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 , dis- 9 Menorca; Dept. of Rheumatology, that were treated with TCZ. section and rupture of the (1-4). Hospital Universitario San Juan, Alicante; 10Bone and Joint Research Laboratory, Results. The mean age±SD was Giant cell (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), (GCA) probably the most frequent causes of Rheumatology, Hospital Virgen del Rocío, (n=7), (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. and 19% . 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 , 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),

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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 TCZ therapy was given due immunosuppressive drugs and in some double-checked. The following data to aortitis refractory to standard syn- cases to other biologic agents. were assessed: clinical, laboratory, di- thetic immunosuppressive drugs and Patients were diagnosed as having aor- agnosis, treatment, prognosis and ad- in some cases to other biologic agents. titis between January 1999 and Decem- verse events. Fever was defined as a The patient with aortitis and retroperi- ber 2012 at the Rheumatology or Auto- temperature >38ºC, and constitutional toneal fibrosis started with TCZ with- immune units of 11 centres from Spain. syndrome as asthenia and/or anorexia out having previously received con- The diagnosis of aortitis was based on and weight loss of at least 4 kg. ventional immunosuppressive drugs imaging techniques (computed tomo- Data on routine laboratory markers of because he was also diagnosed of sec- graphy-CT angiography, magnetic res- disease activity, including full blood cell ondary amyloidosis (Fig. 1). onance-MR angiography, helical CT or count, erythrocyte sedimentation rate The median duration of aortitis before 18F-fluorodeoxyglucose positron emis- (ESR), C-reactive protein (CRP) level, TCZ onset was 12 months [IQR: 7-45]. sion CT (FDG PET/CT) scan. liver enzymes levels, creatinine serum TCZ was prescribed as monotherapy Six of the 7 patients that fulfilled the level, proteinuria and hematuria were (6 cases) or combined with other tra- ACR classification criteria for GCA collected. The ESR was considered to ditional synthetic immunosuppressive (50) also had a positive temporal be increased when it was higher than 20 drugs, usually MTX (7 cases), my- biopsy. All 7 patients diagnosed with or 25 mm/1st hour for men or women, cophenolate mofetil (2 cases), and aza-

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Table I. Main features of 16 patients before and after tocilizumab therapy.

Case Age/ Underlying Diagnosis of aortitis Previous traditional Prednisone Prednisone CRP /ESR CRP /ESR Follow-up Serious side effects Sex disease immunosuppressive drugs dose (at TCZ dose (at last (at TCZ (at last visit) with TCZ due to TCZ to TCZ onset) mg/d visit) mg/d onset) (months)

1 7/F TakA MRI-A, echocardiogram MTX, CYP, MM, ETN, IFX 30 0 12/72 < 0.1/5 24 None 2 57/F TakA MRI-A CYP 45 5 3.3/99 0.2/2 18 None 3 26/F TakA CT-A, PET/CT MTX, AZA, IFX 50 7.5 2.8/33 <0.1/2 12 None 4 16/F TakA MRI-A, PET/CT MTX, ADA 50 7.5 0.5/14 0.1/7 12 None 5 45/F TakA PET/CT MTX, AZA, MM, IFX 25 0 <0.1/28 < 0.1/3 13 None 6 41/F TakA MRI-A, PET/CT MTX, ADA, IFX 40 10 3.7/29 <0.1/10 3 None 7 46/F TakA CT, PET/CT CyA 25 5 14.9/5 0.2/5 4 Thrombocytopenia 8 77/F GCA PET/CT MTX 10 2.5 3.7/120 1.7/7 5 None 9 59/F GCA CT MTX 60 5 <0.1/2 <0.1/2 16 None 10 65/F GCA PET/CT MTX 17.5 0 <0.1/3 <0.1/2 20 Severe neutropenia 11 67/F GCA PET/CT MTX 10 0 1.9/44 <0.1/2 6 Pneumonia 12 74/F GCA PET/CT MTX 0 0 0.8/46 <0.1/4 11 None 13 64/F GCA PET/CT MTX 15 10 0.1/ND <0.1/ND 3 Hypotension 14 53/M GCA MRI-A, PET/CT MTX 30 10 25.6/43 5.4/17 5 None 15 50/F RP CT MTX, CyA, LFN, CYP, IFX 30 5 0.9/13 <0.1/13 20 None 16 75/M RF CT-A None 0 0 ND/98 ND/ND 17 None

TCZ: tocilizumab; TakA: Takayasu arteritis; GCA: giant cell arteritis; RP: relapsing polychondritis; RF: retroperitoneal fibrosis; AZA: azathioprine; CyA: cyclosporine A; CYP: cyclophosphamide; LFN: leflunomide; MM: mycophenolate mofetil; MTX: methotrexate; ADA: adalimumab; ETN: etanercept; IFX: infliximab; RTX: rituximab; CRP:C- reactive protein (mg/dL); ESR: erythrocyte sedimentation rate in 1st hour; CT: computed tomography; CT-A: computed tomography angiography; MRI-A: magnetic resonance angiography; PET: positron emission tomography; ND: Not described.

thioprine (1 case). The initial TCZ dose was 8 mg/kg every 4 weeks in 15 cases and every 2 weeks in 1 case. Mainte- nance TCZ dose ranged between 4-8 mg/kg every 2 or every 4 weeks. Most patients experienced improve- ment of clinical manifestations and laboratory parameters following TCZ therapy. This improvement was evident at the first available measure assessed at month 3. This response to TCZ was maintained over time (Fig. 2). An im- aging technique was usually performed after TCZ onset to confirm improve- ment of the disease (Fig. 3 correspond- ing to case 14 in Table I).

Specific subtypes of aortitis – Takayasu arteritis At TCZ onset, the 7 patients with TakA (corresponding to cases 1–7 of Table I) showed the following clinical manifes- tations: constitutional syndrome (n=2), fever (n=3), chest pain (n=1), abdomi- nal pain (n=1), in the lower limbs (n=1), headache (n=1), transient ischaemic attacks (n=1), malaise (n=1) and nodular scleritis (n=1). All of them had received treatment with several traditional immunosuppressive drugs such as MTX (n=5), cyclophosphamide (n=2), azathioprine (n=2), mycophe- Fig. 1. Previous treatment with A) traditional immunosuppressive drugs and B) biologic drugs in 16 nolate mofetil (n=2) and cyclosporine patients receiving tocilizumab therapy due to refractory non-infectious aortitis. A (n=1). Since they were refractory to

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Fig. 2. Rapid and maintained improvement following Tocilizumab therapy in 16 patients with refractory non infectious aortitis. Data are expressed as mean or median values compared with basal results: A) CRP; B) ESR and C) corticosteroid dosage. these drugs, five of the seven patients MR angiography. In the other 2 patients – Relapsing polychondritis were initially treated with TNF-α in- there was a significant decrease in FDG A 50-year-old woman with relapsing hibitors. One patient undergoing treat- PET/CT uptake following TCZ therapy. polychondritis (case 15 of Table I) ment with adalimumab and another persisted with asthenia, deafness, pro- with etanercept were switched to inf- – Giant cell arteritis fuse sweating, fever, abdominal pain liximab. Finally, all the five patients on The main features of the 7 patients with and keratitis despite of treatment with anti-TNF-inhibitors had to be changed GCA (corresponding to cases 8–14 of corticosteroids, MTX, cyclosporine, to TCZ due to lack of response to anti- Table I) at TCZ onset were the follow- leflunomide and cyclophosphamide. TNF-α inhibitors. In addition, two pa- ing: PMR (n=3), constitutional syn- Because of that she was initially tients treated with non-biologic agents drome (n=2), jaw (n=1), treated with infliximab at a dose of 5 were also changed to TCZ. After 3 headache (n=1), scapular pain (n=1), mg/kg at 0, 2 and then every 6 weeks months of therapy with TCZ, 3 patients intermittent claudication of the lower without improvement. Therefore, she were asymptomatic, 3 patients had extremities (n=1), and chest pain (n=1). was switched to TCZ 8 mg/kg/4 weeks substantial improvement and only 1 Besides corticosteroids and before showing complete clinical-laboratory had not experienced any improvement. TCZ therapy, all the patients with GCA improvement at month 3. Corticoster- Further improvement following TCZ had received MTX. TCZ was started oid dose was also reduced. A CT angio- therapy was achieved. In this regard, because of lack of efficacy of MTX. graphy showed a significant decrease at last available visit, 6 patients were After 3 months on TCZ therapy, 5 pa- in the intimal thickness. asymptomatic and 1 patient had mild tients were asymptomatic; 1 patient asthenia. Moreover, in all them the dose had mild asthenia and another patient – Aortitis associated with of corticosteroids was reduced; and in persisted with intermittent claudica- retroperitoneal fibrosis 2 of them it was discontinued (cases 1 tion of the lower extremities. Labora- A 75-year-old man with retroperitoneal and 5). During the follow-up, imaging tory parameters also improved. At last fibrosis and nephrotic syndrome due techniques also showed improvement available visit, corticosteroid dose was to AA amyloid deposition started with in the 6 patients in whom they were reduced in all GCA patients. In 3 of constitutional syndrome and musculo- performed. With respect to this, in 4 them corticosteroids were completely skeletal pain more intense in the dorsal of them there was an improvement of discontinued. region (case 16 of Table I). A CT angio-

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Discussion Non-infectious aortitis is frequently associated with GCA and TakA (35). These two entities have similar patho- logical findings (55) and share common pathogenic pathways that differentiate them from other vasculitides. Cellular immune responses involving T cells, antigen-presenting cells, and mac- rophages are relevant elements in GCA and TakA pathogenesis (35). However, they differ in the age at clinical onset and vascular involvement (12, 56). GCA is a vasculitis quite common in European countries and North America involving vessels of medium and large caliber characterised by the granu- lomatous involvement of the aorta and its major branches with a predilection for the cranial of people over 50 years of age (12, 57-59). The most common serious complication of GCA is irreversible visual loss due to optic nerve ischaemia (57, 60). GCA is as- sociated with the upregulation of mul- tiple proinflammatory cytokines, such as IL-6, secreted by several cell types, predominantly T-cells, macrophages, and endothelial cells (20, 61). IL-6 plays a variety of pivotal biologi- cal functions depending on the target cell (61, 62). Thus, during physiologi- cal inflammatory responses, IL-6 - par ticipates in the synthesis of acute phase proteins, promotes the passage of acute to chronic , and facilitates development of adaptative immunity (61, 63). Moreover, IL-6 modulates activation, proliferation and differen- tiation of various T cell lines including Fig. 3. A) PET scan of a patient with GCA (case 14 from Table I) showing an increased FDG uptake in the ascending aorta, aortic arch, descending aorta, carotid, subclavian, axillary and brachial arteries CD8 T, Th17 and Treg cells. This pro- suggestive of active vasculitis. B) The same patient 4 months after the onset of treatment with tocili- inflammatory cytokine also stimulates zumab. Marked reduction of mural diffuse uptake of large vessels and their main branches was seen terminal differentiation of B cells and (Courtesy of Dr. Narváez. Department of Radiology, Hospital Universitari de Bellvitge). improves survival of plasma cells (61). Increased IL-6 serum levels have ben graphy showed mild aortic but intense thrombocytopenia and because of that observed in patients with active GCA periaortic inflammation. A retroperito- TCZ dose had to be reduced; 2) A and a correlation of IL-6 with disease neal biopsy showed severe fibrosis and 64-year-old woman with GCA suffered activity has also been observed (20). inflammatory cells that supported a during the second infu- Also, temporal artery biopsies in GCA diagnosis of periaortitis. Improvement sion of TCZ; 3) A 67-year-old woman show an increase in the local expres- following TCZ therapy was observed. with GCA suffered a pneumonia; 4) sion of IL-6 (40-42). A 65-year-old woman diagnosed with TCZ is a humanised anti-IL6 recep- Outcome GCA (case 10 of Table I) developed tor monoclonal antibody. This biologic After a mean±SD follow-up of severe neutropenia (351 neutrophils) agent has proved to be effective not only 11.8±6.6 months, only 4 patients had after 20 months of TCZ therapy and, in , but also in pa- experienced side effects: 1) A 46-year- because of that, the drug was discon- tients with systemic inflammatory dis- old woman with TakA developed a tinued. eases such as Still’s disease (40, 64-66).

S-83 REVIEW Aortitis and tocilizumab / J. Loricera et al. Ref. Salvarani (47) Seitz (48) Seitz (48) Seitz (48) Beyer (44) Beyer (44) Beyer (44) Christidis (45) Unizony (49) Unizony (49) Pazzola (43) Outcome Clinical improvement Clinical remission Clinical remission Clinical remission Clinical remission Clinical remission Clinical remission Clinical remission Clinical remission Clinical remission Clinical remission CRP before / after CRP TCZ 5.4/ 0.07 0.6/ <0.03 0.6/ <0.03 0.1/ <0.03 16.8 /normal (NV) 30.7/ Normal (NV) Elevated (NV)/ normal (NV) 7.8/0.1 5.1/0.07 3.3/0.06 8.9/0.02 ESR before / TCZ after 95/ 4 91/ 2 100/ 2 44/ 8 ND/ND ND/ND ND/ND ND/ND 64/7 90/4.8 120/8 hour; FDG: fluordeoxyglucose; CT: computed tomography; CT-A: computed tomography angiography; MRI-A: computed tomography; CT-A: hour; FDG: fluordeoxyglucose; CT: st Imaging technique after TCZ Imaging technique after decreased FDG uptake in PET/CT: the involved vessels MRI-A: resolved MRI-A: resolved MRI-A: resolved no metabolic activity PET/CT: ND partial response with reduction PET/CT: in uptake the abdominal aorta ND ND (decrease FDG uptake): PET/CT PET/CT: no metabolic activity PET/CT: carotid, subclavian arteries, thoracic and abdominal aorta Imaging technique before TCZ Imaging technique before (FDG uptake) in numerous PET/CT vessels MRI-A: aortitis MRI-A: aortitis MRI-A: aortitis (FDG uptake) in aorta, PET/CT subclavian and carotid arteries MRI-A: subclavian and femoral (FDG uptake) in aorta, PET/CT subclavian arteries axillary, MRI-A: carotid, subclavian, CT-A, aorta and iliac artery involvement MRI-A: aortic involvement CT-A, (FDG uptake): carotid, PET PET/CT: large-vessel vasculitis large-vessel PET/CT: artery involvement subclavian, thoracic and abdominal aorta.

Previous therapy GCs, IFX, ETN None None GCs, MTX AZA GCs, AZA, MM GCs, GCs, MTX GCs, MTX, AZA LFN, GCs, CYM, IFX GCs, MTX None Clinical features Systemic manifestations Malaise, PMR, peripheral occlusive arterial disease Malaise, PMR, Malaise, PMR, amaurosis fugax night sweats and weight loss Fever, loss, sweats, anorexia, uveitis, Weight subungueal haemorrhages Systemic symptoms, headache, diplopia, night sweats, anorexia PMR, headache, fatigue, transient visual loss, anorexia, loss of weight PMR, headache, jaw and upper extremity claudication Headache, jaw claudication headache, weight loss, Fever, weakness, pain of neck, shoulder and pelvic girdles, carotidynia aortitis and/or its main branches associated with Giant Cell Arteritis. Reported series and case reports on the use of tocilizumab in aortitis and/or its main branches associated with Giant Cell Table II. Table Age / Sex 64/M 63/M 73/M 79/F 79/M 72/F 71/F 63/F ND/ ND ND/ND 72/F TCZ: tocilizumab; PMR: polymyalgia rheumatica; GCs: AZA: glucocorticosteroids; azathioprine; CyA: A; cyclosporine CYP: cyclophosphamide; LFN: leflunomide ; MM: Mycophenolate mofetil; MTX: ADA: methotrexate; adalimumab; RTX: rituximab; CRP: C-reactive protein (mg/dL); ESR: erythrocyte sedimentation rate in 1 ETN: etanercept; IFX: infliximab; no numerical value. positron emission tomography; ND: not described; NV: magnetic resonance angiography; PET:

S-84 Aortitis and tocilizumab / J. Loricera et al. REVIEW Ref. Seitz (48) Seitz (48) Seitz (48) Salvarani (47) Salvarani (47) Salvarani (47) Salvarani (75) Unizony (49) Unizony (49) Nishimoto (46) Bredemeier (76) Clinical remission Clinical remission Clinical remission Clinical improvement Clinical remission Clinical remission Clinical remission Clinical remission Clinical improvement Clinical improvement Outcome after TCZ after CRP before / CRP 0.4/ <0.03 0.5/ <0.03 4.02/ 0.06 0.99/0.05 4.8/0.01 7.2/Normal (NV) 0.8/0.03 1.7/0.56 12.6/Normal (NV) 6.6/ <0.3 after TCZ after 80/ 5 40/ <3 45/3 67/2 84/2 69/Normal (NV) 15/3.6 34/8.7 ND/ND 70/2

ESR before /

Imaging technique after TCZ Imaging technique after MRA: improvement in aortitis MRA: improvement in aortitis decrease in FDG uptake PET/CT: decrease in FDG uptake PET/CT: decrease in FDG uptake PET/CT: in aorta decrease in FDG uptake PET/CT: ND ND reduction in aortitis CT: reduction in aortitis; progression CT-A: of in renal, subclavian and vertebral artery.

Imaging technique before TCZ Imaging technique before MRI-A: aortitis MRI-A: aortitis (FDG uptake): PET/CT multiple arteries (FDG uptake): multiple PET/CT arteries (FDG uptake): numerous PET/CT vessels (FDG uptake): PET/CT brachiocephalic, carotid arteries. Abdominal angiography: stenosis US: carotid and of celiac artery. subclavian involvement. Cross-sectional imaging (CT-A, carotid and MR-A): pulmonary, subclavian artery stenosis MRI-A: aortic arch CT-A, and external iliac artery stenosis aortitis, and stenosis of Chest CT: the left subclavian artery. MRI-A: subclavian and axillary arteries involvement

hour; FDG: fluordeoxyglucose; CT: computed tomography; CT-A: computed tomography angiography, MRI-A: magnetic resonance angiography; PET: positron emission tomography; tomography; emission positron PET: angiography; resonance magnetic MRI-A: angiography, tomography computed CT-A: tomography; computed CT: fluordeoxyglucose; FDG: hour; st Previous therapy GCs GCs, MTX, GCs, MTX None None GCs, MTX, ADA MM, IFX, GCs GCs GCs, CyA, CYP, AZA, MM, MTX GCs, MTX, AZA, MM, CYP, ADA IFX, AZA, IFX Reported series and case reports on the use of Tocilizumab in aortitis and/or its main branches associated with Takayasu arteritis. Takayasu in aortitis and/or its main branches associated with Tocilizumab Reported series and case reports on the use of Clinical features Leakage of a graft the thoracic aorta and ischaemic pain Malaise, arms and legs claudication headache, bilateral Myalgia, fever, carotid bruits weight loss, Arthro-myalgia, fever, carotidynia, subclavian bruit Malaise, myalgia, weight loss Myalgia, arthralgia, headache, fever, arm claudication, abdominal bruit, fatigue, carotidynia Upper estremity claudication, deficit, pulmonary Lower extremity claudication, pulse deficit, hypertension Left cervical pain, left chest syncope, weight loss Arthralgia, cervicalgia, fever, weakness, sweats, weight loss, hypertension, radial pulselessness Table III. Table Age/ Sex 40/M 27/ F 21/F 40/F 54/M 25/F ND/ND ND/ND 20/F 28/F TCZ: tocilizumab; GCs: glucocorticosteroids; AZA: azathioprine; CyA: cyclosporine A; CYP: cyclophosphamide; MM: mycophenolate mofetil; MTX: methotrexate; IFX: infliximab; ADA: adalimumab;1 ETN:in etanercept;rate sedimentation CRP:erythrocyte C-reactive ESR: (mg/dL); protein no numerical value. ND: not described; NV: US: ultrasonography.

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Interestingly, several studies indicate TakA is another large-vessel vascultis with MTX, azathioprine and inflixi- that TCZ may be a useful therapy in pa- that involves the aorta, its large branch- mab. Due to lack of response, TCZ was tients with non-infectious aortitis. Table es, and the proximal portions of renal, started in both cases. Following this II and Table III show avaliable informa- coronary and pulmonary arteries (67). procedure, complete clinical response tion on the use of TCZ in aortitis and/ Incidence of TakA is 1.2-2.6/million with normalisation of CRP and ESR or its large branches in GCA and TakA. per year in western population and was observed. However, one of them Of paticular interest is the case reported 100-times higher approximately in the relapsed after 8 months of treatment. by Salvarani et al. (47); a patient with countries of The Silk Road (56, 68, 69). Unizony et al. (49) also described 2 biopsy-proven GCA that had previously This entity is more common in women patients diagnosed of TakA and treated been diagnosed with spondyloarthritis, between 20–40 years (9, 68). Clinical- with TCZ with good response. In con- having been initially treated with inflix- ly it is characterised by fever, weight trast, Bredemeier et al. (76) described a imab and then with etanercept. Besides loss, joint pain, claudication of affected 28-year-old woman with TakA that suf- corticosteroids, MTX had been added limbs, decrease or loss of , carot- fered progression of vascular stenosis to etanercept for one year without im- idynia, headache, amaurosis, diplopia, despite treatment with TCZ. provement. The patient experienced renal failure, cerebrovascular events, RP is a rare systemic disease charac- frequent relapses, including systemic heart failure, acute myocardial infarc- terised by recurrent inflammation and manifestations, elevated acute phase tion and aneurysms (70-74). destruction of cartilaginous structures reactants and inflammation of large ves- As occurs in the GCA, IL-6 is also ex- as well as other structures rich in prote- sels confirmed by PET/CT when pred- pressed in TakA tissue. Furthermore, oglicans such as eyes, heart, blood ves- nisone dose was decreased below 12.5 serum levels of IL-6 are elevated in sels, middle ear and kidneys (77-79). mg/day. Thus, MTX and etanercept patients with TakA correlating very Little is known on the use of TCZ in were changed to TCZ. One month after well with disease activity. Therefore, patients with RP. With respect to this, TCZ onset the patient achieved clinical, pharmacological blockade of IL-6 is Narshi and Allard (80) described a laboratory and PET/CT improvement also a potential target to be considered 43-year-old woman with RP and aor- and the dose of prednisone was success- in this kind of vasculitis. Nishimoto et titis requiring emergency aortic valve fully tapered (47). Seitz et al. (48) pub- al. (46) published in 2008 the case of replacement. The patient had poor lished five patients with GCA treated a 20-year-old woman diagnosed with response to conventional therapy. Be- with TCZ (8 mg/kg). The patients expe- TakA five years before. She also had ul- cause of that, infliximab was started in rienced clinical improvement that cor- cerative colitis. The patient was treated combination with oral MTX and defla- related with improvement in imaging with corticosteroids, immunosuppres- zacort, but she suffered a relapse of the techniques. Because of that, corticoster- sive agents and leukapheresis. Despite disease associated with elevation of the oid dose was successfully reduced (48). this, the patient could not reduce the laboratory markers of inflammation. Beyer et al. (44) reported 3 patients dose of prednisolone below 30 mg/day Adalimumab was then started show- with GCA that received treatment with because the symptoms recurred. For ing improvement. However, since the TCZ because of active disease associ- this reason, TCZ was started achieving patient developed a recurrence of the ated with aortitis and/or femoral inflam- a disease remission, allowing to taper disease despite of increasing the cor- mation on PET. Rapid and maintained the dose of corticosteroids. Ulcerative ticosteroid dose and the frequency of improvement was found in all patients colitis also improved. adalimumab, she was switched to TCZ following TCZ therapy, and corticos- Salvarani et al. (47) published a study (8 mg/kg/ every 4 weeks). Following teroid dose was successfully tapered. on 3 patients with TakA who expe- TCZ the patient achieved a rapid im- Unizony et al. (49) described 7 patients rienced important improvement fol- provement with normalisation of CRP. with GCA refractory to corticosteroid lowing TCZ therapy. Also, this group Other authors such as Kawai et al. or therapy and immunosuppressive agents. (75) reported a 25-year-old woman more recently Wallace and Stone also For this reason, they started on TCZ with TakA that started treatment with published good results in RP patients 4-8 mg/kg every month. They got into prednisone. Then, the patient received treated with TCZ (81, 82). Wendling et remission and were able to taper corti- MTX, mycophenolate mofetil, inf- al. (83) reported a 46-year-old woman costeroid dose. Recently, Pazzola et al. liximab and adalimumab, but none with RP that had received treatment (43) described a woman diagnosed with of them managed to reach control the with prednisone, dapsone, several dis- GCA and PMR. She began with TCZ disease activity. Therefore, TCZ was ease-modifying anti-rheumatic drugs, as monotherapy at a dose of 8 mg/Kg started (8 mg/kg) every 4 weeks for 6 infliximab, etanercept and anakinra, monthly. Clinical improvement and re- months. Clinical activity, inflammatory achieving clinical remission with the duction of ESR and CRP was observed. markers and PET/CT findings became last one. However, when anakinra was Six months after the onset of TCZ the normal, while prednisone dosage was discontinued she suffered a relapse of patient was asymptomatic and the im- successfully tapered. Seitz et al. report- symptoms. At that time, she refused age techniques showed markedly de- ed 2 cases of TakA (48). One of them to start again with subcutaneous injec- creased of vascular FDG uptake in the had only been treated with corticoster- tions and because of that iv infusions affected vessels. oids while the other had been treated of TCZ (8 mg/kg/monthly) were given.

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The patient experienced clinical im- logic agent effective and relatively safe EL: Incidence and predictors of large-artery provement within the first week after in patients with inflammatory aortitis complication (, aortic dissec- tion, and/or large-artery stenosis) in patients the first infusion of TCZ. However, refractory to corticosteroids or to other with giant cell arteritis: a population-based subsequently, no improvement was ob- biologic immunosuppressive drugs. study over 50 years. Arthritis Rheum 2003; served and the patient had to return to However, additional studies including 48: 3522-31. 5. BEJERANO C, BLANCO R, GONZÁLEZ-VELA anakinra. randomised controlled trials are needed C, AGÜERO R, CARRIL JM, GONZÁLEZ-GAY Idiopathic isolated aortitis is charac- to evaluate the long-term efficacy and MA: Refractory polymyalgia rheumatica as terised by giant cells or lymphoplas- safety of TCZ in patients with aortitis. presenting manifestation of large-vessel vas- macytic inflammation of the aorta. culitis associated to sarcoidosis. Successful response to adalimumab. Clin Exp Rheuma- Isolated aortitis generally manifests as This study was presented in part at the tol 2012; 30 (Suppl. 70): S94-97. an ascending aortic aneurysm and it is 2013 ACR/ARHP Annual Meeting in 6. BEJERANO C, BLANCO R, GONZÁLEZ-VELA usually discovered incidentally within a San Diego, CA, USA. C et al.: Polymyalgia rheumatic as present- pathological study of a sample of aortic ing manifestation of vasculitis involving the lower extremities in a patient with ulcerative wall after surgery (8). Pazzola et al. (43) Acknowledgements colitis. Clin Exp Rheumatol 2012; 30 (Suppl. described 57-year-old man with idio- We wish to thank the members of the 70): S110-3. pathic aortitis and diabetes mellitus that participating hospitals. 7. JENNETTE JC, FALK RJ, BACON PA et al.: received TCZ as monotherapy at the 2012 Revised International Chapel Hill Con- sensous Conference Nomenclature of Vascu- dose of 8 mg/kg monthly for 6 months. Author list litides. Arthritis Rheum 2013; 65: 1-11. After 2 months of treatment the patient Javier Loricera, Ricardo Blanco, 8. VAL-BERNAL JF, CARNICERO S, GARIJO MF, experienced clinical improvement with Santos Castañeda, Alicia Humbría, ENJUTO J, HERREROS J: Isolated (idiopathic) active aortitis in ascending aortic aneurysms: normalisation of inflammation markers. Norberto Ortego-Centeno, An underrecognized vasculitis. Rev Esp Pa-

A PET/CT performed after 6 months of Javier Narváez, Cristina Mata, tol 2012; 45: 175-80. TCZ therapy did not disclose abnormal Sheila Melchor, Elena Aurrecoechea, 9. KERR GS, HALLAHAN CW, GIORDANO J et FDG uptake. Jaime Calvo-Alén, Pau Lluch, al.: Takayasu arteritis. Ann Intern Med 1994; 120: 919-29 Some authors have included within the Concepción Moll, Mauricio Mínguez, 10. MATSUMARA K, HIRANO T, TAKEDA K et al.: category of idiopathic aortitis to cases Gabriel Herrero-Beaumont, Incidence of aneurysms in Takayasu’s arteri- of chronic periaortitis, idiopathic retrop- Beatriz Bravo, Esteban Rubio, tis. Angiology 1991; 42: 308-15. eritoneal fibrosis (Ormond disease), in- Mercedes Freire, Enriqueta Peiró, 11. PROVEN A, GABRIEL SE, ORCES C, O’FALLON WM, HUNDER GG: Glucocorticoid therapy in flammatory abdominal aortic aneurysm, Carmen González-Vela, giant cell arteritis: duration and adverse out- perianeurysmal aortitis and idiopathic Javier Rueda-Gotor, Trinitario Pina, comes. Arthritis Rheum 2003; 49: 703-8. isolated abdominal periaortitis (2, Natalia Palmou-Fontana, 12. SALVARANI C, CANTINI F, BOIARDI L, HUN- DER GG: Polymialgia rheumatica and giant- 84- 90). We support this consideration Vanesa Calvo-Río, cell arteritis. N Engl J Med 2002; 347: 261- and, because of that, we defined patient Francisco Ortiz-Sanjuán, 71. number 16 from our series (Table I) as Miguel A. González-Gay 13. De SILVA M, HAZLEMAN BL: Azathioprine in aortitis associated with retroperitoneal giant cell arteritis/polymyalgia rheumatica: a double-blind study. Ann Rheum Dis 1986; fibrosis. Interestingly, a recent study Funding 45: 136-8. conducted by Vaglio et al. supports the This study was supported by a grant 14. HENES JC, MUELLER M, PFANNENBERG C, use of TCZ in patients with chronic from “Fondo de Investigaciones Sani- KANZ L, KOETTER I: Cyclophosphamide periaortitis who are refractory or have tarias” PI12/00193 (Spain). This work for large vessel vasculitis: assessment of response by PET/CT. Clin Exp Rheumatol contrainications for the use of corticos- was also partially supported by RET- 2011; 29 (Suppl. 64): S43-8. teroids (91). In this regard, according to ICS Programs, RD08/0075 (RIER) and 15. HOFFMAN GS, CID MC, HELLMANN DB et the the results derived form this study, RD12/0009/0013 from ‘‘Instituto de al.: A multicenter, randomized, doubleblind, TCZ should be considered in cases of Salud Carlos III’’ (ISCIII) (Spain). placebo-controlled trial of adjuvant MTX treatment for giant cell arteritis. Arthritis chronic periaortitis refractory to other Rheum 2002; 46: 1309-18. immunosuppressive drugs. TCZ added References 16. JOVER JA, HERNÁNDEZ-GARCÍA C, MORA- to ongoing therapy with prednisone and 1. EVANS JM, O´FALLON WM, HUNDER GG: DO IC, VARGAS E, BAÑARES A, FERNÁN- MTX allowed prednisone withdrawal Increased incidence of aortic aneurysm and DEZ-GUTIÉRREZ B: Combined treatment of in giant cell (temporal) arteritis: giant cell arteritis with MTX and prednisone: and induced resolution of symptoms, a population-based study. Ann Intern Med a randomized, double-blind, placebo-con- acute-phase reactant normalisation, and 1995; 122: 502-7. trolled trial. Ann Intern Med 2001; 134: 106- reduction in FDG PET uptake in one 2. GORNIK HL, CREAGER MA: Aortitis. Circu- 14. lation 2008; 117: 3039-51. 17. MAHR AD, JOVER JA, SPIERA RF et al.: case (91). In another case of chronic 3. GONZALEZ-GAY MA, GARCIA-PORRUA C, Adjunctive MTX for treatment of giant cell periaortitis, TCZ in monotherapy in- PIÑEIRO A et al.: Aortic aneurysm and dis- arteritis: an individual patient data meta- duced sustained clinical and laboratory section in patients with biopsy-proven giant analysis. Arthritis Rheum 2007; 56: 2789-97 remission, FDG uptake disappearance, cell arteritis from northwestern Spain: a pop- 18. SPIERA RF, MITNICK HJ, KUPERSMITH M et ulation-based study. Medicine (Baltimore) al.: A prospective, double-blind, randomized, and chronic periaortitis shrinkage. 2004; 83: 335-41. placebo controlled trial of MTX in the treat- In conclusion, taking all these evidenc- 4. NUENNINGHOFF DM, HUNDER GG, CHRIS- ment of giant cell arteritis (GCA). Clin Exp es together, TCZ appears to be a bio- TIANSON TJ, McCLELLAND RL, MATTESON Rheumatol 2001; 19: 495-501.

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