Review Tocilizumab in refractory aortitis: a study on 16 patients and literature review J. Loricera1*, R. Blanco1*, S. Castañeda2, A. Humbría2, N. Ortego-Centeno3, J. Narváez4, C. Mata5, S. Melchor6, E. Aurrecoechea7, J. Calvo-Alén7, P. Lluch8, C. Moll8, M. Mínguez9, G. Herrero-Beaumont10, B. Bravo11, E. Rubio12, M. Freire13, E. Peiró1, C. González-Vela1, J. Rueda-Gotor1, T. Pina1, N. Palmou-Fontana14, V. Calvo-Río1, F. Ortiz-Sanjuán1, M.A. González-Gay1 1Dept. of Rheumatology, Hospital ABSTRACT Conclusion. TCZ appears to be effec- Universitario Marqués de Valdecilla, Objective. Non-infectious aortitis is of- tive and relatively safe in patients with 2 IDIVAL, Santander; Dept. of Rheumatology, ten refractory to standard immunosup- inflammatory aortitis refractory to cor- Hospital Universitario La Princesa, IIS-Princesa, Madrid; 3Dept. of Autoimmune pressive therapy. Since IL-6 has been ticosteroids or to other biologic immu- Diseases, Hospital San Cecilio, Granada; implicated in the pathogenesis of aorti- nosuppressive drugs. 4Dept. of Rheumatology, Hospital tis, we assessed the efficacy of the anti- Universitari de Bellvitge, L´Hospitalet de IL6 receptor monoconal antibody toci- Introduction 5 Llobregat, Barcelona; Dept. of lizumab (TCZ) in a series of patients Aortitis encompasses a wide spectrum Rheumatology, Hospital de Laredo; with refractory non-infectious aortitis. of infectious and non-infectious patho- 6Dept. of Rheumatology, Hospital Universitario 12 de Ocubre, Madrid; Methods. Review of 16 patients (14 logic conditions characterised by in- 7Dept. of Rheumatology, Hospital de women/2 men) with refractory aortitis flammation of the aortic wall. In some Sierrallana, Torrelavega; 8Dept. of diagnosed by imaging (CT angiogra- cases it may be associated with severe Rheumatology, Hospital Mateu Orfila, phy, MR angiography, and/or PET) complications such as aneurysms, dis- 9 Menorca; Dept. of Rheumatology, that were treated with TCZ. section and rupture of the aorta (1-4). Hospital Universitario San Juan, Alicante; 10Bone and Joint Research Laboratory, Results. The mean age±SD was Giant cell arteritis (GCA) and Takayasu IIS-Fundación Jiménez Díaz, Madrid; 51.4±20.1 years. The underlying con- arteritis (TakA) including in the cat- 11Paediatric Rheumatology Unit, Hospital ditions were: Takayasu arteritis (TakA) egory of large-vessel vasculitides are Virgen de las Nieves, Granada; 12Dept. of (n=7 cases), giant cell arteritis (GCA) probably the most frequent causes of Rheumatology, Hospital Virgen del Rocío, (n=7), relapsing polychondritis (RP) 13 non-infectious aortitis. Nevertheless, Sevilla; Dept. of Rheumatology, Complexo (n=1), and aortitis associated with re- non-infectious aortitis may present as Hospitalario A Coruña (CHUAC); 14Rheumatology Division, Hospital troperitoneal fibrosis (n=1). TCZ was an isolated entity or be associated with General de Almansa, Albacete, Spain. the first biologic drug used in all pa- other well defined conditions (2, 5- 8). *Javier Loricera and Ricardo Blanco tients with GCA and in the patient with First-line treatment in non-infectious shared first authorship. aortitis associated with retroperitoneal aortitis includes the use of corticos- Please address correspondence to: fibrosis but in only 2 of 7 TakA patients. teroids, usually at high doses (9-12). Miguel A. González-Gay or Ricardo In the remaining cases anti-TNF inhibi- Other therapies are often required to Blanco, Rheumatology Division, tors were prescribed before TCZ (stand- achieve control of the disease or as Hospital Universitario Marqués ard dose was 8 mg/kg/iv/4 weeks). Af- corticosteroid sparing agents. Differ- de Valdecilla, IDIVAL, Avda. Valdecilla ter a mean±SD follow-up of 11.8±6.6 ent synthetic traditional immunosup- s/n., 39008, Santander, Spain. E-mail: [email protected] months most patients experienced clini- pressive drugs such as methotrexate or: [email protected] cal improvement, showing reduction (MTX), azathioprine or cyclophospha- Received on December 26, 2013; accepted of erythrocyte sedimentation rate from mide have been used for this purpose in revised form on February 4, 2014. 43±36 mm/1st h to 5±4 mm/1st h at last (13-18). However, the efficacy of these Clin Exp Rheumatol 2014; 32 (Suppl. 82): visit. At TCZ onset, 25% of patients had drugs to control the activity of the dis- S79-S89. fever and 19% polymyalgia rheumatica. ease is often insufficient and they are © Copyright CLINICAL AND These manifestations disappeared after frequently associated with potential se- EXPERIMENTAL RHEUMATOLOGY 2014. 3 months of TCZ therapy. A corticos- vere side effects. teroid sparing effect was also achieved In patients with large-vessel vasculitis, Key words: aortitis, giant cell arteritis, (from 27.3±17.6 mg/day of prednisone especially in GCA, a number of studies Takayasu arteritis, idiopathic aortitis, at TCZ onset to 4.2±3.8 mg/day at last have shown the presence of abnormal tocilizumab visit). TCZ had to be discontinued in a production of pro-inflammatory cyto- Competing interests: none declared. patient because of severe neutropenia. kines, such as interleukin-1 (IL-1), S-79 REVIEW Aortitis and tocilizumab / J. Loricera et al. IL-6, IL-18, tumour necrosis factor-α TakA fulfilled the 1990 ACR criteria respectively. We defined high CRP val- (TNF-α) or interferon-γ, by T lympho- for the classification for this vasculitis ue when it was higher than 0.5 mg/dL. cytes and macrophages (19-35). Due (51). A patient with aortitis was diag- to this, several studies were performed nosed as having relapsing polychondri- Statistical analysis to determine the efficacy of anti-TNF tis according to the criteria proposed by Statistical analysis was performed us- drugs on large-vessel vasculitides. Re- Michet et al. (52). Another patient with ing the software STATISTICA (Stat- grettably, in most cases, evidence sup- aortitis also fulfilled definitions for re- Soft Inc. Tulsa, Oklahoma, USA). Re- porting the use of anti-TNF-α inhibi- troperitoneal fibrosis (53). Polymyal- sults were expressed as mean±SD for tors in aortitis refractory to corticoster- gia rheumatica (PMR) in the setting of variables with normal distribution, or as oids is weak (36-40). GCA was diagnosed according to the median, range or [25th-75th interquartile IL-6 is another pro-inflammatory piv- criteria proposed by Chuang et al. (54). range (IQR)] when they were not nor- otal cytokine that has been implicated In most cases management started with mally distributed. in the pathogenesis of aortitis (26, 35, corticosteroids. In a second phase, All of the following variables were 41-43). Since tocilizumab (TCZ) is a synthetic traditional immunosuppres- compared: clinical manifestations, humanised monoclonal anti-IL6 recep- sive drugs and in some cases biologic ESR, CRP, and daily prednisone dose. tor (IL-6R) antibody, the use of this therapy was given. Comparisons of these variables were monoclonal antibody was described in Before biologic treatment, evidence of made between baseline and 3, 6 and some case reports and small series. The malignancy or systemic infection was 12 months after initiation of treatment. analysis of these reports suggests a po- excluded including hepatitis B or hepa- Comparison of continuous variables tential efficacy of TCZ therapy in the titis C. According to national guide- was performed using the Wilcoxon test. treatment of aortitis, mainly in the set- lines in all patients receiving biologic ting of GCA and TakA (40, 43, 44-49). drugs latent tuberculosis was excluded Results To further investigate into the potential by a tuberculin skin testing (PPD) and/ We studied 16 patients (14 women and efficacy of anti-IL6-R blockade in pa- or quantiferon and chest radiograph. In 2 men) with non-infectious aortitis. tients with large-vessel vasculitis, we patients with latent tuberculosis proph- The mean-age ± SD was 51.4±20.1 assessed a series of patients with non- ylaxis with isoniazid was initiated at years (range: 7–77 years). Table I sum- infectious aortitis refractory to corti- least 4 weeks before the onset of the marises the main features of the pa- costeroids and in some cases to anti- biologic therapy. Overall, prophylaxis tients included in this series. Aortitis TNF-α inhibitors. with isoniazid was maintained for 9 was associated to the following under- months. Since TCZ is an off-label indi- lying conditions: TakA (n=7 patients), Patients and methods cation in non infectious aortitis, written GCA (n=7), relapsing polychondritis Patient population informed consent was requested and (n=1), and aortitis with retroperitoneal We conducted an interventional case obtained from all patients. fibrosis (n=1). series, open-label, multicentre study on As discussed Methods, the diagnosis 16 patients diagnosed as having non- Data collection and clinical definitions of aortitis was made by imaging tech- infectious aortitis, either idiopathic or Clinical and laboratory data were ex- niques such as FDG PET/CT scan, MR in the setting of well-defined autoim- tracted from the clinical records accord- angiography, and/or CT angiography. mune or inflammatory conditions. In ing to a specifically designed protocol In the patient with aortitis and retro- all of them, TCZ therapy was given that was designed beforehand. They peritoneal fibrosis the diagnosis was because patients were refractory to were stored in a computerised file. To performed by a retroperitoneal biopsy. corticosteroids and standard synthetic minimise entry error, all the data were In 15 cases