Primary biliary cirrhosis (PBC) and multiple sclerosis (MS) are considered autoimmune diseases with a multifactorial aetiology which is thought to be due to a combination of genetic predisposition and environmental triggers. An association of both diseases has been previously described in sporadic case reports. Fingolimod, an antagonist of the sphingosine 1 phosphate receptor family (S1P1/3/4/5), is a promising and effective drug in the treatment of MS. Here we describe a case of PBC like syndrome that was unmasked, concomitantly or consequently to Epstein Barr virus (EBV) infection reactivation, in a 34 year old male patient with relapsing remitting multiple sclerosis who was receiving fingolimod treatment

Adinolfi, Luigi Elio

Alfieri, G

DALLA MORA, Liliana

Lus, Giacomo

Marrone, Aldo

Rainone, I

Rinaldi, L

Signoriello, E

MARRONE, Aldo

ADINOLFI, Luigi Elio

LUS, Giacomo

Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli"

3312014Epstein Barr virus infectionreactivation as a possibletrigger of primary biliarycirrhosis-like syndrome in apatient with multiple sclerosisin the course of fingolimodtreatmentRiattivazione dell’infezione da Epstein Barr virus come possibile trigger di cirrosi biliare-like syndrome in un paziente con sclerosi multipla in trattamento con fingolimodAldo Marrone1, Elisabetta Signoriello2, Gennaro Alfieri2, Liliana Dalla Mora3, Luca Rinaldi1, Ilaria Rainone1, Luigi Elio Adinolfi4, Giacomo Lus21Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; 2Department of Clinical and Experimental Medicine and Surgery “F. Magrassi e A. Lanzara”; 3Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); 4Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italyn INTRODUCTIONPrimary biliary cirrhosis (PBC) is a chroniccholestatic liver disease characterized bythe immune-mediated destruction of in-trahepatic bile ducts, resulting in chronic liverinjury and evolving to fibrosis, cirrhosis andliver failure. A distinguishing feature of PBC isthe presence of antimitochondrial antibodies(AMA) in serum, found in 90%-95% of patientsand less than 1% of normal controls [1, 2]. Mul-tiple sclerosis (MS) is a complex immune-medi-ated inflammatory disease of the central ner-vous system affecting an estimated 2 millionpeople worldwide [3]. Both MS and PBC areconsidered autoimmune diseases although theetiopathogenesis is still unclear. An associationof both diseases has been previously describedin sporadic case reports [4]. Fingolimod is the first orally administered dis-ease-modifying drug and was approved in 2010for the treatment of relapsing-remitting multi-ple sclerosis. Increased alanine aminotrans-ferase (ALT) values >3 times the upper limit ofnormal (ULN) is reported to have occurred in94 of 1,172 (8.0%) patients treated with fin-golimod 0.5 mg. Furthermore, because fin-golimod is a potent immunomodulator, an in-creased susceptibility to infections must be ex-pected. To this regard one case of fatal dissem-inated primary varicella zoster (VZV) and onecase of fatal herpes simplex (HSV) encephalitishave been described [5]. We describe the case of a 34-year-old man withrelapsing-remitting MS since 2001 who present-CasoclinicoCasereportsLe Infezioni in Medicina, n. 4, 331-336, 2014Corresponding authorAldo Marrone E-mail: aldo.marrone@unina2.it3322014ed an ALT and gamma-glutamyl transpepti-dase (GGT) increase at the seventh month offingolimod treatment and was diagnosed withPBC-like syndrome.n CASE REPORTWe describe the case of a 34-year-old man whohad been diagnosed with relapsing-remittingmultiple sclerosis in 2002 according to the McDonald criteria. He received therapy with inter-feron (IFN) beta 1a from 2002 to 2010, but thetreatment was discontinued because ineffectiveaccording to the brain magnetic resonanceimaging evidence. No alterations in liver chem-istry were reported throughout this period. InMarch 2011 the patient started second-linetreatment with fingolimod 0.5 mg once daily.The following clinical and laboratory evalua-tions were made before starting treatment:hematological evaluation with complete bloodcount, routine liver chemistry, IgM and IgG forvaricella zoster virus (VZV), fundus examina-tion and cardiology consultation with ECG. Allresults were normal and there was no evidenceof impaired liver function. Serology results forVZV showed IgG positivity. Hematological andbiochemistry parameters were evaluatedmonthly. After two weeks of therapy he pre-sented a slight ALT elevation of 1.5 fold theULN and GGT of 1.5 fold the ULN. Liver en-zymes increased over the months up to the sev-enth month of treatment when values  of 3-4fold the ULN were reached (Figure 1). Duringthis period, coincidentally with these findings,the patient felt mild pain in the right hypochon-drium and abdominal discomfort after meals.Of note, about a month after treatment wasstarted, an episode of fever with nausea, vomit-Figure 1 - Clinical course of a 34-year-old man with MS who received fingolimod treatment. The patient, withmultiple sclerosis previously treated with beta-IFN for eight years, started fingolimod 0.5 mg/day and stop-ped at the 7th month of therapy due to ALT and GGT elevation. The liver chemistry test alterations were pre-ceded by an episode of fever and lymphadenopathy associated with EBV-infection reactivation and positiveIgM anti-EBV, followed by AMA titer increase. Fingolimod discontinuation and ursodeoxicholic administrationled to liver enzyme normalization but with a persistence of IgM anti-EBV and AMA positivity. ALT: alanine ami-notransferase; GGT: gamma-glutamyl transpeptidase; ALP: alkaline phosphatase; EBV: Epstein-Barr Virus sero-logy; AMA: antimitochondrial autoantibodies; ULN: upper limit of normal.3332014ing, fatigue, upper abdominal pain and cervicallymphadenopathy occurred. Fingolimod thera-py was discontinued at the seventh month andthe patient was hospitalized for a complete liv-er function assessment. The physical examina-tion revealed: pain on deep palpation of theright hypochondrium and increased liver size.Liver chemistry showed an ALT increase of 3.5times the ULN, GGT 3.7 times the ULN, alka-line phosphatase (ALP) 1.3 times the ULN andnormal bilirubin values. Total serum IgMs wereslightly elevated (256 mg/dl). There was no ev-idence of hepatitis A, B or C virus infections.Serology for cytomegalovirus (CMV) and HSVwas IgG-positive and IgM-negative. IgG andIgM anti-Toxoplasma gondii resulted negative.Interestingly, IgG and IgM were both positivefor Epstein Barr virus (EBV). Serum liver-relat-ed autoantibodies revealed: anti-nuclear-anti-body (ANA) negativity, anti-smooth muscle-antibody (ASMA) negativity, anti liver-kidneymicrosomal antibody (anti-LKM) negativityand, surprisingly, anti-mitochondrial-antibody(AMA) positivity ≥1:320. Liver US examinationshowed mild steatosis and slight he-patomegaly, no signs of bile duct obstructionand normal spleen size. A sample of the pa-tient’s serum taken prior to fingolimod admin-istration was AMA-positive at a lower titer(1/160) and EBV-IgG-positive but EBV-IgM-negative. Treatment with ursodeoxycholic acid(15 mg/Kg/die) was started and after threemonths of therapy the liver function parame-ters normalized. After eight months of follow-up the patient presented normal liver enzymes,AMA positivity ≥1:320 and was still EBV-IgM-positive. The patient did not give consent forliver biopsy.During fingolimod treatment the patient didnot show any worsening in disability and noevidence of clinical or instrumental MS relapse.The liver enzymes, EBV serology and AMAtiters over the course of fingolimod treatmentand follow-up after fingolimod was discontin-ued are shown in Figure 1. Auto-antibodieswere tested by indirect immunofluorescenceand by a line immunoassay (Euroimmun TestSystems, Luebeck, Germany). The auto-anti-body profile at the time fingolimod was discon-tinued is given in Table 1.n DISCUSSIONWe describe a case of PBC-like syndrome thatwas unmasked, concomitantly or consequentlyto EBV reactivation, in a patient with relapsingmultiple sclerosis who was receiving fin-golimod treatment. The relationship betweenviral infections and the occurrence of autoim-munity and overt autoimmune disease is com-plex and intriguing. Pathogenetic mechanismssuch as molecular mimicry, bystander activa-tion, persistent virus infection and others havebeen investigated and proposed. However, ac-cumulating evidence shows that infectiveagents can initiate, promote and even abrogateautoimmunity [6, 7-9]. There is strong epidemi-ological evidence that MS and PBC patientshave a higher sero-prevalence of EBV antibod-ies, and increased levels of EBV DNA havebeen detected in the PBMC, liver tissue andsaliva of PBC patients [6, 10, 11]. Although theepidemiological relationship is clear, the etio-logical role of EBV in both diseases is still un-certain. Recently an in-vitro study showed thatEBV can exert its helper function for torqueteno virus (TTV) replication, which is believedto play a role in the pathogenesis of MS [12].In this clinical case, both the physicians and pa-tient were unaware of AMA positivity beforestarting fingolimod, and at that time all liverTable 1 - Auto-antibody profile at the time of fingolimod discontinuation.*AMA: ≥1/320 *ANA: neg *ASMA: neg ^Anti-AMA-M2: neg ^Anti-M2-3E (BPO): pos ^Anti-Sp100: neg ^Anti-PML: neg ^Anti-gp210: neg ^Anti-LKM-1: neg^Anti-LC-1: neg ^Anti-SLA/LP: neg ^Anti-Ro-52: negAMA: anti-mitochondrial antibodies; ANA: anti-nuclear antibodies ; ASMA: anti-smooth muscle autoantibodies were tested by indirect im-munofluorescence (IIF)*. Nine different autoantibodies involved in autoimmune diseases were tested by a line immunoassay (LIA, Eu-roimmun)^: Anti-AMA-M2: anti-pyruvate dehydrogenase complex; Anti-M2-3E: anti-fusion protein of the E2 subunits of alpha-2-oxoaciddehydrogenases of the inner mitochondrial membrane; Anti-Sp100: anti-nuclear antigen; Anti-PML: anti-promyelocytic leukemia protein;Anti-gp210: anti-nuclear; Anti-LKM-1: anti-liver-kidney microsomes-1; Anti-LC-1: liver cytosolic antigen type 1; Anti-SLA/LP: anti-solu-ble liver antigen/liver-pancreas antigen; Anti-Ro-52.3342014chemistry tests were normal. After about onemonth of fingolimod therapy, the patient pre-sented an episode of fever, fatigue and cervicallymphadenopathy associated with an ALT andGGT increase that persisted until the seventhmonth when laboratory data showed anti-EBV-IgM positivity and higher AMA titers com-pared to the data before starting treatment. Fin-golimod discontinuation and the administra-tion of ursodeoxycholic acid led to liver chem-istry normalization, but IgM anti-EBV positivi-ty persisted for eight more months. The IgM an-ti-EBV seropositivity and possibly the fever, fa-tigue and cervical lymphadenopathy constitutethe evidence for EBV reactivation. So we sup-pose that fingolimod immunosuppression wasresponsible for EBV-infection reactivation,which in turn triggered or unmasked latentPBC-like syndrome. Chen recently reported the case of a 41-year-oldman with relapsing-remitting multiple sclerosiswho was receiving fingolimod and presentedacute hepatitis with jaundice. The initial pre-sumptive diagnosis was drug-induced liver in-jury (DILI) due to fingolimod, but subsequent-ly, acute hepatitis E virus (HEV) was diagnosed[13]. HEV is usually responsible for acute he-patitis but it can evolve to a chronic disease inpost-transplant immunosuppressed patients.Cases, even fatal, of herpes virus infection reac-tivation have been described in the course offingolimod treatment, so it is conceivable thatin our case, EBV reactivation was due to the im-munomodulatory effect of fingolimod. Recently, Pender proposed an interesting uni-fying multi-step hypothesis which correlatesEBV infection to the development of autoim-mune diseases. In this hypothesis, geneticallydetermined CD8+ T-cell deficiency is a generalfeature of chronic autoimmune diseases andunderlies their development by impairingCD8+ T-cell control of EBV infection, with theconsequence that EBV-infected autoreactive Bcells accumulate in the target organ, where theyproduce pathogenic autoantibodies and pro-vide costimulatory survival signals to autoreac-tive T cells. The final evolution of these steps isthe development of ectopic lymphoid folliclescontaining EBV-infected autoreactive B cells inthe target organ [14].Fingolimod is an antagonist of the sphingosine-1-phosphate receptor family (S1P1/3/4/5) thatinhibits lymphocyte egress and their recircula-tion and presence in the central nervous sys-tem, trapping B and T lymphocytes in sec-ondary lymphoid tissues. This reduces the le-sion load and disability progression in multiplesclerosis. So fingolimod does not cause lym-phopenia by depletion but by redistribution oflymphocytes. It has been demonstrated that inpatients with PBC, there is a 100-fold to 150-fold increase in autoreactive CD4 PDC-E2–spe-cific T cells and a 10-fold to15-fold increase inautoreactive CD8 PDCE2–specific T cell infil-trates in the liver and regional lymph nodescompared to the blood [1]. Although the mech-anism of action is not completely known, it isreasonable to suppose, in our case, that by af-fecting T-cell recirculation, fingolimod deter-mined, first, EBV-infection reactivation and,secondly, the clinical emergence of PBC-likesyndrome, in accordance with the Pender hy-pothesis. It is difficult to establish in this case ifthe patient became symptomatic because ofEBV reactivation or because of the im-munomodulating action of fingolimod. How-ever, after fingolimod was discontinued and ur-sodeoxycholic acid administered, the liver en-zymes became normal but IgM-anti-EBV per-sisted for several months and the AMA titer in-creased. It is not surprising that a clinical worsening ofPBC occurs under immunosuppression. Re-cently a very rapid progression to cirrhosis wasdescribed in a patient with PBC and a gastriclymphoma who was receiving rituximab [15].In our case, the sequence of EBV reactivation,liver enzyme alteration, AMA titer increase andthe clinical improvement after fingolimod dis-continuation and ursodeoxycholic acid admin-istration makes the immunosuppression-viralreactivation-autoimmune disease sequenceplausible.Fingolimod is a promising and effective drug inthe treatment of MS. Nevertheless, an increasedsusceptibility to infections, particularly relatedto the herpes viruses, and an elevation of liverenzymes in 8% of patients have been reportedin the course of treatment. The causes of thesehepatic effects are unknown and are generallyattributed to drug-induced liver injury. Ourcase shows that some other underlying mecha-nism, such as immunosuppression, may havebeen responsible for a latent EBV-virus-infec-tion reactivation and, consequently, the activa-tion of PBC-like syndrome. Biological immuno-suppressive drugs are changing the therapeuticarmamentarium of onco-hematological, au-toimmune, dermatological and neurologicaldiseases but the risk of reactivation of occult in-3352014fections such as hepatitis B, herpes virus, JCvirus and others must always be considered[16, 17].In conclusion, this clinical case suggests to in-clude a thorough liver assessment with com-plete virological and autoimmune screening inall patients with MS before starting fingolimod,and apply careful monitoring during therapy.We would like to conclude by quoting theprovocative statement by Zinkernagel: “If weknow the infection, we call the disease im-munopathologically mediated; if we do not rec-ognize or know it, we call the disease autoim-mune” [18]. However, if the infection directlyinfects autoreactive B cells, then the tissue dam-age may be mediated by autoimmune mecha-nisms rather than immunopathological mecha-nisms.Disclosure of interestThe authors declare that they have no conflictsof interest concerning this article.Keywords: Epstein Barr virus, primary biliarycirrhosis, multiple sclerosis, fingolimod, reacti-vation.La cirrosi biliare primitiva (PBC) e la sclerosi multipla(MS) sono entrambe considerate malattie autoimmuniad eziologia multifattoriale cui concorrono condizionigenetiche predisponenti e fattori scatenanti ambientali.Un’associazione di entrambe le malattie è stata prece-dentemente descritta in sporadici casi clinici. Fingoli-mod, antagonista recettori della sfingosina 1-fosfato(S1P1/3/4/5), è un promettente ed efficace farmaco per iltrattamento della sclerosi multipla. Descriviamo un ca-so di cirrosi biliare-like syndrome insorto in concomi-tanza o conseguentemente alla riattivazione dell’infe-zione da Epstein Barr (EBV) in un paziente con sclero-si multipla recidivante-remittente in trattamento confingolimod.RIASSUNTOPrimary biliary cirrhosis (PBC) and multiple scle-rosis (MS) are considered autoimmune diseaseswith a multifactorial aetiology which is thought tobe due to a combination of genetic predispositionand environmental triggers. An association of both diseases has been previous-ly described in sporadic case reports. Fingolimod,an antagonist of the sphingosine-1-phosphate re-ceptor family (S1P1/3/4/5), is a promising and ef-fective drug in the treatment of MS. Here we de-scribe a case of PBC-like syndrome that was un-masked, concomitantly or consequently to EpsteinBarr virus (EBV)-infection reactivation, in a 34-year-old male patient with relapsing-remittingmultiple sclerosis who was receiving fingolimodtreatment.SUMMARYn REFERENCES[1] Lindor K.D., Gershwin M.E., Poupon R., KaplanM., Bergasa N.V., Heathcote E.J. Primary biliary cir-rhosis. Hepatology 50, 291-308, 2009. [2] Poupon R. Primary biliary cirrhosis: a 2010 up-date. J. Hepatol. 52, 745-758, 2010. [3] Compston A., Coles A. Multiple sclerosis. Lancet359, 1221-1231, 2002. [4] Pontecorvo M.J., Levinson J.D., Roth J.A. A pa-tient with primary biliary cirrhosis and multiple scle-rosis. Am. J. Med. 92, 433-436, 1992.[5] Cohen J.A., Chun J. Mechanisms of fingolimod’sefficacy and adverse effects in multiple sclerosis.Ann. Neurol. 69, 759-777, 2011. [6] Selmi C., Papini A.M., Pugliese P., Alcaro M.C.,Gershwin M.E. 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Epstein Barr virus infection reactivation as a possible trigger of primary biliary cirrhosis-like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment.

Epstein Barr virus infection reactivation as a possible trigger of primary biliary cirrhosis-like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment.

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