Adler, Sabine

Boller, Christoph

Furrer, HansJakob

Garzoni, Christian

Villiger, Peter M.

RERO DOC Digital Library

Disclosure statement: The authors have declared noconflicts of interest.Johan M. Lorenzen1, Robert Kra¨mer1,Matthias Meier1, Thomas Werfel2,Katja Wichmann2, Marius M. Hoeper3,Gabriela Riemekasten4, Mike O. Becker4,Hermann Haller1 and Torsten Witte51Department of Medicine, Division of Nephrology andHypertension, 2Department of Dermatology, Allergology andVenerology, 3Division of Pulmonary Medicine, HanoverMedical School, Hanover, 4Division of Rheumatology andClinical Immunology and German Rheumatology ResearchCentre, Charite´ University Hospital, Berlin and 5Division ofImmunology and Rheumatology, Hanover Medical School,Hanover, Germany.Accepted 14 June 2010Correspondence to: Johan M. Lorenzen, Division ofNephrology, Department of Medicine, Hanover MedicalSchool, Carl-Neuberg-Strasse 1, 30625 Hanover, Germany.E-mail: j.m.lorenzen@gmail.comReferences1 Black CM. The aetiopathogenesis of systemic sclerosis:thick skin-thin hypotheses. The Parkes Weber Lecture1994. J R Coll Physicians Lond 1995;29:119.2 Systemic sclerosis: current pathogenetic concepts andfuture prospects for targeted therapy. Lancet 1996;347:1453.3 Mazzali M, Kipari T, Ophascharoensuk V, Wesson JA,Johnson R, Hughes J. Osteopontin—a molecule for allseasons. Q J Med 2002;95:3–13.4 Collins AR, Schnee J, Wang W et al. Osteopontinmodulates angiotensin II-induced fibrosis in the intactmurine heart. J Am Coll Cardiol 2004;43:1698–705.5 Wolak T, Kim H, Ren Y, Kim J, Vaziri ND, Nicholas SB.Osteopontin modulates angiotensin II-induced inflamma-tion, oxidative stress, and fibrosis of the kidney. Kidney Int2009;76:32–43.6 Pardo A, Gibson K, Cisneros J et al. Up-regulation andprofibrotic role of osteopontin in human idiopathicpulmonary fibrosis. PLoS Med 2005;2:e251.7 Mori R, Shaw TJ, Martin P. Molecular mechanismslinking wound inflammation and fibrosis: knockdown ofosteopontin leads to rapid repair and reduced scarring.J Exp Med 2008;205:43–51.8 Fan K, Dai J, Wang H et al. Treatment of collagen-inducedarthritis with an anti-osteopontin monoclonal antibodythrough promotion of apoptosis of both murine and humanactivated T cells. Arthritis Rheum 2008;58:2041–52.Rheumatology 2010;49:1991–1993doi:10.1093/rheumatology/keq146Advance Access publication 20 May 2010Possible role of anti-TNF monoclonal antibodies inthe treatment of Mycobacterium marinum infectionSIR, TNF plays a major role in mycobacterial defence.Mycobacterium marinum (M. marinum) infection typicallypresents with chronic inflammation of hands and feet[1, 2]. Its diagnosis is often delayed and antibiotic treat-ment is long-standing. Safe re-exposition to anti-TNFtherapy after successful bacterial elimination wasreported [3], yet addition of anti-TNF monoclonal anti-bodies to control inflammation seemed paradoxical so far.A 44-year-old Caucasian farmer presented with dacty-litis of a toe. Local glucocorticoid injection induced achronic fistula, which was surgically removed. Severalmonths later carpal arthritis and tenosynovitis developedand the patient reported inflammatory back pain.Suspecting spondyloarthritis, NSAIDs and glucocorticoidswere introduced, later co-medicated with MTX, yet provedinsufficient. Assessment of latent tuberculosis beforeanti-TNF therapy showed a positive IFN-g-release assay[IGRA; QuantiFERON-TB Gold in Tube (QFT), CellestisLtd, Victoria, Australia; Fig. 1a] [4]. Isoniazid was intro-duced against latent tuberculosis. Etanercept wasadded 1 month later and within few weeks synovitis andback pain improved. Unexpectedly carpal tenosynovitisFIG. 1 (a) Laboratory findings regarding M. marinum in-fection. np: not performed; in: PCR reaction inhibited; INH:isoniazid; R: rifampin; E: ethambutol; C: clarithromycin.(b) Histological findings of synovial tissue. Synovial tissuespecimens of the carpus showing classical findings ofM. marinum infection: granuloma formation, denseinfiltrates of mononuclear cells and several giant cells(arrow).Culture M. marinumPCR M. marinum QuantiFERON TB np + – –in + np ++ + + –R/E/C R/EInfliximabEtanerceptINH1. Synovial biopsy2. Synovial biopsySynovial puncture3. Synovial biopsyMTX100 m(a)(b)www.rheumatology.oxfordjournals.org 1991Letters to the Editordeteriorated. Synovial biopsy revealed granuloma forma-tion with giant cells (Fig. 1b). Microbiological cultures werenot performed and PCR for mycobacteria failed due toreaction inhibition (Fig. 1a). MTX was stopped due to ele-vated liver enzymes. Synovitis flared and the fistula of thetoe reopened. A second synovial biopsy led to the detec-tion of M. marinum and to the discontinuation of etaner-cept. Histology was unchanged. Given the high-gradeinfection in an immunocompromized patient, standardtherapy with ethambutol, clarithromycin and rifampinwas initiated and after 4 months clarythromycin wasstopped [2]. Yet carpal synovitis progressed. MRIshowed synovial proliferation with bone oedema withoutdestructive osteomyelitis. After thorough discussion andwith informed consent of the patient, we added a treat-ment with the monoclonal TNF antibody infliximab at adosage of 5 mg/kg/month. Hereby, clinical remissionwas induced. After stopping anti-bacterial therapy, athird synovial biopsy of the carpus showed marked im-provement of inflammation and part resolution of thegranuloma. There was no growth of mycobacteria, yetPCR for M. marinum was positive. QFT was then negative.Infliximab was stopped. Ten months later the patient hadno signs of cutaneous or soft tissue inflammation.On-demand NSAIDs are sufficient to control intermittentback pain.The positive QFT was interpreted as latent tuberculosisinfection and treated accordingly. Yet, further work basedon relapse during etanercept and MTX revealed active M.marinum infection in the cultured biopsy (Fig. 1a). QFTmeasures IFN-g release by T lymphocytes in responseto specific antigens. Notably, few non-tuberculous myco-bacteria like M. marinum, Mycobacterium kansasii andMycobacterium szulgai also express the antigens usedin the QFT [4, 5] explaining the positive IGRA.The positive M. marinum-PCR in the third biopsy is notsurprising as it might equally detect dead and vital par-ticles of bacterial DNA and is therefore not helpful in sur-veillance [6]. Even more so as the initial PCR had failed.Follow-up can only be properly managed by thoroughclinical controls, instruction of the patient and repeatingbacterial cultures.As TNF is known to play a central role in granulomapersistence, it might surprise that despite anti-TNF treat-ment with etanercept, the pathologist reported classicalfindings of M. marinum infection such as granuloma for-mation and giant cells (Fig. 1b). Current data show thatmonoclonal antibodies to TNF, but not the soluble recep-tor etanercept, are effective in treating granulomatous dis-eases like Crohn’s disease, sarcoidosis or localized WG.Thus, our histological data are in perfect agreement withdifferential clinical effects of soluble receptors vs mono-clonal antibodies.Reactivation of latent Mycobacterium tuberculosis in-fection caused by TNF-blocking therapy may be fatal.Therefore, clinicians are often reluctant to re-expose pa-tients to anti-cytokine therapy after successful antibiotictreatment. However, recently a TNF-blocking strategy wassuccessful in controlling inflammation in a life-threateningtuberculous paradoxical reaction [7]. The question wasraised whether anti-TNF strategies might be helpful in crit-ical situations of tuberculous paradoxical reactions [8].Regarding M. marinum, recent case reports documentM. marinum infection under TNF inhibition, but also safere-exposition to anti-TNF therapy after elimination of thebacteria [3, 9, 10]. In our case, local and systemic in-flammation persisted for months despite adequateanti-microbial treatment. Based on the considerationsabove, we decided to use the monoclonal antibody inflix-imab with the intent to control clinical signs of inflamma-tion and to destroy local granuloma. This procedureproved to be successful and raises the provocative ques-tion of whether continuation or introduction of TNF inhib-ition by monoclonal antibodies should not be advocated incases of localized granulomatous infections with M. mar-inum. It is tempting to speculate that time to elimination ofbacteria as well as time to remission of inflammation couldbe considerably shortened.Rheumatology key message. Anti-TNF monoclonal antibodies may help to con-trol inflammation caused by M. marinum infection.Disclosure statement: The authors have declared noconflicts of interest.Christian Garzoni1,*, Sabine Adler2,*,Christoph Boller1, HansJakob Furrer2 andPeter M. Villiger11Department of Rheumatology, Clinical Immunology andAllergology and 2Division for Infectious Diseases, UniversityHospital and University of Bern, Bern, Switzerland.Accepted 13 April 2010Correspondence to: Peter M. Villiger, Department of Rheu-matology and Clinical Immunology and Allergology, Inselspi-tal, University Hospital and University of Bern, CH-3010, Bern,Switzerland. E-mail: peter.villiger@insel.ch*Christian Garzoni and Sabine Adler equally contributed tothis work.References1 Aubry A, Chosidow O, Caumes E, Robert J, Cambau E.Sixty-three cases of Mycobacterium marinum infec-tion: clinical features, treatment, and antibiotic suscepti-bility of causative isolates. Arch Intern Med 2002;162:1746–52.2 Griffith DE, Aksamit T, Brown-Elliott BA et al. Anofficial ATS/IDSA statement: diagnosis, treatment,and prevention of nontuberculous mycobacterialdiseases. Am J Respir Crit Care Med 2007;175:367–416.3 Dare JA, Jahan S, Hiatt K, Torralba KD. Reintroduction ofetanercept during treatment of cutaneous Mycobacteriummarinum infection in a patient with ankylosing spondylitis.Arthritis Rheum 2009;61:583–6.4 Villiger PM, Zellweger J-P, Moeller B. Novel screeningtools for latent tuberculosis: time to leave an old friend?Curr Opin Rheumatol 2009;21:238–43.1992 www.rheumatology.oxfordjournals.orgLetters to the Editor5 Arend SM, van Meijgaarden KE, de Boer K et al.Tuberculin skin testing and in vitro T cell responses toESAT-6 and culture filtrate protein 10 after infection withMycobacterium marinum or M. kansasii. J Infect Dis 2002;186:1797–807.6 Thomsen VO, Kok-Jensen A, Buser M, Philippi-Schulz S,Burkhardt HJ. Monitoring of patients with pulmonary tu-berculosis: can PCR be applied? J Clin Microbiol 1999;37:3601–7.7 Wallis RS, van Vuuren C, Potgieter S. Adalimumab treat-ment of life-threatening tuberculosis. Clin Infect Dis 2009;48:1429–32.8 Wallis RS. Infectious complications of tumor necrosisfactor blockade. Curr Opin Infect Dis 2009;22:403–9.9 Rallis E, Koumantaki-Mathioudaki E, Frangoulis E,Chatziolou E, Katsambas A. Severe sporotrichoid fishtank granuloma following infliximab therapy. Am J ClinDermatol 2007;8:385–8.10 Chopra N, Kirschenbaum AE, Widman D. Mycobacteriummarinum tenosynovitis in a patient on etanercept therapyfor rheumatoid arthritis. J Clin Rheumatol 2002;8:265–8.Rheumatology 2010;49:1993–1994doi:10.1093/rheumatology/keq161Advance Access publication 26 May 2010Reversible cerebral vasoconstriction syndrome in afemale patient with systemic lupus erythematosusSIR, Headaches are common in patients with SLE, espe-cially those suffering from CNS involvement (CNS-SLE)with or without cerebral vasculitis [1, 2]. Reversible cere-bral vasoconstriction syndrome (RCVS) is characterizedby the association of severe ‘thunderclap headaches’with or without additional neurological manifestationsand a ‘string of beads’ appearance on cerebral arteries,which resolves spontaneously in 1–3 months [3]. RCVSand cerebral vasculitis have several overlapping features.We report a case of RCVS in an SLE patient that wasmisdiagnosed initially as lupus-associated cerebralvasculitis. To our knowledge, this is the first case ofRCVS described in an SLE patient.A 40-year-old female patient was diagnosed with SLE atthe age of 25 years. She presented at the age of 27 yearswith a severe flare-up characterized by intra-alveolarhaemorrhage and CNS-SLE (headaches, psychosis andseizure). She had no aPLs. Her follow-up was character-ized by poor treatment adherence.Since December 2008, she has been followed up in ourdepartment for World Health Organization classes IV–Vlupus nephritis and treated according to the Euro-Lupusregimen. While clinico-biological remission was noted,she presented 2 days before the fifth cyclophosphamidepulse with an acute severe headache that disappearedspontaneously and the patient received the planned500 mg i.v. cyclophosphamide. Her treatment includedprednisone (30 mg/day), atorvastatin, omeprazole, calciumcarbonate and cholecalciferol.She was readmitted to the hospital 2 days later foracute severe headache associated with nausea andvomiting. The headache was of sudden onset, recurrent,described as ‘thunderclap headache’, peaking in <10 swith maximal pain intensity graded as 9.5/10 on thevisual scale. She also experienced a brief generalizedseizure. Physical examination was normal. A head CTscan was normal. The cerebrospinal fluid was haematic.A cerebral magnetic resonance angiogram (MRA) demon-strated multifocal cerebral arterial stenosis (Fig. 1A). Thediagnosis of lupus-associated cerebral vasculitis wasconsidered; she was treated promptly with three dailypulses of 750 mg i.v. methylprednisolone, plasmapheresisand levetiracetam.The headaches persisted leading us to reconsider thediagnosis. A careful awareness of the characteristics ofheadaches and the neuro-angiographic findings led usto advocate the hypothesis of RCVS; cyclophosphamidewas suspected to contribute to the cerebralvasoconstriction.We then changed our strategy: i.v. nimodipine, discon-tinuation of plasmapheresis and replacement of cyclo-phosphamide by mycophenolate mofetil (3 g/day). TheFIG. 1 Cerebral MRA findings. MRA showing multifocal segmental stenosis of cerebral arteries (A). Control MRA done40 days later showing resolution of the cerebral arterial vasoconstriction (B). Arrows refer to the multifocal arterialstenoses (A) that have almost completely regressed (B).www.rheumatology.oxfordjournals.org 1993Letters to the Editor

Possible role of anti-TNF monoclonal antibodies in the treatment of Mycobacterium marinum infection

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library