Adler, Sabine

Cottier, Silvia

Jonczy, Maciej

Koelzer, Viktor H.

Roux-Lombard, Pascale

Villiger, Peter M.

RERO DOC Digital Library

References1 Seror R, Sordet C, Guillevin L et al. Tolerance and efficacyof rituximab and changes in serum B cell biomarkers inpatients with systemic complications of primary Sjo¨gren’ssyndrome. Ann Rheum Dis 2007;66:3517.2 Meijer JM, Pijpe J, Vissink A et al. Treatment of primarySjogren syndrome with rituximab: extended follow-up,safety and efficacy of retreatment. Ann Rheum Dis 2009;68:2845.3 Meiners PM, Arends S, Brouwer E et al. Responsivenessof disease activity indices ESSPRI and ESSDAI in patientswith primary Sjo¨gren’s syndrome treated with rituximab.Ann Rheum Dis 2012;71:1297302.4 Meijer JM, Meiners PM, Vissink A et al. Effectiveness ofrituximab treatment in primary Sjo¨gren’s syndrome: arandomized, double-blind, placebo-controlled trial.Arthritis Rheum 2010;62:9608.5 Pijpe J, van Imhoff GW, Vissink A et al. Changes in salivarygland immunohistology and function after rituximabmonotherapy in a patient with Sjogren’s syndrome andassociated MALT lymphoma. Ann Rheum Dis 2005;64:95860.6 Dass S, Bowman SJ, Vital EM et al. Reduction of fatigue inSjo¨gren syndrome with rituximab: results of a randomised,double-blind, placebo-controlled pilot study. Ann RheumDis 2008;67:15414.7 Devauchelle-Pensec V, Pennec Y, Morvan J et al.Improvement of Sjo¨gren’s syndrome after two infusions ofrituximab (anti-CD20). Arthritis Rheum 2007;57:3107.8 Pijpe J, van Imhoff GW, Spijkervet FKL et al. Rituximabtreatment in patients with primary Sjo¨gren’s syndrome: anopen-label phase II study. Arthritis Rheum 2005;52:274050.Rheumatology 2014;53:13501352doi:10.1093/rheumatology/ket452Advance Access publication 5 February 2014A simple Baker’s cyst? Tocilizumab remitsparaneoplastic signs and controls growthof IL-6-producing angiomatoid malignantfibrous histiocytomaSIR, A 47-year-old male presented with severe systemicinflammatory response syndrome. A year previously hehad noticed a painless swelling in the right fossa popliteainterpreted as Baker’s cyst. Laboratory analysis docu-mented CRP (97 mg/l), ESR (102 mm/h), haemoglobin(98 g/l), slightly elevated liver enzymes and hyperferritinae-mia (1236mg/l), but no autoantibodies. Diagnostic workupcomprised bone marrow aspiration, liver biopsy, MRIangiography of the thorax and abdomen, temporal arterybiopsy, upper and lower gastrointestinal (GI) endoscopyand biopsies to search for Whipple’s disease, tuberculosisand malignancy. Differential diagnoses such as adultStill’s disease or occult vasculitis were discussed. Shortcourses of glucocorticoids with 1 mg/kg body weighttapered to 20 mg/day and MTX at 20 mg i.m. weeklywere ineffective. Treatment with infliximab at doses of3.3 mg/kg body weight (in total 200 mg/kg) at weeks 0, 2and 6 did not elicit any clinical benefit. CRP remainedunchanged (150 mg/l).Three years later he was referred to our outpatientclinic. His condition had worsened: haemoglobin 74 g/l,CRP 156 mg/l, ESR 125 mm/h and polyclonal gammopa-thy had developed (24.9 g; norm <14.6 g/l). Briefly, thepatient showed the classical symptoms and signs of un-controlled IL-6 production [1]. The cellular source of thiscytokine remained enigmatic. The only inflammatorytissue to be identified by imaging methods was theBaker’s cyst, which was judged by experienced radiolo-gists to be an uncomplicated cyst (Fig. 1A).The patient agreed to off-label therapy using the IL-6-neutralizing monoclonal antibody tocilizumab. He experi-enced rapid and full remission. Laboratory parametersand his physical condition normalized within a fewweeks. Infusions, the first two given at fortnightly intervals,were continued at 4-week intervals at a dosage of 8 mg/kgbody weight.One year later, in a further attempt to identify the sourceof IL-6, the MRI of the knee was repeated (Fig. 1B).Surprisingly, the morphology of the Baker’s cyst had chan-ged considerably. A substantial part of the heterogeneoustumour was replaced by a large cyst containing homoge-neous liquid. We recommended surgical removal, stoppedtocilizumab and started to prospectively collect sera forcytokine measurements. Histological analysis docu-mented the unexpected diagnosis of angiomatoid malig-nant fibrous histiocytoma (aMFH) with production of IL-6by histiocytoma cells (Fig. 1CF) [2, 3]. Excision of the neo-plasm resulted in complete and lasting remission. Cytokinemeasurements continuously showed normal concentra-tions of IL-1, TNF-a and soluble tumour necrosis factorreceptor (sTNFR). IL-6 was strongly elevated in synovialfluid and normalized in sera within 8 weeks after surgery.Many studies have reported elevated systemic levels ofproinflammatory cytokines and their antagonists in activeautoimmune and inflammatory diseases. Yet clinically it isusually impossible to differentiate between the clinicaleffects induced by each of the three cytokines. In thiscase, however, IL-1b, TNF-a and sTNFR-75 remainednormal throughout the observation period, while IL-6was highly elevated until surgery. In addition, blockadeof TNF-a using infliximab was completely ineffective withrespect to clinical signs as well as control of the acutephase response (e.g. CRP levels), whereas blockade ofIL-6 resulted in rapid and lasting complete remission ofall pathology findings. In summary the clinical picture andlaboratory alterations represent the pleiotropic biologicaleffects of IL-6.In contrast to its well-characterized effects in inflamma-tion and immunity, the relevance of IL-6 as a mediator ofparaneoplastic signs is still unclear. This case is the first todocument a remission-inducing effect of IL-6 blockadeusing tocilizumab in aMFH, thus identifying IL-6 as thekey pathogenic factor in the generation of paraneoplasias.In addition to rapid and sustained clinical benefit, aLetters to the Editor1350 www.rheumatology.oxfordjournals.orgstriking finding was the change in morphology of the neo-plasm in response to 1 year of IL-6 blockade. The MRIsuggested a decrease in aMFH volume replaced by alarge cyst. This tumour evolution could best be explainedby an autocrine growth effect of IL-6, as described forexample for multiple myeloma and prostate cancer [4].The effect of IL-6 on differentiation of terminal B cellsinto antibody-producing plasma cells was recognizedmany years ago [1]. In multiple myelomas, substantialquantities of IL-6 have been shown to be produced in aparacrine fashion by surrounding stromal cells [5]. In ourcase, immunohistochemistry showed impressive amountsof IL-6 in aMFH cells, clinically reflected by polyclonalgammopathy. However, IL-6 was virtually absent inplasma cells. This pattern suggests that IL-6 producedand secreted by the aMFH acted as a growth factor forplasma cells as well as tumour cells. Documenting a highdensity of polyclonal plasma cells in close proximity totumour cells supports this hypothesis, suggesting an ex-planation for the formation of one tumour by two cellpopulations of different origin.Collectively, the patient’s history and described findingsshow that the signs and symptoms of our case reflect theeffects of chronic IL-6 exposure. It identifies IL-6 as thepathogenic factor for paraneoplastic signs and symptomsin aMFH. Finally, it illustrates that complete response toFIG. 1 MRI and histology of Baker’s cystLetters to the Editorwww.rheumatology.oxfordjournals.org 1351IL-6 blockade in a case resistant to TNF neutralizationshould prompt a second diagnostic workup.Rheumatology key message. Neutralization of IL-6 by tocilizumab inducescomplete clinical remission and controls thegrowth of popliteal angiomatoid malignant fibroushistiocytoma.Disclosure statement: The authors have declared noconflicts of interest.Peter M. Villiger1, Silvia Cottier1, Maciej Jonczy2,Viktor H. Koelzer3, Pascale Roux-Lombard4 andSabine Adler11Department of Rheumatology, Clinical Immunology andAllergology, 2Institute of Radiology, University Hospital andUniversity of Bern, 3Institute of Pathology, University of Bern,Bern and 4Laboratory for Immunology and ClinicalAllergology, University Hospital Geneva, Geneva, Switzerland.Accepted 22 November 2013Correspondence to: Peter M. Villiger, Department ofRheumatology, Clinical Immunology and Allergology,University Hospital and University of Bern, Freiburgstrasse,3010 Bern, Switzerland. E-mail: peter.villiger@insel.chReferences1 Oshugi Y. Recent advances in immunopathophysiology ofinterleukin-6: an innovative therapeutic drug, tocilizumab(recombinant humanized anti-human interleukin-6 recep-tor antibody), unveils the mysterious etiology of immune-mediated inflammatory diseases. Biol Pharm Bull 2007;30:20016.2 Tanas MR, Rubin BP, Montgomery EA et al. Utility of FISHin the diagnosis of angiomatoid fibrous histiocytoma: aseries of 18 cases. Mod Pathol 2010;23:937.3 Hamada T, Komiya S, Hiraoka K et al. IL-6 in a pleo-morphic type of malignant fibrous histiocytoma presentinghigh fever. Hum Pathol 1998;29:75861.4 Kawano M, Kuramoto A, Hirano T et al. Cytokines asautocrine growth factors in malignancies. Cancer Surv1989;8:90516.5 Klein B, Bataille R. Cytokine network in human multiplemyeloma. Hematol Oncol Clin North Am 1992;6:27384.Rheumatology 2014;53:13521353doi:10.1093/rheumatology/keu019Advance Access publication 7 March 2014Fulminant myocarditis and macrophage activationsyndrome secondary to adult-onset Still’s diseasesuccessfully treated with tocilizumabSIR, Adult-onset Still’s disease (AOSD) is a rare multisysteminflammatory condition, the aetiology of which remains un-known. Studies have shown that IL-1b, IL-6, IL-18, IFN-gand TNF play pathogenic roles [1]. Commonly used biologicagents in AOSD treatment include IL-1 receptor antagon-ists and TNF-a blockers [2]. Treatment with tocilizumab asboth an initial agent and in multirefractory AOSD has beenreported [3]. Its use in macrophage activation syndrome(MAS) has not.Refractory or untreated AOSD may progress to MAS.MAS results in excessive activation and expansion ofT lymphocytes and macrophagic histiocytes that exhibithaemophagocytic activity. This leads to a massivesystemic inflammatory response associated with threecardinal features: cytopenia, liver dysfunction and coagu-lopathy. MAS is a life-threatening condition with reportedmortality rates of 2050% [4].We report the case of a 32-year-old man who pre-sented with recurrent pyrexia and arthralgia.Investigations for infective causes including EBV, CMVand atypical pneumonia were negative. Autoimmuneand HIV testing were also negative. Cardiac echoshowed a left ventricular ejection fraction (LVEF) of>60%. Over a 4-week period he received numerouscourses of i.v. antibiotics, including gentamicin, tazocin,meropenum, metronidazole and teicoplanin. However,he continued to spike temperatures to 41.3C. CRP >400 mg/l (normal <5) and a white cell count of 24 109/l(normal 4.010.0) were persistently elevated.Rheumatology evaluation elicited a rash and synovitis,in keeping with AOSD (as classified using Yamaguchicriteria) [5]. Serum ferritin was 11 683 mg/l (normal1325).An initial response was seen with prednisolone40 mg/day. Over the following 48 h deterioration occurred,with hypertriglyceridaemia, anaemia, thrombocytopenia,tachycardia, hypotension, hypofibrinoginaemia andhyperferritinaemia (peaking at 30 739mg/l). He requiredtransfer to the intensive care unit, where inotropic supportwas commenced along with i.v. methylprednisolone andanakinra.An echocardiograph revealed a severely impaired LVEFof 30%. High-sensitivity cardiac troponin peaked at154 ng/l (normal <14), with clinical findings suggestive ofmyocarditis.A bone marrow biopsy indicated a hypercellular filmwith myeloid hyperplasia and evidence of a left shift,with reduced erythropoiesis. Plentiful macrophages ex-hibiting haemophagocytosis were seen, in keeping withMAS. No improvement was noted following 3 days ofanakinra. Our patient continued to decline, with increasinginotropic support, worsening lactic acidosis and persist-ent tachycardia.Immunoglobulins, 70 g over 3 days, and ciclosporin3 mg/kg were commenced. Treatment failure necessitatedtocilizumab 8 mg/kg. At this point intubation, vasopressorsupport and dialysis were required. Repeat echocardiog-raphy prior to tocilizumab infusion showed an estimatedejection fraction of 20%, with severe global impairment,a moderately dilated right ventricle, severely impairedsystolic function and a mildly dilated right atrium.Cardiac arrest occurred within 48 h of the initial infusionof tocilizumab, in the setting of worsening cardiogenicLetters to the Editor1352 www.rheumatology.oxfordjournals.org

A simple Baker's cyst? Tocilizumab remits paraneoplastic signs and controls growth of IL-6-producing angiomatoid malignant fibrous histiocytoma

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