CASE BASED REVIEWSustained response to tocilizumab in a patient with relapsing polychondritis with aortic involvement:a case based reviewRebecca Stael &Vanessa Smith &Ruth Wittoek &David Creytens &Herman MielantsReceived:30April 2014/Accepted:5May 2014/Published online:16May 2014#Clinical Rheumatology 2014Abstract This paper presents a case with refractory relapsing polychondritis (RPC),complicated with severe aortic involve-ment,which is successfully treated with tocilizumab.Previous treatments consisted of methotrexate,corticosteroids,cyclo-sporine,cyclophosphamide,infliximab,and etanercept.With these treatments,the patient had recurrent episodes of fever,polyarthritis,tenosynovitis,subcutaneous nodules,and pro-gressive cardiac disease.One year after the start of treatment with tocilizumab,there is resolution of all symptoms,normal-ization of C-reactive protein (CRP)and erythrocyte sedimen-tation rate (ESR),and the dose of prednisolone is tapered down to 2mg/day.We have reviewed the English literature for reports of patients with refractory RPC,successfully treat-ed with tocilizumab.We found five additional case reports.In one case report,a patient with refractory RPC complicated with aortitis was successfully treated with tocilizumab.In three case reports,patients with refractory RPC complicated with laryngotracheal involvement were successfully treated with tocilizumab.All cases had,like our patient,failed con-ventional treatment.We also reviewed the literature for reports of the effect of biologicals on cardiac involvement in RPC.Current literature is presented and discussed.Keywords Aortic wall biopsy .Aortitis .Auriculair chondritis .Relapsing polychondritis .TocilizumabIntroductionRelapsing polychondritis (RPC)is a rare immune-mediated disease which is associated with inflammation in the cartilag-inous tissue throughout the body.Especially the cartilaginous structures of the ear,nose,joints,and respiratory tract are affected.The incidence is estimated to be three per million population with an onset around 40–60years [1–3].Established diagnostic criteria are the original McAdam ’s criteria that require the presence of three or more of the following clinical features:bilateral auricular chondritis,nonerosive,seronegatieve inflammatory polyarthritis,nasal chondritis,ocular inflammation,respiratory tract chondritis,and chochlear and/or vestibular dysfunction [1–5].In addition to corticosteroids,several immunomodulatory and anti-inflammatory drug regimes have been used to treat the dis-ease.Some reports are made on the successful treatment of RPC with biological agents including anti-tumor necrosis factor alpha and anti-interleukine 1receptor antagonists [1,2,5].In this case,we report a man with refractory RPC compli-cated with aortitis,successfully treated with tocilizumab,anti-interleukine 6receptor antagonist,along with a literature review of similar published cases.CaseA 25-year old male was referred to our rheumatology clinic in 2003because of a new onset of inflammatory joint complaints of the knees and the ankles.He was diagnosed with peripheral spondyloarthritis based on HLA-B27positivity,an asymmet-rical oligoarthritis,and a tendinitis of the achilles tendon.Treatment was initiated with sulfasalazine 3g daily and non-steroidal anti-inflammatory drug piroxicam 20mg daily.Due to poor response to this conventional treatment,etanerceptR.Stael (*):V .Smith :R.Wittoek :H.MielantsDepartment of Rheumatology,University Hospital of Ghent,De Pintelaan 185,9000Ghent,Belgium e-mail:rebecca_stael@D.CreytensDepartment of Pathology,University Hospital of Ghent,De Pintelaan 185,9000Ghent,BelgiumClin Rheumatol (2015)34:189–193DOI 10.1007/s10067-014-2670-750mg,once a week subcutaneously,was initiated in May 2003.Despite this therapy,biochemical inflammation persisted and he had recurrent flares.Three years later,he developed auricular inflammation and nodules at the elbows and the fingers (Fig.1).Histologic examination of a biopsied lesion of the thumb showed a palisaded neutrophilic granulomatous dermatitis.This is a rare skin disease possibly related to underlying autoimmune pathology.In the same year,he developed a scleritis of the left eye.Etiology was considered of autoimmune origin and it was treated with methylprednisolone 16mg daily and methotrex-ate 10mg weekly.In 2007,he was admitted because of a pneumonia with severe sepsis.During the admission,he de-veloped a cardiogenic shock caused by acute severe aortic regurgitation.Emergency aortic valve replacement was per-formed and the patient recovered.Tissue samples were taken during surgery and showed signs of chronic focal active endocarditis.A few histopathologic changes being present could be related to RPC including increase of vasa vasorum,endothelial swelling,and cuffing of lymphocytes (Fig.2a,b ).Based on these new findings,the diagnosis of peripheral spondyloarthritis was rejected and RPC was retained based on the presence of bilateral auricular chondritis,ocular inflam-mation (scleritis),peripheral joint disease (oligoarthritis and tendinitis of the Achilles tendon),aortic valve disease,and skin involvement (subcutaneous nodules).Besides this,the presence of HLA-B27positivity was considered not signifi-cant.The ocular inflammation was not due to an uveitis,a known nonspinal feature associated with spondyloarthritis,but due to a scleritis.At the time of diagnosis of RPC,therapy with corticoste-roids (prednisolone 10mg/day)and cyclosporine (2×100mg /day)was initiated.Whenever the patient developed an arthritis,this was managed with local corticosteroid in-jection or treatment with a nonsteroidal anti-inflammatory drug.In May 2008,he developed a partial dehiscence of his mechanical aortic valve due to presence of fragile aortic tissue.This caused a paravalvular leakage which was treated surgically.Unfortunately,in 2010,the paravalvular leakage relapsed and could only be treated conservatively (pharmacologically)since the operative risk had become too high.The secondary aortic regurgitation caused adilata-Fig.1Subcutaneous nodules at thefingersFig.2Biopsy from the aortic wall taken during surgery in 2007showed a chronic focal active endocarditis and b mild increase of vasa vasorum,endothelial swelling,and cuffing oflymphocytes.Biopsy from the aortic wall taken during operation in 2012showed c more active mesaortitis and d more prominent increase of vasa vasorum,endothelial swelling,and cuffing of lymphocytestion of the left ventricle and cardiac arrhythmias.Eventually, a pacemaker needed to be implanted because of a complete atrioventricular block.In2011,despite therapy,the patient developed polyarthritis and had recurrent episodes of fever.A treatment with cyclo-phosphamide500mg intravenously,every3weeks,was commenced in combination with prednisolone20mg/day. He received three pulses of cyclophosphamide,but in spite of this therapy,he experienced recurrent polyarthritis.In May2011,an anti-TNF-alpha antibody,infliximab (5mg/kg)eight times weekly,was commenced in combination with prednisolone20mg/day.Under this therapy,symptoms improved;the patient developed less fever and arthritis.There was a good biochemical response(decrease of C-reactive protein(CRP)and erythrocyte sedimentation rate(ESR))and the dose of prednisolone was tapered to10mg/day.After initial resolution of the symptoms for a few months,they reappeared and CRP and ESR values increased again to pretreatment levels.By the end of2011,the dose frequency of infliximab was increased to four times weekly and methotrexate15mg was initiated.The dose of prednisolone was again increased to 20mg/day.In February2012,the patient developed an episode of scleritis.Despite of the therapy changes,he failed to show clinical remission.Therefore,in June2012,treatment was switched to toci-lizumab(intravenously,8mg/kg)administered monthly in combination with corticosteroids(prednisolone10mg/day)and methotrexate15mg weekly.Again,there was a good clinical and biochemical response and the dose of predniso-lone could be lowered.In August2012,the patient was admitted to the hospital because of sustained ventricular tachycardia.He suffered from severe aortic regurgitation with dilatation of the left ventricle.Again,surgical treatment was needed and a total aortic root replacement with a composite valve graft and implantation of the coronary arteries was performed (Bentall procedure).The pacemaker was replaced by a defibrillator.The biopsy from the aortic wall taken during surgery showed more active mesaortitis.The aortic wall was infiltrated with collections of neutrophilic granulocytes and fibrinoid necrosis of the aortic wall was seen.Also,an infiltrate of lymphocytes and macrophages was present.A more prominent increase of vasa vasorum was seen togeth-er with endothelial swelling and perivascular cuffing of lymphocytes(Fig.2c,d).In November2012,the patient had a recurrent episode of ventricular tachycardia which was treated with amiodarone. Subsequently,the cardiac situation stabilized.One year after initiating treatment with tocilizumab,symp-toms have markedly improved.Treatment using this anti-IL-6 receptor antagonist resulted in normalization of CRP and ESR and resolution of all symptoms(no fever,no arthritis,disap-pearance of the subcutaneous noduli at the fingers).The dose of methotrexate could be tapered down to7.5mg a dayandFig.3Evolution of the inflammation parameters(CRP and ESR)and the changes of doses of prednisolone and methothrexate in function of the administration of infliximab(5mg/kg eight times weekly),infliximab (5mg/kg four times weekly),and tocilizumab(8mg/kg monthly).The administration of tocilizumab was started at day0the dose of prednisolone was tapered down to 2mg a day (Fig.3).DiscussionA standardized therapeutic protocol for RPC has not yet been established.Current medical therapy is largely empiric and based on case reports [1–5].Pharmacological options should be made according to the clinical presentation and consist of steroids,nonsteroidal anti-inflammatory drugs,colchicine,and immunomodulatory agents such as methotrexate,cyclo-phosphamide,azathioprine,dapsone,cyclosporine,mycophe-nolate mofetil,and intravenous immunoglobulin [1,6].A number of case reports have suggested that blockade of the pro-inflammatory cytokines such as TNF-alpha and IL-1can be used to successfully treat RPC.Moreover,serum cytokine profiles of patients with active RPC have shown elevated levels of IL-8,monocyte chemotactic protein-1,and macrophage inflammatory protein-1-beta,but no statistically significant elevation of serum TNF-alpha,IL-1,or IL-6levels [7].However,several case reports indicate efficacy of bio-logics in RPC for a variety of disease-related manifestations.Especially,anti-TNF-alpha agents (infliximab first and fore-most,but also etanercept and adalimumab)have been used in RPC.Some case reports also mention effectiveness of anakinra and abatacept in the treatment of RPC.The main limitation of this therapeutic strategy is the lack of supporting evidence from any randomized controlled trial.Five case reports of patients with refractory RPC treated with tocilizumab have been published earlier (Table 1).In one case report,two patients with RPC complicated with laryngotracheal involvement were successfully treated with tocilizumab.One of these patients was first treated with infliximab with partial response.Nine months after initiating tocilizumab,the clinical symptoms improved,there was a normalization of the CRP-level,and the dose of corticosteroids could be tapered.The other patient was directly treated with tocilizumab.Five months later,he showed a good clinical and biochemical response [9].In the other case report,a patient with RPC complicated by aortitis was successfully treated with tocilizumab.Previously,the patient had been treated with infliximab and adalimumab,which initially resulted in a com-plete resolution of symptoms,but was stopped afterwards because of recurrence of symptoms.In contrast to infliximab,adalimumab resulted in a sustained remission for 6years.Treatment with tocilizumab resulted in immediate normaliza-tion of the CRP and complete resolution of all symptoms.A sustained response to tocilizumab was reported for at least 18months [10].In the third case report,a patient with RPC complicated with Sweet ’s syndrome was successfully treated with tocilizumab.Before that,the patient had been treated with adalimumab and etanercept,which initially resulted in aT a b l e 1S u m m a r y o f r e p o r t e d c a s e s o f r e f r a c t o r y R P C s u c c e s s f u l l y t r e a t e d w i t h t o c i l i z u m a b (8m g /k g m o n t h l y )[8–12]R e f e r e n c eA g e (s e x )D i s e a s e d u r a t i o n O r g a n i n v o l v e m e n t F o r m e r b i o l o g i c a l t r e a t m e n t O u t c o m e c r i t e r i a O n s e t o f e f f i c a c y D u r a t i o n o f f o l l o w -u p A d v e r s e e v e n t s K a w a i e t a l [9]29y e a r s (F )N A L a r y n g o t r a c h e a l i n v o l v e m e n t I n f l i x i m a b C l i n i c ,C R P ,C T s c a n ,s t e r o i d r e g i m e n N A 12m o n t h s N o K a w a i e t a l [9]52y e a r s (M )N A A o r t i t i s N o f o r m e r b i o l o g i c a l t r e a t m e n t C l i n i c ,C R P ,s t e r o i d r e g i m e n N A N A N o N a r s h i e t a l [10]43y e a r s (F )20y e a r s L a r y n g o t r a c h e a l i n v o l v e m e n t I n f l i x i m a b ,a d a l i m u m a b C l i n i c ,C R P ,s t e r o i d r e g i m e n R a p i d 18m o n t h s N o C h a n a e t a l [11]68(M )N A N o o r g a n i n v o l v e m e n t A d a l i m u m a b ,e t a n e r c e p t C l i n i c ,C R P ,s t e r o i d r e g i m e n R a p i d N A N o W a l l a c e e t a l [12]65(F )9m o n t h s L a r y n g o t r a c h e a l i n v o l v e m e n t I n f l i x i m a b C l i n i c ,C R P ,s t e r o i d r e g i m e n R a p i d N A N o W e b e r e t a l [12]40(M )3y e a r s L a r y n g o t r a c h e a l i n v o l v e m e n t I n f l i x i m a b C l i n i c ,C R P ,s t e r o i d r e g i m e n ,m e t h o t r e x a t e r e g i m e n 2n d m o n t h N A N oN A n o t a v a i l a b l eresponse,but failed to suppress the disease activity.After administration of adalimumab,the patient developed an ery-thematous pustular rash,consistent on biopsy with Sweet’s syndrome[11].In the fourth and the fifth case report,patients with refractory RPC complicated with laryngotracheal in-volvement were successfully treated with tocilizumab[12, 13].Our case supports the potential use of IL-6receptor blockade in at least a subset of patients with refractory RPC.Cardiovascular complications affect approximately one quarter of patients with RPC.Cardiac involvement is more prominent in the male population and requires more invasive procedures and complex surgery[14].After cardiac surgery, second-line immunosuppressive therapy should be initiated promptly in order to taper the corticosteroids.This approach may prevent or reduce the severity of some of the serious sequelae of RPC[14].The effect of biologicals on cardiac involvement is not very clear.We found three case reports where a beneficial effect on the aortic tissue was described.In one case report,a reduction of aortic aneurysm size was seen in a patient with RPC treated with infliximab[15].In another case report,a reduction of aortic aneurysm size was observed in a patient with MAGIC (mouth hand genital ulcers with inflamed cartilage)syndrome, treated with infliximab[16].In another case of RPC,a treat-ment with adalimumab seemed to be effective for aortitis[17]. In our case report,the cardiac situation had stabilized after initiating tocilizumab.We hypothesize a possible beneficial effect of tocilizumab on the cardiac involvement in RPC. More detailed studies with respect to cardiac tissue complica-tions are needed[14].In conclusion,we report a sustained response to toci-lizumab in a patient with refractory RPC with aortic involve-ment.Tocilizumab can be considered a therapeutic option in RPC patients who have failed anti-TNF therapy.However,to date,no clinical trial data on how to use biologics in RPC are available.More research is needed to assess the efficacy and adverse reactions of these agents in RPC since their use is currently restricted to patients not responding to conventional medical therapy[1,8].Disclosures None.Referenceshmer T,Treiber M,V on Werder A,Foerger F,Knopf A,HeemannU,Thuermel K(2010)Relapsing polychondritis:an autoimmunedisease with many faces.Autoimmun Rev9:540–546.doi:10.1016/ j.autrev.2010.02.0162.Rapini RP,Warner NB(2006)Relapsing polychondritis.J ClinDermatol24:482–4853.Zeuner M,Straub RH,Rauh G,Albert ED,Schölmerich J,Lang B(1997)Relapsing polychondritis:clinical and immunogenetic analy-sis of62patients.J Rheumatol24:96–1014.McAdam LP,O’Hanlan MA,Bluestone R,Pearson CM(1976)Relapsing polychondritis:prospective study of23patients and a review of the literature.Med(Baltimore)55(3):193–2155.Kent PD,Michet CJ Jr,Luthra HS(2004)Relapsing polychondritis.Curr Opin Rheumatol16(1):56–616.Kemta Lekpa F,Kraus VB,Chevalier X(2012)Biologics in relaps-ing polychondritis:a literature review.Semin Arthritis Rheum41: 712–719.doi:10.1016/j.semarthrit.2011.08.0067.Stabler T,Piette JC,Chevalier X,Marini-Portugal A,Kraus VB(2004)Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation.Arthritis Rheum50:3663–3667 8.Sharma A,Gnanapandithan K,Sharma K,Sharma S(2013)Relapsing polychondritis:a review.Clin Rheumatol32:1575–1583.doi:10.1007/s10067-013-2328-x9.Kawai M,Hagihara K,Hirano T,Shima Y,Kuwahara Y,Arimitsu J,Narazaki M,Ogata A,Kawase I,Kishimoto T,Tanaka T(2009) Sustained response to tocilizumab,anti-interleukin-6receptor anti-body,in two patients with refractory relapsing polychondritis.Rheumatology(Oxford)48:318–331.doi:10.1093/rheumatology/ ken46810.Narshi CB,Allard SA(2012)Sustained response to tocilizumab,anti-IL-6antibody,following anti-TNF-alpha failure in a patient with relapsing polychondritis complicated by aortitis.Rheumatology51: 952–953.doi:10.1093/rheumatology/ker45111.Chana JK,Ahmed AA,Edmonds S(2012)Successful use oftocilizumab in a Caucasian patient with relapsing polychondritis complicated by Sweet’s syndrome.Rheumatology51(suppl3): iii153–iii15412.Wallace ZS,Stone JH(2013)Refractory relapsing polychondritistreated with serial success with interleukin6receptor blockade.J Rheumatol40(1):100–101.doi:10.3899/jrheum.12038113.Weber E,Gaultier JB,Paul S,Guichard I,Monard E,Cathébras P(2013)Sustained response with tocilizumab in a case of refractory relapsing polychondritis.Rev Med Interne.doi:10.1016/j.revmed.2013.02.01914.Dib C,Moustafa SE,Mookadam M,Zehr KJ,Michet CJ Jr,Mookadam F(2006)Surgical treatment of the cardiac manifestations of relapsing polychondritis:overview of33patients identified through literature review and the mayo clinic records.Mayo Clin Proc81(6):772–77615.Marie I,Lahaxe L,Josse S,Levesque H(2009)Sustained response toinfliximab in a patient with relapsing polychondritis with aortic involvement.Rheumatology(Oxford)48:1328–1329.doi:10.1093/ rheumatology/kep22416.Mekinian A,Lambert M,Beregi JP,Morell-Dubois S,Launay D,Queyrel V,Midulla M,Hachulla E,Hatron PY(2009)Aortic aneu-rysm in MAGIC syndrome successfully managed with combined anti-TNF-alpha and stent grafting.Rheumatology(Oxford)48: 1169–1170.doi:10.1093/rheumatology/kep17217.Seymour MW,Home DM,Williams RO,Allard SA(2007)Prolonged response to anti-tumour necrosis factor treatment with adalimumab(Humira)in relapsing polychondritis complicated by aortitis.Rheumatology(Oxford)46:1738–1739。
