Assante LR

Barra E

BOCCHINO, MARIALUISA

Ferrara G

SANDUZZI ZAMPARELLI, ALESSANDRO

Zuccarini G

English

Archivio della ricerca - Università degli studi di Napoli Federico II

1442014Tuberculosis of the tongue in a patient with rheumatoid arthritis treated with methotrexate and adalimumabTubercolosi della lingua in un paziente affetto da artrite reumatoide trattato con metotrexate e adalimumabLuca Rosario Assante1, Enrica Barra2, Marialuisa Bocchino1, Giacomo Zuccarini1, Gerardo Ferrara3, Alessandro Sanduzzi11Section of Respiratory Diseases, Department of Surgery and Clinical Medicine,University “Federico II”, Naples, Italy;2Unit of Pathology, AORN Ospedali dei Colli, Naples, Italy;3Unit of Pathology, AO G. Rummo, Benevento, Italyn INTRODUCTIONA ccording to the World Health Organiza-tion (WHO) tuberculosis (TB) remains amajor health problem with one third ofthe world population infected and 8,6 millionnew cases in 2012 [1]. Oral tuberculosis is a rareentity that accounts for 0,1-5% of all TB infec-tions. Mycobacterium tuberculosis can infect allparts of the mouth such as the gingiva, soft andhard palate, lips, maxilla, mandible and thetongue. The tongue is the most common site oforal TB. Lesions commonly appear as a single, swollennon-healing ulcer that often resembles malig-nant neoplasms. Tuberculosis is rarely consid-ered in differential diagnosis of oral ulcers andoften diagnosis is made by pathological exami-nation [2]. In recent years rheumatoid arthritis(RA) treatment takes advantage of biologicaldrugs that inhibit Tumor Necrosis Factor alpha(TNFα). TNFα inhibitors include monoclonalantibodies like infliximab (IFN) or adalimumab(ADA), and the soluble TNF receptor-Fc fusionprotein etanercept (ETA). This therapy is asso-ciated with an increased risk of active TB, espe-cially due to latent tuberculosis (LTB) reactiva-tion [3]. Risk of tuberculosis is higher for monoclonal an-tibodies than ETA [4]. Therefore, RA guidelinesintroduced TB screening by TST and, more re-cently, by in vitro Interferon-γ release assays(IGRAs) before treatment with anti-TNFαagents to prevent LTB reactivation [5, 6]. Wedescribe a case of a RA patient treated for longtime with MTX and ADA suffering from a non-healing ulcer of the tongue.n CASE PRESENTATIONA 71-year-old woman was admitted to our di-vision in March 2011 with two months historyof ulcerated, non-healing lesion of the tongue.The patient suffered from RA for 20 years andshe was on ADA and MTX treatment for thelast 6 years. Previously she was treated withprednisone, INF and ETA. Pretreatment TST was reported to be negativeand no IGRAs were performed. The patient hadno history of BCG vaccination. She reported as-thenia, pharyngodinia, dysphagia, low gradefever and night sweats in the last 3 months. OnCasoclinicoCasereportLe Infezioni in Medicina, n. 2, 144-148, 2014Corresponding authorAlessandro Sanduzzi E-mail: sanduzzi@unina.it 1452014physical examination, the patient had an ulcer-ated swelling on the left border of the base ofthe tongue, cervical lymphadenopathy and ul-nar deviation of metacarpophalangeal joints bi-laterally. Thoracic examination was normal. Cervical CTscan revealed a reduced lumen of the pharynxwith an infiltrated left wall, left cervical lymphadenopathy and left pyriform sinusobliteration. Chest CT showed mediastinal cal-cified lymphadenopathies (Figure 1). An initialdiagnosis of squamous cell carcinoma of thetongue was pointed out. Biopsy of the lesionshowed chronic inflammatory changes, numer-ous epithelioid and Langhan’s giant cells gran-ulomata without malignant cells (Figure 2). Routine blood tests revealed mild anemia (Hb11,4 g/dl), normal white blood cells count, erythrocyte sedimentation rate 73 mm/hr, C-reactive protein 56 mg/L (reference <5 mg/L).Serologic tests for HIV, Epstein Barr Virus, Cy-tomegalovirus, Herpes simplex virus, Brucellaand Toxoplasma gondii were all negative. TSTwas strongly positive (35x35 mm) and T-SPOT-TB test was also reactive. Biopsy specimenswere negative for acid-fast bacilli but mycobac-terial culture was positive. Afterwards MTXand ADA were discontinued and the patientwas treated for 2 months with isoniazid 300 mgper day, rifampicin 600 mg per day, ethambutol1200 mg per day and pyrazinamide 1500 mgper day and then received isoniazid and ri-fampicin at the same dose for other 7 months. Three months after discontinuation of RA ther-apy the patient presented polyarticular synovi-tis with severe functional impairment. The pa-tient reintroduced MTX and received rituximabwith functional improvement. Six months later,the ulcer was completely healed and cervicallymphadenopathies were reduced in numberand size.Figure 1 - a) Neck CT show the infiltration of the hy-popharynx wall with left pyriform sinus obliteration(black arrows); b) chest CT show subcarinal calcifiedlymph node (black arrowhead).a bFigure 2 - Biopsy specimen show granulomatous in-flammation with epitelioid cells and giant cells thatcauses ulceration of the mucosa.1462014n DISCUSSIONWe presented a case of tuberculosis of thetongue in a RA patient treated with MTX andADA for 6 years. Previously the patient received high dose ofprednisone, INF and subsequently ETA. TNFαis the most important cytokine in the host re-sponse to TB infection. Particularly TNFα is es-sential for macrophage activation, inflammato-ry cell recruitment, granuloma formation andmaintenance of granuloma integrity [7]. Although the probability of TB infection is verylow for MTX, this risk is more consistent forTNFα inhibitors with an increased risk to de-velop extrapulmonary and disseminate TB dis-ease [8]. In the literature there are only two reports onoral TB in RA patients treated with ADA andMTX. In one report the patient developed TBafter 3 months of treatment and no pretreat-ment TST result was reported. As in our case, in the second report TB arose af-ter a long time of treatment, TST was reportedto be negative pre-therapy and conversed posi-tive when the patient developed oral TB [9, 10].Oral TB is a rare entity and may be either pri-mary or, more often, secondary to pulmonaryTB. Primary oral TB is more common in youngpeople while secondary form is more commonin adults [11]. The tongue is affected most commonly. The in-tegrity of oral mucosa, the cleaning action ofsaliva, the presence of oral saprophytes andsubmucosal antibodies presents a natural resis-tance to Mycobacterium invasion. Oral trauma, inflammatory conditions, poororal hygiene or tooth extraction may representa route of entry for Mycobacterium [2]. Howev-er, in our case, the patient didn’t report any ofthese risk factors. Primary oral TB presents mainly as painfulchronic non healing ulcers and are more oftenassociated with cervical lymphadenopathy [11].Since 2008 American College of Rheumatology(ACR) guidelines for the use of TNFα inhibitorsin RA patients put strong attention to thescreening of LTB with an initial TST in all pa-tients, being considered for therapy with TNFαinhibitors, regardless of the presence of risk fac-tors for LTB or BCG vaccination status. Al-though 2012 ACR revised guidelines indicateIGRAs as an alternative to TST, it is not stillclarified if these tests are more useful than TSTin RA patients because they are also influencedby host immunological status. Severely im-munocompromised or paediatric patients havehigh rate of IGRA indeterminate results [12, 13].However, in recent studies IGRAs seem to bemore specific and more sensitive than TST inrheumatologic patients [14, 15]. In the present case, an initial TST was negativeand later both TST and IGRA were positive.The risk to develop TB seems to be differentamong different TNFα inhibitors. Patientstreated with ADA or INF have a 3 to 4 fold in-creased risk to develop TB compared withthose treated with ETA. These differences seem to be explained by dif-ferent pharmacokinetics and pharmacodynam-ics properties. INF and ADA bind TNFα in astable manner, their biologic effect is prolongedand they have proven to induce apoptosis of Tcells whereas ETA biologic effect is reversibleand has no cytotoxic effects. The mean time to TB diagnosis from the start ofTNFα inhibitors is relatively short, which sug-gests reactivation of LTB [3]. However, as inour patient, TB may occur after years of treat-ment with ADA. Annual testing for TB is recommended only inpatients who have a high rate of TB exposureand it was not performed in our patient becauseshe was considered a low risk patient. Ritux-imab is a chimeric monoclonal antibody thattargets CD20 positive B cells. It was recommended in RA patients with TNFinhibitors inadequate response or adverseevents. Rituximab seems to be safe in RA pa-tients who have an elevate risk of TB and it maybe a valid choice in such patients [6, 16].Keywords: oral tuberculosis, rheumatoid arthri-tis, adalimumab, metotrexate, IGRA.1472014In recent years Tumor Necrosis Factor alpha (TNFα) inhibitors have been highly effective intreating rheumatoid arthritis (RA). However, pa-tients receiving these inhibitors have an increasedrisk of developing tuberculosis (TB). We describe arare case of tuberculosis of the tongue in an RA pa-tient treated with methotrexate (MTX) and the TN-Fα inhibitor adalimumab (ADA) for the previoussix years. Pre-treatment tuberculin skin test (TST) was nega-tive. The patient was admitted to our divisioncomplaining of a sore throat for months. Clinicalexamination revealed a swollen non-healing ulcerat the base of the tongue, which was suspected tobe a squamous cell carcinoma. Histopathologicalassessment unexpectedly revealed a chronic gran-ulomatous inflammation compatible with tubercu-losis. TST was strongly positive and the T-Spot-TBtest was also reactive. MTX and ADA were discontinued and the patientreceived antituberculous treatment with completehealing of the lesion. After three months our patient had a worseningRA that was treated with MTX and rituximab withno TB-related adverse events. This case highlightsthe importance of considering tuberculosis in thedifferential diagnosis of ulcerative lesions of theoral cavity, especially in immunocompromised pa-tients treated with TNFα inhibitors. Rituximab canbe a valid alternative therapy in such patients.SUMMARYNegli ultimi anni gli inibitori del Tumor NecrosisFactor alpha (TNFα) si sono dimostrati molto efficacinel trattamento dell’artrite reumatoide (AR). Tuttavia ipazienti trattati con questi inibitori hanno un aumenta-to rischio di sviluppare la tubercolosi (TB). Qui presen-tiamo un raro caso di tubercolosi della lingua in una pa-ziente affetta da AR trattata negli ultimi 6 anni con me-totrexate (MTX) e l’inibitore del TNFα adalimumab(ADA). Il test cutaneo alla tubercolina (TST) prima deltrattamento era negativo. La paziente è giunta alla no-stra osservazione poiché lamentava mal di gola da alcu-ni mesi. L’esame obiettivo ha rivelato una tumefazioneulcerata alla base della lingua che si sospettava essereun carcinoma squamoso. Inaspettatamente, l’esameistologico ha mostrato una flogosi granulomatosa croni-ca compatibile con infezione tubercolare. Adesso il TSTrisultava fortemente positivo ed il T-Spot-TB era reatti-vo. MTX ed ADA sono stati sospesi e la paziente ha co-minciato il trattamento antitubercolare, con completaguarigione della lesione. Dopo tre mesi la paziente hapresentato un peggioramento dell’AR trattato con MTXe rituximab in assenza di eventi avversi correlabili allaTB. Questo caso clinico sottolinea l’importanza di con-siderare la tubercolosi nella diagnosi differenziale dellelesioni ulcerate del cavo orale, in modo particolare neipazienti immunodepressi trattati con inibitori delTNFα. Il rituximab potrebbe essere una valida alterna-tiva per il trattamento di tali pazienti.RIASSUNTOcan College of Rheumatology 2008 Recommenda-tions for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoidarthritis. Arthritis Rheum. 59, 6, 762-784, 2008.[6] Singh J.A., Furst D.E., Bharat A., et al. Update ofthe 2008 American College of Rheumatology recom-mendations for the use of disease-modifying an-tirheumatic drugs and biologic agents in the treat-ment of rheumatoid arthritis. Arthritis Care Res.(Hoboken). 64, 5, 625-639, 2012.[7] Roach D.R., Bean A.G., Demangel C., France M.P.,Briscoe H., Britton W.J. TNF regulates chemokine in-duction essential for cell recruitment, granuloma for-mation, and clearance of mycobacterial infection. J.Immunol. 168, 9, 4620-4627, 2002.[8] Keane J., Gershon S., Wise R.P., et al. Tuberculo-sis associated with infliximab, a tumor necrosis fac-tor alpha-neutralizing agent. N. Engl. J. Med. 345, 15,1098-1104, 2001. n REFERENCES[1] Global tuberculosis report 2013. WHO 2013. Re-trieved from http://www.who.int/tb/publications/global_report/en/ 2013. Last accessed March 24,2014.[2] Kakisi O.K., Kechagia A.S., Kakisis I.K., RafailidisP.I., Falagas M.E. Tuberculosis of the oral cavity: asystematic review. Eur. J. Oral. Sci.118, 103-109, 2010.[3] Dixon W.G., Hyrich K.L., Watson K.D., et al.Drug-specific risk of tuberculosis in patients withrheumatoid arthritis treated with anti-TNF therapy:results from the British Society for Rheumatology Bi-ologics Register (BSRBR). Ann. Rheum. Dis. 69, 3, 522-528, 2010.[4] Wallis R.S. Tumor necrosis factor antagonists:structure, function, and tuberculosis risks. Lancet In-fect. Dis. 8, 601-611, 2008.[5] Saag K.G., Teng G.G., Patkar N.M., et al. Ameri-1482014[9] Kolokotronis A., Avramidou E., Zaraboukas T.,Mandraveli K., Alexiou S., Antoniades D. Oral tuber-culosis associated with a treatment with anti-rheumatic drugs. J. Oral. Pathol. 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Tuberculosis of the tongue in a patient with rheumatoid arthritis treated with methotrexate and adalimumab.

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Tuberculosis of the tongue in a patient with rheumatoid arthritis treated with methotrexate and adalimumab.

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