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Journal of Crohn's and Colitis (2013) 7, e143–e145

SHORT REPORT

Anti-tumor necrosis factor-α induced systemic lupuserythematosus in a patient with metastatic Crohn'sdisease—what is the role of anti-TNF antibody?Klaudia Farkas a, Ferenc Nagy a, László Kovács b,Tibor Wittmann a, Tamás Molnár a,⁎

a First Department of Medicine, University of Szeged, Szeged, Hungaryb Department of Rheumatology, University of Szeged, Szeged, Hungary

Received 11 May 2012; received in revised form 30 May 2012; accepted 25 June 2012

⁎ Corresponding author at: TamásMedicine, University of Szeged, H-67Hungary. Tel.: +36 62 545186; fax: +3

E-mail address: molnar.tamas@me

1873-9946/$ - see front matter © 2012doi:10.1016/j.crohns.2012.06.016

KEYWORDSCrohn's disease;Infliximab;TNF-α antagonist-inducedlupus-like syndrome;Autoantibodies;Cross reactivity

Abstract

Biological therapies are supposed to trigger the development of autoimmune diseases. Wereport a case of a 27-year old woman presenting with drug induced systemic lupuserythematosus (SLE) associated with infliximab therapy. The development of paradoxicalinflammation in immune-mediated inflammatory diseases patients treated with anti TNF-αsuggests that an unknown inflammatory pathway may be provoked by inhibiting TNF-α. Wesuppose that in our case a cross reactivity between anti-infliximab antibodies and autoanti-

bodies may lead to the development of TNF-induced immune disease.© 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Molnár, First Department of20, Korányi fasor 8, Szeged,6 62 545185.d.u-szeged.hu (T. Molnár).

European Crohn's and Colitis

1. Introduction

Drug induced lupus erythematosus like syndrome is a rarelydescribed condition in Crohn's disease; however patientstreated with biological therapy are slightly more susceptiblefor developing such an adverse reaction.1 The use of anti-TNFagents has been associated with an increasing number ofautoimmune diseases, mainly lupus, vasculitis, and intestinal

Org

lung disease.2 Biological therapies are supposed to trigger thedevelopment of autoimmune diseases, although allergic reac-tion or loss of response due to the production of antibodiesagainst the TNF blockers may also play role in the developmentof these complications. From another point of view, themechanism in the background of this effect may be stimulatedhumoral immunity: production of autoantibodies due to theneutralization of TNF-α or inhibition of cytotoxic T lymphocytesby TNF blockade.3,4 Although the development of autoanti-bodies is common during infliximab therapy; drug induced lupuserythematosus like syndrome is still rare. A study of 500 Crohn'sdisease patients from the Mayo Clinic revealed only threepatients who developed drug induced lupus during the

anisation. Published by Elsevier B.V. All rights reserved.

Figure 2 Closed preauricular fistula after infliximab inductiontherapy.

e144 K. Farkas et al.

therapy.5 In Hungary infliximabwas approved for the treatmentof moderate to severe Crohn's disease in 2001. We report a caseof a 27-year old woman presenting with drug induced systemiclupus erythematosus (SLE) associated with infliximab therapy.In the past 10 years, the present is the only case of the morethan 230 patients who have been on biological therapy whenanti-TNF α therapy provoked the occurrence of SLE at ourcenter.

2. Case report

Crohn's disease of our female patient was diagnosed in 2007at age 22 years when she was presented with fever, diarrhea,aphthous stomatitis and a painful mass in the preauricularregion requiring surgical intervention. Ileocolonoscopy iden-tified aphthous lesions in the ileum, the right side of thecolon and the transverse colon. After initiating the treatmentwith mesalazine and corticosteroids her symptoms graduallyimproved. Two years later she developed active symptomsand perianal abscess. Mesalazine was stopped because ofloss of efficacy. After adding azathioprine and draining theabscess the patient shortly achieved remission. However, inJanuary 2010 she presented with recently activated 2×1-cmdischarging preauricular and perianal fistula; thereforeinfliximab therapy was started (Fig. 1). The histology offacial skin manifestation showed epitheloid histiocytes andmassive mononuclear infiltration. The activity-related pre-auricular fistula was suspected as metastatic Crohn's disease.With the infusion regimen of 5 mg/kg at 8-week intervals thepreauricular fistula remitted (Fig. 2) and the discharge of theperianal fistula reduced significantly. However, at the end ofthe one-year treatment period, the patient presented withswelling and pain in her fingers, wrists, elbows, knees andankles and her walking became difficult. Her bowel symp-toms were still in remission, although the perianal fistulastarted to discharge again.

Physical examination revealed swollen and tender shoul-ders, fingers, knees and toes without cutaneous symptoms.Laboratory investigation showed elevated C-reactive protein(24.5 mg/l) and erythrocyte sedimentation rate (66 mm/h),a positive serum anti-nuclear antibody, significantly elevatedanti-Sjogren's syndrome A antibody (181 U/ml) and anti-Sjogren's syndrome B antibody (N200 U/ml). Anti-double-stranded (ds)DNA, anti-ribonuclear protein/anti-Smith anti-body and anti-histone antibodies were also positive. C3 andC4 levels were normal. The patient was negative for anti

Figure 1 Preauricular fistula before infliximab therapy.

cardiolipin antibodies (IgG, IgM, IgA) and anti Beta-2-glycoprotein-1 (IgG, IgM, IgA). She did not have any sign ofrenal involvement; urea and creatinine levels were in normalrage. The pharmacokinetic examinations revealed low inflix-imab trough levels (2.75 ng/ml) and high levels of antibodiesagainst infliximab (ATI-3194 ng/ml). On the basis of the clinicalsymptoms, the autoimmune and pharmacokinetic measure-ments the diagnosis of infliximab induced SLE was established.Infliximab was stopped and low dose oral methylprednisolone(8 mg daily) was administered. Her symptoms resolvedcompletely within 2 months after stopping infliximab and hergastrointestinal symptoms also remained in remission withazathioprine monotherapy. Methylprednisolone was graduallytapered and stopped after 4 months of therapy. Because of herdischarging perianal fistula, Seton placement was performed inJanuary 2012.

3. Discussion

Metastatic Crohn's disease presents as cutaneous manifesta-tion of Crohn's disease characterized by ulcerative lesions. Theskin lesions may precede the diagnosis of Crohn's disease andusually show simultaneous activity with the clinical course.The presence of granulomas in MCD is the most prominenthistopathologic finding, and Langerhans giant cells arefrequently seen along with epithelioid histiocytes and anaccompanying lymphoplasmacytic infiltrate.6

Biopsies of these lesions show noncaseating granulomasthat are characteristic of Crohn's disease.7 In our case, thesimultaneous appearance of preauricular fistula and theintestinal symptoms suggested the diagnosis of metastaticCrohn's disease, although metastatic Crohn's disease on theface is a rare entity.8,9 Infliximab has not only proven itsefficacy in the treatment of metastatic Crohn's disease;furthermore, it seems to be the most beneficial in themanagement of mucocutaneous manifestations.10,11

In the last two decades anti-tumor necrosis factor(TNF)-α has been extensively used for the treatment ofimmune-mediated diseases. However, with the increasing useof anti TNF-α therapy, the number of anti TNF-α related sideeffect is also increasing. Paradoxical inflammatory reactionshave been described in patients with immune-mediatedinflammatory diseases receiving biological therapy. The reviewof Fiorino et al.12 revealed the onset of psoriasis in 18 cases ofpatients with inflammatory bowel disease treated with anti

e145Anti-tumor necrosis factor-α induced SLE in a patient with metastatic Crohn's disease

TNF therapy. In the majority of the patients, psoriatic lesionsresolved after cessation of biological therapy. The develop-ment of paradoxical inflammation in immune-mediated in-flammatory diseases patients treated with anti TNF-α suggeststhat an unknown inflammatory pathway is provoked byinhibiting TNF-α. According to the hypothesis of Fiorino et al.interferon (IFN) α may play an important role in thedevelopment of TNF-α induced psoriasis. Withdrawing biolog-ical therapy or switching to another anti TNF agent may beconsidered in these very rare conditions.

The least rigorous criteria for diagnosis of drug inducedlupus need one or more symptoms compatible with lupuserythematosus, ongoing exposure to a drug known to causedrug induced lupus, no prior history of lupus erythematosus,and resolution of symptoms when the offending drug isdiscontinued.13 In our case, the patient suffered fromarthritis, had antibodies to dsDNA and ANA positivity (threesymptoms compatible with SLE) was also detected; shereceived infliximab which had been shown to provoke druginduced lupus, never had SLE before and her symptomsresolved after discontinuing anti TNF therapy.

Treatment with infliximab can cause immunogenicity andthe formation of ATI.14 Detectable infliximab in the serumpredicts higher rates of remission and endoscopic improve-ment,15 while ATI positive patients are associated withlower response to infliximab and with the development ofadverse reactions.16 Infliximab-treated patients also devel-op autoantibodies in some cases, including ANA andanti-dsDNA antibodies that may be associated with SLE.17

Patients with ANA positivity before infliximab therapy aremore susceptible to develop dsDNA antibodies and druginduced lupus. Compared to drug-related lupus, dsDNA ispositive in 100% of TNF-α antagonist-induced lupus-likesyndrome.18 The concept of TNF-α antagonist-inducedlupus-like syndrome (TAILS) was first referred in a publicationof Williams and Cohen.13 They postulated some hypotheses forthe development of TAILS, including the role of anti TNF-αinduced apoptosis, the activation B lymphocytes and thereforethe increased autoantibody production, and finally thesuppression of cytotoxic T-lymphocytes.18 In our case, ATIand autoantibodies like anti dsDNA and ANA antibodies weredetected simultaneously. The results of a recent study19

suggest a role for autoantibodies in the development of ATIand the development of loss of response under treatment withinfliximab in psoriasis. It has been previously shown thatmicrobial stimulation of the immune system may provoke theproduction of auto-antibodies.20,21 The study of Zhang andReichlin22 demonstrated that anti-dsDNA antibodies from lupuspatients can react with burkholderia fungorum bacterialcell lysates. This supports the hypothesis that the origin ofanti-dsDNA antibodies in SLE may be associated with burkhol-deria bacterial infection and this crossreactivitymay play a rolein the development of autoimmunity. We suppose that in ourcase a cross reactivity between ATI and the autoantibodiesmayalso lead to the development of TNF induced immune disease.

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