to vestibulo-auditory response in DMARDS and steroid-refractory Cogan syndrome
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The 5 and 10-years incidence of relapse increased under steroids and DMARDS, while it stayed stable with infliximab
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ACCEPTED MANUSCRIPT INTRODUCTION Cogan syndrome was first described in 1945 by an ophthalmologist, David G. Cogan, who reported on a “syndrome of non-syphilitic interstitial keratitis and vestibule-auditory symptoms” that resembled Meniere's disease (1). Other ocular signs such as conjunctivitis, uveitis, scleritis and choroiditis have been described recently and are considered atypical forms in the absence of interstitial keratitis.
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Since 1945, more than 250 cases of Cogan syndrome have been reported, and the disease seems to have an autoimmune origin; no easily available autoantibodies have been clearly
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associated with this syndrome (2, 3). Alleviating the vestibulo-auditory symptoms, and in
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particular the hearing loss, remains challenging. Because of the rarity of the disease, no controlled study has been performed, with only small reported series, and the value of
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immunosuppressive treatment, particularly the place of disease-modifying anti-rheumatic drugs (DMARDs), remains to be determined. The 2 largest case-series, of 32 and 60 patients, mainly described the efficacy of steroids alone (2, 3). Among the 60 patients, 57 (95%)
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received steroids, with vestibulo-auditory and ophthalmological improvements in 58% (3). However, no studies have compared the benefit of DMARDs added to steroids and the
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potential efficacy of various DMARDs. Recently, a few case reports demonstrated the benefit
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of biologic targeted treatments, mainly infliximab, but larger studies are needed to determine their benefit for vestibulo-auditory involvement (4-8) (9). A recent literature review analyzed treatment strategies in 141 patients, including various DMARDs and biologics, suggesting the
(10).
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value of immunosuppressive drugs but could not compare the efficacy of various regimen
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In this largest French nationwide study and literature review, we report the long-term outcome of 62 patients with Cogan syndrome receiving steroids, DMARDs and/or tumor necrosis factor α (TNF-α) antagonists and compare their efficacy. MATERIALS AND METHODS We conducted a retrospective multicenter study in the French network of internal medicine (SNFMI) and the Club Rhumatisme and Inflammation (CRI) between July 2014 and 2016. Data were collected retrospectively from physicians in charge of patients. The physicians were asked to complete a standardized questionnaire online.
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ACCEPTED MANUSCRIPT The inclusion criteria were 1) ocular signs consistent with non-syphilitic interstitial keratitis and/or conjunctivitis, episcleritis, scleritis or uveitis; 2) rapidly progressive vestibuloauditory involvement; and 3) time between the vestibulo-auditory and ocular symptoms less than 2 years (typical forms) and more than 2 years (atypical forms) (11). Patients’ clinical and laboratory data and treatments were analysed at baseline, at initiation and the end of each treatment regimen, and at the last available visit. For clinical data, the
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presence of constitutional symptoms and non-infectious fever, lung, vestibulo-auditory, nervous system, skin, joint, eye, vascular and heart impairments were recorded. Laboratory
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data collected were antinuclear, anti-neutrophil cytoplasmic and anti-citrullinated protein antibodies; HIV and syphilis serologies; and histological analysis from biopsies if available.
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Routine laboratory indicators of disease activity, including erythrocyte sedimentation rate (ESR) and C-reactive protein level (CRP) were collected. Steroid dose was analysed at the
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initiation of each new treatment regimen and during follow-up. The different lines of steroids, immunosuppressive agents (DMARDS) and biologic targeted treatments (infliximab,
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adalimumab, tocilizumab) were analysed separately for each patient. DMARDs and biologic targeted treatments were prescribed for 73% of patients because of inadequate disease control or intolerance to steroids (n=15), relapse (n=27) or adverse events (n=2) (Figure 1). Relapse
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was defined as the reappearance of signs after at least 3 months’ remission. Follow-up was
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considered from the diagnosis to the last available news and/or death.
Treatment response definitions
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Treatment response with any regimen (steroids, DMARDs, biologic targeted treatment) was defined as complete response (complete clinical improvement and regression of acute-phase
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reactants) or partial response (at least 50% clinical improvement and 50% regression of acutephase reactants) at 6 months and/or at the end of each treatment line if interrupted before 6 months. Clinical response was separately defined for vestibulo-auditory, systemic and ocular signs. Non-response was considered for the remaining situations.
Literature search strategy Two investigators (CD and AM) searched for articles published from 2004 to 2015 in MEDLINE via PubMed, Web of Science and the Cochrane Library using the keywords Cogan’s
disease,
“interstitial
keratitis”,
treatment,
“DMADRDs”,
“methotrexate”,
“leflunomide”, “azathioprine”, “ciclosporine”, “cyclophosphamide”, “TNFα antagonists”,
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inhibitors”,
“infliximab”,
“adalimumab”,
“etanercept”,
“tocilizumab”,
“rituximab”. All articles with sufficient data on treatments and efficacy for vestibulo-auditory and ocular signs were included in the literature review. Overall, 22 cases from 16 papers were included (6-9, 12, 13) (11, 14-16) (17) (15) (18) (19) (20). Statistical analysis Data are presented as median (range) for continuous variables and frequency (%) for
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qualitative variables. Because each patient could have multiple treatments, we evaluated the vestibulo-auditory, ocular and systemic response by a logistic multivariable regression model
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with a patient random effect, estimating odds ratios (ORs) and 95% confidence intervals (95%
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CIs). Moreover, analyses were adjusted on treatment indication and number of previous therapeutic lines. Relapse was defined as disease becoming active after a remission period
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requiring a change in the treatment regimen. Because each patient could experience multiple relapses, we considered an Andersen-Gill approach, with treatment as a time-dependent covariate. Thus, the time origin for each treatment was when the patient started on that
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regimen. Treatment switch due to lack of efficacy or intolerance was considered a competing event of relapse without intolerance. In case of no event, patients were censored at the last
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follow-up. The cumulative incidence of relapse for each treatment period was estimated by using the Gray estimator, considering lack of efficacy, intolerance or complication as
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competitive events. All tests were two-sided and a P < 0.05 was considered statistically significant. Data were analyzed by using R version 3.3.1 (https://www.R-project.org).
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Results
Baseline characteristics of patients
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We included 40 personal cases and 22 from the literature, for 62 patients (31 females; median age 37 years [range 2-76]). The median time from the first symptoms to diagnosis was 12 months [0-231]. At diagnosis, 61 patients (98%) had vestibulo-auditory symptoms, in particular, bilateral hearing loss for 41% and deafness for 31% (Supplementary Table 1). Ocular signs were present in 57 patients (92%), with interstitial keratitis in 31 (51%). The median time between vestibulo-auditory and ocular symptoms was 2 months [0-180]. Other signs were mainly constitutional symptoms (fever, weight loss) and arthromyalgias. Cerebral MRI showed non-specific white-matter hyperintensities in 7/59 patients (12%), and vestibulo-auditory MRI was consistent with labyrinthitis in 4/47 (9%). For 60 patients, no
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ACCEPTED MANUSCRIPT specific autoantibodies were found. Associated autoimmune disease was noted in 6 patients: sarcoidosis (n=2), Takayasu arteritis, polyarteritis nodosa, relapsing polychondritis and spondylarthritis (n=1 each). Atypical Cogan syndrome was present in 31 patients (50%) (Supplementary Table 2). As compared with patients with typical Cogan syndrome (presence of interstitial keratitis and time between vestibulo-auditory and ocular signs < 2 years), those with atypical disease
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differed in only sex (68% vs 32% females, p<0.05) and frequency of scleritis and episcleritis (10% vs 55%; p<0.05).
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Treatment
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The median treatment time from diagnosis for 61/62 patients (98%) was 4 months [range 0145]. The first-line treatment consisted of steroids alone (n=43; 70%) or with other
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immunosuppressive drugs (n=18; 30%) (Supplementary Figure 1). The median steroid dose was 60 mg/day (20-120) (Supplementary Table 1). Overall, 17/61 patients (28%) showed a vestibulo-auditory response, whereas 47/58 (81%) and 33/42 (79%) showed an ocular and
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general response, respectively. In total, 13/43 (30%) and 4/18 (22%) patients showed a vestibulo-auditory response under steroids and with an associated immunosuppressive
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regimen, respectively (p=0.8); 32/39 (82%) and 15/19 (79%) showed an ocular response, respectively, and 23/28 (82%) and 10/14 (71%) a systemic response, respectively
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(Supplementary Figure 1). A second-line treatment was used in 44 patients for steroids dependence (n=4), inefficacy (n=10), relapse (n=27) or adverse effects (n=3). Second-line treatment consisted in steroids for all 44 patients, with associated drugs in 37 (84%). A total
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of 22/42 patients (50%) showed a vestibulo-auditory response and 27/27 (100%) and 18/18 (100%) an ocular and systemic response, respectively. Frequency of vestibulo-auditory,
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ocular and systemic response was similar for patients under steroids alone and with associated immunosuppressive drugs (Figure 1). Third-line treatment was started in 15 patients (25%) for inefficacy (n=4) and relapse (n=11). Frequency of vestibulo-auditory, ocular and systemic response was similar for patients with typical and atypical Cogan syndrome (Supplementary Table 2). Comparison of responses with infliximab and DMARDs/steroids Overall, 61 patients received 126 lines of treatment that consisted of steroids alone (n=51 patients), steroids associated with DMARDs (n=65) and biologic targeted treatment
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ACCEPTED MANUSCRIPT (infliximab, n=10). Among DMARDs, cyclophosphamide was used in 25 lines, methotrexate in 19, azathioprine in 14, mycophenolate mofetil in 4 and ciclosporine in 7. At initiation of biologic targeted versus steroids and DMARDs treatment, patients did not differ in vestibulo-auditory or general signs or steroids dose, but CRP level was higher, as was number of previous treatment regimens [median 2.5 (range 2-6) vs 2 (1-5), p<0.05] (Table 1). Vestibulo-auditory response was significantly more frequent with infliximab than DMARDs
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or steroids alone (80% vs 39% and 35%, respectively), whereas ocular, systemic and acutephase reactants response rates were similar. Probability of vestibulo-auditory improvement
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was significant for only infliximab (odds ratio [OR] 20.7 [95% CI 1.65; 260], p=0.019) and was high but not significantly for azathioprine (OR 3.7 [0.83; 16.5], p=0.08) and not
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significant for methotrexate, azathioprine, cyclophosphamide and steroids alone (Figure 1),
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even after adjustment for treatment lines and line indication.
During a median follow-up of 35 months [range 0-578], 43 relapses occurred, with 5- and 10-
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year cumulative incidence of relapse of 13% and 31%, respectively (Supplementary Figure 2). The 3-years cumulative incidence of relapse was equal to 17%, 0% and 12% at year 3 for steroids, DMARDS and infliximab respectively. The 5 and 10-years incidence increased to
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29% and 3% and 54%, 19% for steroids and DMARDS, respectively, while it stayed stable
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with infliximab (Supplementary Figure 3).
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At the last evaluation, hearing loss was still noted in 37/60 patients (62%), with ocular and systemic features in 2/60 patients (3%). For 43 patients, the treatment at the last visit was
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ongoing, with steroids for 39/60 (65%) (median 5 mg/day [range 2-100]) and other immunosuppressive agents for 28/60 (47%), including DMARDS for 23/60 (38%) (methotrexate for 12 patients, azathioprine for 6 patients, mycophenolate mofetil for 3 patients, and cyclophosphamide, hydroxychloroquine and leflunomide for 1 patient each) and biologic targeted treatments for 4 (infliximab for 3 patients and tocilizumab for 1 patient). Cochlear implants were needed for 12/60 patients (20%). Discussion In our series of individuals with Cogan syndrome, sex ratio, age at diagnosis, and prevalence of vestibulo-auditory, ocular and systemic signs were similar to previous data from the Mayo
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ACCEPTED MANUSCRIPT Clinic and French nationwide series (2, 3). Associated autoimmune diseases were present in 8% of patients from the Mayo Clinic and in 10% of our patients (21). Only one previous large series compared features of typical and atypical Cogan syndrome, mainly showing more frequent joint and neurological involvements (2). In our series, patients with atypical Cogan syndrome were predominantly male, without any striking differences from those with the typical syndrome in various organ involvements, treatments and outcome, except for the expected more frequent scleritis and episcleritis in atypical forms.
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Treatment of Cogan syndrome is challenging and particularly concerns vestibulo-auditory impairment. In the literature review of 111 cases by Grasland et al., 54% and 37% of cases
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with typical and atypical Cogan syndrome remained deaf in both ears despite treatment (2).
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Overall, 58% patients under steroids treatment showed improved vestibulo-auditory and ocular signs, with improvement in hearing and balance (3). Only case reports and small case
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series reported the potential efficacy of immunosuppressive drugs such as methotrexate, azathioprine and cyclophosphamide, but no previous large-data studies compared these various drugs and their efficacy.
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We demonstrated that a TNF-α antagonist (infliximab) could overcome DMARDS and steroids-refractory Cogan syndrome for vestibulo-auditory response, with 80% frequency of
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improvement (i.e., complete and partial responders) at 6 months. We also show that patients with atypical and typical Cogan syndrome had a similar treatment response. Relapse rates
10 years, respectively.
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remained low during follow-up in that 13% and 31% of patients experienced relapse at 5 and
One of the most striking results of our study concerns the comparison of the efficacy of
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steroids alone, associated with DMARDs, or infliximab for vestibulo-auditory recovery. Despite the frequency of various signs, CRP level, and prednisone amounts being similar
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among groups, patients who finally received infliximab had significantly more previous treatment lines. Despite more previous treatment lines, patients receiving infliximab experienced significant improvement in vestibulo-auditory signs, different from patients with steroids alone or DMARDs. Even if the study design and low number of patients limit definite conclusions for this important finding, the use of biologic targeted drugs as first-line treatment in patients with vestibulo-auditory impairment could be discussed. With a difference in vestibulo-auditory impairment, the outcome of systemic and ocular signs is usually favorable with steroids alone. Among 60 patients, 82% recovered normal vision at the last follow-up, and only 3% of our patients showed persistent ocular impairment (3). The improvement in systemic and ocular signs in our study was similar with steroids alone, DMARDs and
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ACCEPTED MANUSCRIPT infliximab, which argues for the use of steroids alone in the absence of vestibulo-auditory signs. Several limitations of the study should be mentioned. The retrospective design of this series resulted in lack of uniformity in treatments. Treatment decisions were left to the physician’s discretion. The evaluation of the efficacy of infliximab is difficult because of the low number of patients receiving these drugs, and other biologic targeted treatments could not be analyzed. Nevertheless, results observed were similar if the potential association between
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observations due to the multiple treatments per patient is considered. Adjustment on lines of treatments and the indication (relapse, steroid dependence or inefficacy) could limit bias
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Conclusions
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related to the statistical model used in this study.
In DMARD and steroids-refractory Cogan syndrome, infliximab can lead to vestibulo-
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auditory response, with 80% frequency of improvement at 6 months. Prospective studies are warranted to confirm these data and determine the place of associated drugs in this rare
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condition.
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ACCEPTED MANUSCRIPT Acknowledgements We thank the Club Rhumatismes et Inflammation (CRI) and the French National Society of Internal Medicine (SNFMI) for their help in the organization of this study. Funding Sources: none. Conflicts of interest: none.
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AUTHOR CONTRIBUTIONS
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All authors were involved in drafting the article. Arsene Mekinian had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of data
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analysis.
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Study conception and design. AM, CD
Acquisition of data. AM, CD, TP, TZ, BL, CD, PL, JP, JEK, CL, BDW, RD, GG, EP, TQ,
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MH, PS, TG, AG, OF
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Analysis and interpretation of data. MRR, AM, CD
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ACCEPTED MANUSCRIPT Figure 1. Multiple regression analysis of predictors of vestibulo-auditory responses with
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various treatments (n=129 lines of therapy for 61 patients).
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Charlotte Durtette, Eric Hachulla, Matthieu Resche-Rigon, Thomas Papo, Thierry Zénone, Bertrand Lioger, Christophe Deligny, Marc Lambert, Cédric Landron, Jacques Pouchot, Jean Emmanuel Kahn, Christian Lavigne, Benoit De Wazieres, Robin Dhote, Guillaume Gondran, Edouard Pertuiset, Thomas Quemeneur, Mohamed Hamidou, Pascal Sève, Thomas Le Gallou, Anne Grasland, Pierre-Yves Hatron, Olivier Fain, Arsène Mekinian, CRI, on the behalf of SNFMI PII: DOI: Reference:
S1568-9972(17)30255-0 doi:10.1016/j.autrev.2017.10.005 AUTREV 2072
To appear in: Received date: Accepted date:
7 August 2017 14 August 2017
Please cite this article as: Charlotte Durtette, Eric Hachulla, Matthieu Resche-Rigon, Thomas Papo, Thierry Zénone, Bertrand Lioger, Christophe Deligny, Marc Lambert, Cédric Landron, Jacques Pouchot, Jean Emmanuel Kahn, Christian Lavigne, Benoit De Wazieres, Robin Dhote, Guillaume Gondran, Edouard Pertuiset, Thomas Quemeneur, Mohamed Hamidou, Pascal Sève, Thomas Le Gallou, Anne Grasland, Pierre-Yves Hatron, Olivier Fain, Arsène Mekinian, CRI, on the behalf of SNFMI , Cogan syndrome: Characteristics, outcome and treatment in a French nationwide retrospective study and literature review. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Autrev(2017), doi:10.1016/j.autrev.2017.10.005
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ACCEPTED MANUSCRIPT Cogan syndrome: characteristics, outcome and treatment in a French nationwide retrospective study and literature review Charlotte Durtette1, Eric Hachulla2, Matthieu Resche-Rigon3, Thomas Papo4, Thierry Zénone5, Bertrand Lioger6, Christophe Deligny7, Marc Lambert2, Cédric Landron8, Jacques Pouchot9, Jean Emmanuel Kahn10, Christian Lavigne11, Benoit De Wazieres12, Robin Dhote13, Guillaume Gondran14, Edouard Pertuiset15, Thomas Quemeneur16, Mohamed Hamidou17,
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Pascal Sève18, Thomas Le Gallou19, Anne Grasland20, Pierre-Yves Hatron2, Olivier Fain1,
AP-HP, Hôpital Saint-Antoine, service de médecine interne and Inflammation-
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Arsène Mekinian1, on the behalf of SNFMI and CRI.
University Paris 06, F-75012, Paris, France 2
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Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC
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Service de Médecine Interne et Immunologie Clinique, CHU Lille, Centre national de
référence maladies systémiques et auto-immunes rares, Université de Lille, 59037 Lille cedex, France3AP-HP, Hôpital Saint-Louis, service de Biostatistiques, UPMC Univ Paris 07, F-
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75011, Paris, France
AP-HP, service de médecine interne, Hôpital Bichat-Claude Bernard, Paris, France
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Service de médecine interne, CH Valence, Valence, France
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Service de médecine interne, CHU Tours, Université de Tours, Tours, France
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Service de médecine interne, CHU Martinique, Fort de France, France
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Service de médecine interne, CHU Poitiers, Poitiers, France
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Service de Médecine Interne, Hôpital européen Georges-Pompidou, Assistance Publique
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Hôpitaux de Paris - APHP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France 10
Service de médecine interne, Hôpital Foch, 92150 Suresnes, Université Versailles Saint
Quentin en Yvelines, France 11
Service de médecine interne et Maladies vasculaires, Centre de compétence de Maladies
rares, CHU Angers, Université Angers, 49000 Angers, France
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Service de médecine interne et Maladies vasculaires, Centre de compétence de Maladies
rares, CHU Angers, Université Angers, 49000 Angers, France 12
Service de médecine interne, CHU Nîmes, Nîmes, France.
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Service de médecine interne, Université Paris 13, AP-HP, Avicenne, 93000, Bobigny,
France. Service de médecine interne, CHU Limoges, Limoges, France.
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Service de Rhumatologie, Centre Hospitalier René Dubos, Pontoise
Service de médecine interne et de néphrologie, Hôpital de Valenciennes, Valenciennes,
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France.
Hôpital Hôtel Dieu, service de médecine interne, Université de Nantes, Nantes, France
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Service de médecine interne, Hôpital de la Croix-Rousse, Université de Lyon, Lyon, France AP-HP, service de médecine interne, Hôpital Louis Mourier, Colombes, France
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Original research article
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Correspondence and reprint requests to: Arsene Mekinian, MD, AP-HP, Hôpital Saint Antoine, service de medicine interne and
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Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75012, Paris, France, Phone: + (33) 1 49282387 Fax: + (33) 149282652. E-mail: [email protected]
Running title: Infliximab for Cogan syndrome
Word count: abstract (250), manuscript (), figures (4), tables (2). Key words : Cogan’s syndrome; treatment, infliximab, outcome Conflicts of interest and funding: none.
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ACCEPTED MANUSCRIPT Abstract Background Cogan syndrome is mainly treated with corticosteroids. We aimed to determine the place of DMARDs and biologic-targeted treatments. Patients and Methods
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We conducted a French nationwide retrospective study of patients with Cogan syndrome (n=40) and a literature review of cases (n=22) and analyzed the efficacy of disease-modifying
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anti-rheumatic drugs (DMARDs) and tumor necrosis factor α (TNF-α) antagonists.
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Results
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We included 62 patients (31 females) investigated (median age 37 years [range 2-76]. At diagnosis, 61 patients (98%) had vestibulo-auditory symptoms, particularly bilateral hearing loss in 41% and deafness in 31%. Ocular signs were present in 57 patients (92%), with
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interstitial keratitis in 31 (51%). The first-line treatment consisted of steroids alone (n=43; 70%) or associated with other immunosuppressive drugs (n=18; 30%). Overall, 13/43 (30%) and 4/18 (22%) patients with steroids alone and with associated immunosuppressive drugs,
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respectively (p=0.8), showed vestibulo-auditory response; 32/39 (82%) and 15/19 (79%)
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ocular response; and 23/28 (82%) and 10/14 (71%) general response. In all, 61 patients had used a total of 126 lines of treatment, consisting of steroids alone (n=51 lines), steroids with DMARDs (n=65) and infliximab (n=10). Vestibulo-auditory response was significantly more
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frequent with infliximab than DMARDs or steroids alone (80% vs 39% and 35%, respectively), whereas ocular, systemic and acute-phase reactant response rates were similar.
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Infliximab was the only significant predictor of vestibulo-auditory improvement (odds ratio 20.7 [95% confidence interval 1.65; 260], p=0.019). Conclusion
Infliximab could lead to vestibulo-auditory response in DMARDS and steroid-refractory Cogan syndrome, but prospective studies are necessary.
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ACCEPTED MANUSCRIPT Key messages Vestibulo-auditory response was similar with DMARDs and steroids alone. Infliximab could lead to vestibulo-auditory response in DMARDS and steroid-refractory Cogan syndrome
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The 5 and 10-years incidence of relapse increased under steroids and DMARDS, while it stayed stable with infliximab
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ACCEPTED MANUSCRIPT INTRODUCTION Cogan syndrome was first described in 1945 by an ophthalmologist, David G. Cogan, who reported on a “syndrome of non-syphilitic interstitial keratitis and vestibule-auditory symptoms” that resembled Meniere's disease (1). Other ocular signs such as conjunctivitis, uveitis, scleritis and choroiditis have been described recently and are considered atypical forms in the absence of interstitial keratitis.
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Since 1945, more than 250 cases of Cogan syndrome have been reported, and the disease seems to have an autoimmune origin; no easily available autoantibodies have been clearly
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associated with this syndrome (2, 3). Alleviating the vestibulo-auditory symptoms, and in
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particular the hearing loss, remains challenging. Because of the rarity of the disease, no controlled study has been performed, with only small reported series, and the value of
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immunosuppressive treatment, particularly the place of disease-modifying anti-rheumatic drugs (DMARDs), remains to be determined. The 2 largest case-series, of 32 and 60 patients, mainly described the efficacy of steroids alone (2, 3). Among the 60 patients, 57 (95%)
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received steroids, with vestibulo-auditory and ophthalmological improvements in 58% (3). However, no studies have compared the benefit of DMARDs added to steroids and the
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potential efficacy of various DMARDs. Recently, a few case reports demonstrated the benefit
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of biologic targeted treatments, mainly infliximab, but larger studies are needed to determine their benefit for vestibulo-auditory involvement (4-8) (9). A recent literature review analyzed treatment strategies in 141 patients, including various DMARDs and biologics, suggesting the
(10).
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value of immunosuppressive drugs but could not compare the efficacy of various regimen
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In this largest French nationwide study and literature review, we report the long-term outcome of 62 patients with Cogan syndrome receiving steroids, DMARDs and/or tumor necrosis factor α (TNF-α) antagonists and compare their efficacy. MATERIALS AND METHODS We conducted a retrospective multicenter study in the French network of internal medicine (SNFMI) and the Club Rhumatisme and Inflammation (CRI) between July 2014 and 2016. Data were collected retrospectively from physicians in charge of patients. The physicians were asked to complete a standardized questionnaire online.
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ACCEPTED MANUSCRIPT The inclusion criteria were 1) ocular signs consistent with non-syphilitic interstitial keratitis and/or conjunctivitis, episcleritis, scleritis or uveitis; 2) rapidly progressive vestibuloauditory involvement; and 3) time between the vestibulo-auditory and ocular symptoms less than 2 years (typical forms) and more than 2 years (atypical forms) (11). Patients’ clinical and laboratory data and treatments were analysed at baseline, at initiation and the end of each treatment regimen, and at the last available visit. For clinical data, the
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presence of constitutional symptoms and non-infectious fever, lung, vestibulo-auditory, nervous system, skin, joint, eye, vascular and heart impairments were recorded. Laboratory
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data collected were antinuclear, anti-neutrophil cytoplasmic and anti-citrullinated protein antibodies; HIV and syphilis serologies; and histological analysis from biopsies if available.
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Routine laboratory indicators of disease activity, including erythrocyte sedimentation rate (ESR) and C-reactive protein level (CRP) were collected. Steroid dose was analysed at the
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initiation of each new treatment regimen and during follow-up. The different lines of steroids, immunosuppressive agents (DMARDS) and biologic targeted treatments (infliximab,
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adalimumab, tocilizumab) were analysed separately for each patient. DMARDs and biologic targeted treatments were prescribed for 73% of patients because of inadequate disease control or intolerance to steroids (n=15), relapse (n=27) or adverse events (n=2) (Figure 1). Relapse
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was defined as the reappearance of signs after at least 3 months’ remission. Follow-up was
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considered from the diagnosis to the last available news and/or death.
Treatment response definitions
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Treatment response with any regimen (steroids, DMARDs, biologic targeted treatment) was defined as complete response (complete clinical improvement and regression of acute-phase
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reactants) or partial response (at least 50% clinical improvement and 50% regression of acutephase reactants) at 6 months and/or at the end of each treatment line if interrupted before 6 months. Clinical response was separately defined for vestibulo-auditory, systemic and ocular signs. Non-response was considered for the remaining situations.
Literature search strategy Two investigators (CD and AM) searched for articles published from 2004 to 2015 in MEDLINE via PubMed, Web of Science and the Cochrane Library using the keywords Cogan’s
disease,
“interstitial
keratitis”,
treatment,
“DMADRDs”,
“methotrexate”,
“leflunomide”, “azathioprine”, “ciclosporine”, “cyclophosphamide”, “TNFα antagonists”,
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inhibitors”,
“infliximab”,
“adalimumab”,
“etanercept”,
“tocilizumab”,
“rituximab”. All articles with sufficient data on treatments and efficacy for vestibulo-auditory and ocular signs were included in the literature review. Overall, 22 cases from 16 papers were included (6-9, 12, 13) (11, 14-16) (17) (15) (18) (19) (20). Statistical analysis Data are presented as median (range) for continuous variables and frequency (%) for
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qualitative variables. Because each patient could have multiple treatments, we evaluated the vestibulo-auditory, ocular and systemic response by a logistic multivariable regression model
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with a patient random effect, estimating odds ratios (ORs) and 95% confidence intervals (95%
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CIs). Moreover, analyses were adjusted on treatment indication and number of previous therapeutic lines. Relapse was defined as disease becoming active after a remission period
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requiring a change in the treatment regimen. Because each patient could experience multiple relapses, we considered an Andersen-Gill approach, with treatment as a time-dependent covariate. Thus, the time origin for each treatment was when the patient started on that
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regimen. Treatment switch due to lack of efficacy or intolerance was considered a competing event of relapse without intolerance. In case of no event, patients were censored at the last
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follow-up. The cumulative incidence of relapse for each treatment period was estimated by using the Gray estimator, considering lack of efficacy, intolerance or complication as
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competitive events. All tests were two-sided and a P < 0.05 was considered statistically significant. Data were analyzed by using R version 3.3.1 (https://www.R-project.org).
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Results
Baseline characteristics of patients
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We included 40 personal cases and 22 from the literature, for 62 patients (31 females; median age 37 years [range 2-76]). The median time from the first symptoms to diagnosis was 12 months [0-231]. At diagnosis, 61 patients (98%) had vestibulo-auditory symptoms, in particular, bilateral hearing loss for 41% and deafness for 31% (Supplementary Table 1). Ocular signs were present in 57 patients (92%), with interstitial keratitis in 31 (51%). The median time between vestibulo-auditory and ocular symptoms was 2 months [0-180]. Other signs were mainly constitutional symptoms (fever, weight loss) and arthromyalgias. Cerebral MRI showed non-specific white-matter hyperintensities in 7/59 patients (12%), and vestibulo-auditory MRI was consistent with labyrinthitis in 4/47 (9%). For 60 patients, no
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ACCEPTED MANUSCRIPT specific autoantibodies were found. Associated autoimmune disease was noted in 6 patients: sarcoidosis (n=2), Takayasu arteritis, polyarteritis nodosa, relapsing polychondritis and spondylarthritis (n=1 each). Atypical Cogan syndrome was present in 31 patients (50%) (Supplementary Table 2). As compared with patients with typical Cogan syndrome (presence of interstitial keratitis and time between vestibulo-auditory and ocular signs < 2 years), those with atypical disease
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differed in only sex (68% vs 32% females, p<0.05) and frequency of scleritis and episcleritis (10% vs 55%; p<0.05).
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Treatment
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The median treatment time from diagnosis for 61/62 patients (98%) was 4 months [range 0145]. The first-line treatment consisted of steroids alone (n=43; 70%) or with other
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immunosuppressive drugs (n=18; 30%) (Supplementary Figure 1). The median steroid dose was 60 mg/day (20-120) (Supplementary Table 1). Overall, 17/61 patients (28%) showed a vestibulo-auditory response, whereas 47/58 (81%) and 33/42 (79%) showed an ocular and
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general response, respectively. In total, 13/43 (30%) and 4/18 (22%) patients showed a vestibulo-auditory response under steroids and with an associated immunosuppressive
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regimen, respectively (p=0.8); 32/39 (82%) and 15/19 (79%) showed an ocular response, respectively, and 23/28 (82%) and 10/14 (71%) a systemic response, respectively
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(Supplementary Figure 1). A second-line treatment was used in 44 patients for steroids dependence (n=4), inefficacy (n=10), relapse (n=27) or adverse effects (n=3). Second-line treatment consisted in steroids for all 44 patients, with associated drugs in 37 (84%). A total
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of 22/42 patients (50%) showed a vestibulo-auditory response and 27/27 (100%) and 18/18 (100%) an ocular and systemic response, respectively. Frequency of vestibulo-auditory,
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ocular and systemic response was similar for patients under steroids alone and with associated immunosuppressive drugs (Figure 1). Third-line treatment was started in 15 patients (25%) for inefficacy (n=4) and relapse (n=11). Frequency of vestibulo-auditory, ocular and systemic response was similar for patients with typical and atypical Cogan syndrome (Supplementary Table 2). Comparison of responses with infliximab and DMARDs/steroids Overall, 61 patients received 126 lines of treatment that consisted of steroids alone (n=51 patients), steroids associated with DMARDs (n=65) and biologic targeted treatment
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ACCEPTED MANUSCRIPT (infliximab, n=10). Among DMARDs, cyclophosphamide was used in 25 lines, methotrexate in 19, azathioprine in 14, mycophenolate mofetil in 4 and ciclosporine in 7. At initiation of biologic targeted versus steroids and DMARDs treatment, patients did not differ in vestibulo-auditory or general signs or steroids dose, but CRP level was higher, as was number of previous treatment regimens [median 2.5 (range 2-6) vs 2 (1-5), p<0.05] (Table 1). Vestibulo-auditory response was significantly more frequent with infliximab than DMARDs
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or steroids alone (80% vs 39% and 35%, respectively), whereas ocular, systemic and acutephase reactants response rates were similar. Probability of vestibulo-auditory improvement
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was significant for only infliximab (odds ratio [OR] 20.7 [95% CI 1.65; 260], p=0.019) and was high but not significantly for azathioprine (OR 3.7 [0.83; 16.5], p=0.08) and not
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significant for methotrexate, azathioprine, cyclophosphamide and steroids alone (Figure 1),
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even after adjustment for treatment lines and line indication.
During a median follow-up of 35 months [range 0-578], 43 relapses occurred, with 5- and 10-
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year cumulative incidence of relapse of 13% and 31%, respectively (Supplementary Figure 2). The 3-years cumulative incidence of relapse was equal to 17%, 0% and 12% at year 3 for steroids, DMARDS and infliximab respectively. The 5 and 10-years incidence increased to
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29% and 3% and 54%, 19% for steroids and DMARDS, respectively, while it stayed stable
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with infliximab (Supplementary Figure 3).
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At the last evaluation, hearing loss was still noted in 37/60 patients (62%), with ocular and systemic features in 2/60 patients (3%). For 43 patients, the treatment at the last visit was
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ongoing, with steroids for 39/60 (65%) (median 5 mg/day [range 2-100]) and other immunosuppressive agents for 28/60 (47%), including DMARDS for 23/60 (38%) (methotrexate for 12 patients, azathioprine for 6 patients, mycophenolate mofetil for 3 patients, and cyclophosphamide, hydroxychloroquine and leflunomide for 1 patient each) and biologic targeted treatments for 4 (infliximab for 3 patients and tocilizumab for 1 patient). Cochlear implants were needed for 12/60 patients (20%). Discussion In our series of individuals with Cogan syndrome, sex ratio, age at diagnosis, and prevalence of vestibulo-auditory, ocular and systemic signs were similar to previous data from the Mayo
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ACCEPTED MANUSCRIPT Clinic and French nationwide series (2, 3). Associated autoimmune diseases were present in 8% of patients from the Mayo Clinic and in 10% of our patients (21). Only one previous large series compared features of typical and atypical Cogan syndrome, mainly showing more frequent joint and neurological involvements (2). In our series, patients with atypical Cogan syndrome were predominantly male, without any striking differences from those with the typical syndrome in various organ involvements, treatments and outcome, except for the expected more frequent scleritis and episcleritis in atypical forms.
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Treatment of Cogan syndrome is challenging and particularly concerns vestibulo-auditory impairment. In the literature review of 111 cases by Grasland et al., 54% and 37% of cases
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with typical and atypical Cogan syndrome remained deaf in both ears despite treatment (2).
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Overall, 58% patients under steroids treatment showed improved vestibulo-auditory and ocular signs, with improvement in hearing and balance (3). Only case reports and small case
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series reported the potential efficacy of immunosuppressive drugs such as methotrexate, azathioprine and cyclophosphamide, but no previous large-data studies compared these various drugs and their efficacy.
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We demonstrated that a TNF-α antagonist (infliximab) could overcome DMARDS and steroids-refractory Cogan syndrome for vestibulo-auditory response, with 80% frequency of
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improvement (i.e., complete and partial responders) at 6 months. We also show that patients with atypical and typical Cogan syndrome had a similar treatment response. Relapse rates
10 years, respectively.
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remained low during follow-up in that 13% and 31% of patients experienced relapse at 5 and
One of the most striking results of our study concerns the comparison of the efficacy of
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steroids alone, associated with DMARDs, or infliximab for vestibulo-auditory recovery. Despite the frequency of various signs, CRP level, and prednisone amounts being similar
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among groups, patients who finally received infliximab had significantly more previous treatment lines. Despite more previous treatment lines, patients receiving infliximab experienced significant improvement in vestibulo-auditory signs, different from patients with steroids alone or DMARDs. Even if the study design and low number of patients limit definite conclusions for this important finding, the use of biologic targeted drugs as first-line treatment in patients with vestibulo-auditory impairment could be discussed. With a difference in vestibulo-auditory impairment, the outcome of systemic and ocular signs is usually favorable with steroids alone. Among 60 patients, 82% recovered normal vision at the last follow-up, and only 3% of our patients showed persistent ocular impairment (3). The improvement in systemic and ocular signs in our study was similar with steroids alone, DMARDs and
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ACCEPTED MANUSCRIPT infliximab, which argues for the use of steroids alone in the absence of vestibulo-auditory signs. Several limitations of the study should be mentioned. The retrospective design of this series resulted in lack of uniformity in treatments. Treatment decisions were left to the physician’s discretion. The evaluation of the efficacy of infliximab is difficult because of the low number of patients receiving these drugs, and other biologic targeted treatments could not be analyzed. Nevertheless, results observed were similar if the potential association between
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observations due to the multiple treatments per patient is considered. Adjustment on lines of treatments and the indication (relapse, steroid dependence or inefficacy) could limit bias
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Conclusions
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related to the statistical model used in this study.
In DMARD and steroids-refractory Cogan syndrome, infliximab can lead to vestibulo-
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auditory response, with 80% frequency of improvement at 6 months. Prospective studies are warranted to confirm these data and determine the place of associated drugs in this rare
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ACCEPTED MANUSCRIPT Acknowledgements We thank the Club Rhumatismes et Inflammation (CRI) and the French National Society of Internal Medicine (SNFMI) for their help in the organization of this study. Funding Sources: none. Conflicts of interest: none.
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AUTHOR CONTRIBUTIONS
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All authors were involved in drafting the article. Arsene Mekinian had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of data
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analysis.
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Study conception and design. AM, CD
Acquisition of data. AM, CD, TP, TZ, BL, CD, PL, JP, JEK, CL, BDW, RD, GG, EP, TQ,
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MH, PS, TG, AG, OF
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Analysis and interpretation of data. MRR, AM, CD
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ACCEPTED MANUSCRIPT Figure 1. Multiple regression analysis of predictors of vestibulo-auditory responses with
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various treatments (n=129 lines of therapy for 61 patients).
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