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ARD Online First, published on May 2, 2014 as 10.1136/annrheumdis-2014-205455

Letter

Coxiella burnetii infection (Q fever) in rheumatoid arthritis patients with and without anti-TNFα therapy Q fever is a zoonosis caused by the intracellular bacterium Coxiella burnetii. The Netherlands experienced a major Q fever outbreak between 2007 and 2010, with an estimate of more than 40 000 infected individuals.1 Initial infection is asymptomatic in over 50% of the infected individuals or causes a mostly self-limiting febrile disease.2 However, chronic Q fever may develop months to years after initial infection. This serious, lifethreatening condition presents mostly as endocarditis or infection of an aortic aneurysm or vascular prosthesis, and is accompanied by high IgG antibody titres against phase I C burnetii.3 Individuals most at risk for chronic Q fever are those with preexisting valvulopathy, vascular aneurysm or prosthesis and yet undefined types of immune suppression.4 5 Tumour necrosis

factor-α (TNFα) plays an important role in the defence against intracellular bacteria such as C burnetii. In vitro studies show that TNFα is involved in internalisation and intracellular killing of C burnetii in monocytes.6 7 In addition, C burnetii-infected TNFα knockout mice develop early bacteraemia and severe heart lesions.8 In view of the pivotal role of TNFα in the defence against C burnetii, we questioned whether anti-TNFα therapy, used as treatment for rheumatoid arthritis (RA), increases the risk for C burnetii infection or chronic Q fever. To this end, we examined the seroprevalence of C burnetii infection in patients with RA living in the Q fever epidemic area9 after the outbreak. Patients on anti-TNFα therapy (adalimumab, etanercept or infliximab) for at least 3 months during the preceding outbreak (1 January 2007–1 January 2010) were selected using patients’ records and hospital databases. Accordingly, anti-TNFα naive patients with RA were selected who had used non-biological disease modifying antirheumatic drugs (DMARDs) for at least 3 months during the Q fever outbreak,

Table 1 Baseline characteristics of all included patients

Mean age±SD† Male sex Valvulopathy/prosthetic valve Vascular aneurysm or prosthesis Ischaemic heart disease Peripheral vascular disease Cerebral vascular disease Dyslipidaemia Hypertension Diabetes mellitus (DM)‡ Pregnancy (between 2007 and 2010)§ Malignancy¶ Renal insufficiency** Use of TNFα blocker during epidemic†† Use of etanercept during epidemic Use of adalimumab during epidemic Use of infliximab during epidemic Months of TNFα blocker use (mean±SD)‡‡ Use of DMARD§§ during epidemic Use of methotrexate during epidemic Months of DMARD use (mean±SD) Use of corticosteroids during epidemic Months of corticosteroid use (mean±SD) Use of DMARD or/and corticosteroids during epidemic Use of other biological during epidemic Current use of TNFα blocker Current use of DMARD Current use of corticosteroids Current use of other biological¶¶

Anti-TNFα group n=361 (%)

Anti-TNFα naive group n=398 (%)

p Value*

59.9 (±11.0) 109 (30.2) 14 (3.9) 4 (1.1) 43 (11.9) 7 (1.9) 17 (4.7) 65 (18.0) 110 (30.5) 27 (7.5) 5 (1.4) 8 (2.2) 19 (5.3) 361 (100) 194 (53.7) 148 (40.9) 70 (19.4) 26.0 (±11.6) 283 (78.4) 225 (62.3) 24.4 (±15.2) 103 (28.5) 7.3 (±13.2) 307 (85.0) 29 (8.0) 256 (70.9) 248 (68.7) 81 (22.4) 61 (16.9)

62.1 (±12.2) 128 (32.2) 19 (4.8) 8 (2.0) 53 (13.3) 15 (3.8) 25 (6.3) 86 (21.6) 139 (35.0) 45 (11.3) 3 (0.8) 14 (3.5) 26 (6.5) – – – – – 398 (100.0) 297 (74.6) 30.7 (±9.5) 63 (15.8) 3.2 (±9.1) 398 (100.0) – – 366 (92.0) 40 (10.1) –

0.01 0.58 0.60 0.39 0.59 0.19 0.43 0.24 0.22 0.08 0.49 0.39 0.54 NA NA NA NA NA NA NA NA 0.000 0.000 NA NA NA NA 0.000 NA

*Mean values were compared using independent samples t test. Proportions were compared using Fisher’s exact test. †Age as on 1 November 2011. ‡DM is defined as type 1 or 2. §Pregnant patients did not receive anti-TNF treatment during pregnancy. ¶Patients with a malignancy diagnosed after 1 January 2007; patients who were treated after 1 January 2007 for malignancy or with metastatic disease. Basocellular carcinoma is not included because of diminutive clinical impact. There were no patients with haematological malignancies included in this study. **Renal insufficiency is defined as a glomerular filtration rate (GFR) 1 year during epidemic Months of TNFα blocker use (mean±SD)§ Current use of corticosteroids Corticosteroids during epidemic Corticosteroid use >1 year during epidemic Months of corticosteroid use (mean±SD) Current use of DMARD¶ DMARD during epidemic Methotrexate during epidemic DMARD use >1 year during epidemic Methotrexate use >1 year Months of DMARD use (mean±SD) Months of methotrexate use (mean±SD) Current use of other biologicals** Other biologicals during epidemic

Chronic Q fever infection n=10 (%)

Past Q fever infection n=102 (%)

p Value*

66.3±8.5 6 (60) 3 (30) 4 (40) 7 (70) 5 (50) 16.6 (±15.7) 3 (30) 6 (60) 4 (40) 15.8 (±17.6) 8 (80) 8 (80) 6 (60) 8 (80) 6 (60) 27.5 (±15.1) 20.3 (±17.9) 1 (10) 0 (0)

58.3±10.6 47 (46.1) 7 (6.9) 40 (39.2) 50 (49.0) 41 (40.2) 12.5 (±15.1) 13 (12.7) 23 (22.5) 15 (14.7) 4.3 (±9.9) 87 (85.3) 95 (93.1) 75 (73.5) 84 (82.4) 67 (65.7) 27.5 (±12.3) 21.6 (±15.7) 5 (4.9) 5 (4.9)

0.02 0.51 0.05 1.00 0.32 0.74 0.41 0.15 0.02 0.06 0.002 0.65 0.18 0.46 1.00 0.74 0.99 0.81 0.44 1.00

*Mean values were compared using independent samples t test. Proportions were compared using Fisher’s exact test. †Known risk factors for progression to chronic Q fever infection. ‡Epidemic is defined as the outbreak between 1 January 2007 and 1 January 2010 in the Netherlands. §During epidemic as defined; maximum of 36 months. ¶Use of DMARD: including azathioprine, ciclosporine, gold derivates, hydroxychloroquine, leflunomide, methotrexate or sulfasalazine; not including use of corticosteroids. **Other biologicals were golimumab, certolizumab, abatacept, anakinra, rituximab and tocilizumab. DMARD, disease modifying antirheumatic drug; RA, rheumatoid arthritis; TNFα, tumour necrosis factor-α.

but no anti-TNF or other biological DMARDs during this time frame or thereafter. The study was approved by the local medical ethics committee. Medication details and medical history from participating patients with RA (response rate 759/1319 (61.6%)) were retrieved from patients’ records and additional information was collected in a questionnaire (table 1). Blood samples for microbiological screening were obtained between December 2011 and June 2012. Patients with IgG antiphase I and/or II C burnetii titres ≥1:32, indicating previous C burnetii infection, were defined as seropositives. Seropositive individuals with suspected chronic Q fever underwent further medical assessment. Diagnosis of proven or probable chronic Q fever was based on the Dutch consensus on chronic Q fever diagnostics.10 Proportions were compared using Fisher’s exact test. We found that 57/361 (15.8%) patients on anti-TNFα therapy were seropositive, compared with 55/398 (13.8%) anti-TNFα naive patients ( p=0.47). Thus, the prevalence of C burnetii infection in patients with RA does not seem to be influenced by the use of TNFα blockers. Of these 112 seropositive patients, 10/112 (8.9%) were diagnosed with chronic Q fever: 7/57 (12.3%) patients on anti-TNFα therapy and 3/55 (5.5%) anti-TNFα naive patients, not significantly different ( p=0.32). With this small number of cases, and consequently limited power, only a large effect (>fourfold) of anti-TNFα therapy on the risk for chronic Q fever could have been detected. Univariate analysis in all seropositive patients suggested that higher age, corticosteroid use, and valvulopathy or aneurysm/ vascular prosthesis was associated with the risk to progress to chronic Q fever (table 2). At baseline, patients on anti-TNFα were significantly older and used corticosteroids significantly more often; both might explain increased prevalence of chronic 2

Q fever in this group. Multivariate analysis could not be performed due to the low number of cases. Of note, the observed prevalence of chronic Q fever in infected patients with RA was considerably higher (8.9%) than previously reported in non-selected infected individuals in the same area (1.6%).11 Our data suggest that RA and its treatment, either with or without anti-TNFα, may be considered as a risk factor for the development of chronic Q fever. Therefore, we advise that in case of C burnetii infection, all patients with RA should be carefully monitored for progression to chronic Q fever. T Schoffelen,1 L M Kampschreur,2 S E van Roeden,2 P C Wever,3 A A den Broeder,4 M H Nabuurs-Franssen,5 T Sprong,5 L A B Joosten,1 P L C M van Riel,6 J J Oosterheert,2 M van Deuren,1 M C W Creemers7 1 Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands 2 Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands 3 Department of Medical Microbiology and Infection Control, Jeroen Bosch Hospital, ’s-Hertogenbosch, The Netherlands 4 Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands 5 Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands 6 Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands 7 Department of Rheumatology, Jeroen Bosch Hospital, ’s-Hertogenbosch, The Netherlands

Correspondence to Teske Schoffelen, Department of Internal Medicine, Radboud University Medical Center, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands; [email protected] Acknowledgements We thank Joke Vriezekolk (Sint Maartenskliniek, Nijmegen) for her assistance in conducting the Q fever screening in the Sint Maartenskliniek. Ann Rheum Dis Month 2014 Vol 0 No 0

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Letter Bea Groezen, Dorien van Gülick and Mary Smolders (Department of Medical Microbiology, Canisius Wilhelmina Hospital, Nijmegen) and gratefully acknowledge the staff of the Medical Microbiology Department of the Jeroen Bosch Hospital for their technical support in performing the serological assays. Contributors All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. TS and LMK had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Funding This investigator-initiated study was supported by grants of Pfizer BV and The Netherlands Organisation for Health Research and Development (grant number 205520002 to TS). Competing interests PLCMvR received speaker honoraria and/or consulting fees from Abbvie, UCB, Pfizer, Roch and MSD. All other authors declare that they have no competing interests.

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Patient consent Obtained. Ethics approval Medical Ethical Committee Arnhem-Nijmegen (CMO regio Arnhem-Nijmegen).

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Provenance and peer review Not commissioned; externally peer reviewed. To cite Schoffelen T, Kampschreur LM, van Roeden SE, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/annrheumdis2014-205455 Received 21 February 2014 Revised 2 April 2014 Accepted 13 April 2014 Ann Rheum Dis 2014;0:1–3. doi:10.1136/annrheumdis-2014-205455

Ann Rheum Dis Month 2014 Vol 0 No 0

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Downloaded from ard.bmj.com on May 19, 2014 - Published by group.bmj.com

Coxiella burnetii infection (Q fever) in rheumatoid arthritis patients with and without anti-TNFα therapy T Schoffelen, L M Kampschreur, S E van Roeden, et al. Ann Rheum Dis published online May 2, 2014

doi: 10.1136/annrheumdis-2014-205455

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Coxiella burnetii infection (Q fever) in rheumatoid arthritis patients with and without anti-TNFα therapy.

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