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Letters Table 1 Characteristics of the study populations (TNFi-naïve rheumatoid arthritis (RA), TNFi-exposed RA and general population comparators) at start of follow-up, and characteristics of amyotrophic lateral sclerosis (ALS) cases observed in each population

No association between rheumatoid arthritis, amyotrophic lateral sclerosis, and tumour necrosis factor inhibitor treatment The aetiology of amyotrophic lateral sclerosis (ALS) is poorly understood, and it is unclear if autoimmunity plays a role or if ALS is associated with inflammatory/autoimmune diseases such as rheumatoid arthritis (RA). There have been very few reports of patients with RA who develop ALS, and no epidemiological study examining the co-occurrence of the two diseases has been conducted.1–6 In December 2012, a cluster of ALS cases following treatment with tumour necrosis factor inhibitor (TNFi) was reported using data from the European system for reporting suspected adverse drug reactions, the EudraVigilance database.7 We sought to estimate the ALS rate in RA exposed and unexposed to TNFi using a nationwide, prospective, population-based cohort study design. We used Swedish national registers to identify patients with RA (National Patient Register inpatient care 1969–2011 and outpatient care 2001–2011 and the Swedish Rheumatology Quality Register 1996–2011) and TNFi exposures (Swedish Biologics Register ARTIS 1999–2011). General population comparators were selected from the total population register matched on age, sex, county and date of the matched diagnosis of patients with RA (matching date). ALS diagnosis was defined as ≥2 International Classification of Diseases (ICD) codes for ALS (ICD-8 348.0, ICD-9 335.2, ICD-10 G12.2) listed in the national patient register or cause of death register, and linked to the study populations using each individual’s unique personal identification number. For the TNFi-naïve RA and general populations, follow-up began on the date of RA diagnosis ( patients with RA), matching date (general population) or 1 January 2001 (start of outpatient register), whichever came later. End of follow-up was date of biological initiation, ALS diagnosis, emigration, death or 31 December 2011, whichever came first. For TNFi-exposed RA, follow-up began at TNFi initiation until date of ALS diagnosis, emigration, death or 31 December 2011. Characteristics of each study population are described in table 1. Each population had a similar proportion of people with a first degree relative with ALS (0.2–0.3%). We observed 23 ALS cases in the RA population (incidence rate (IR) 7.8 per 100 000; 95% CI 5.0 to 11.8). Eighteen were TNFi-naïve and five were TNFi-exposed. The age-standardised and sexstandardised IR (using the overall RA population as the standard) for TNFi-naïve RA and TNFi-exposed RA was 7.1 (95% CI 4.2 to 11.5) and 7.8 (95% CI 2.5 to 41.1), respectively. Ann Rheum Dis November 2014 Vol 73 No 11

Female, N (%) Born in a Nordic country, N (%) Age at start of follow-up, mean years (SD) First degree relative with ALS, N (%) No. of ALS Cases* Age at ALS diagnosis, mean years (SD) Time from start of study to ALS diagnosis, mean years (SD) Prescription for riluzole†, N (%)

General population N=180 517

TNFi-naïve RA N=38 754

TNFi-exposed RA N=12 299

129 473 (72) 168 548 (93) 62.5 (13.9)

27 672 (71) 36 925 (95) 62.8 (14.0)

9312 (76) 11 233 (91) 55.7 (13.2)

333 (0.2)

78 (0.2)

32 (0.3)

116 73 (9)

18 75 (8)

5 66 (8)

4.5 (3.0)

4.9 (2.9)

4.5 (4.0)

62 (53)

9 (53)

2 (40)

The general population was matched to the RA population by year of birth, sex and county. *Defined as at least 2 ICD codes for ALS listed in one of the following sources: inpatient register, outpatient register or cause of death register. 139 (86%) cases had at least 1 inpatient visit, 130 (80%) cases had at least 1 outpatient visit and 93 (57%) had ALS listed as cause of death. 13 (8%) cases were identified with only 1 inpatient or outpatient visit and ALS as cause of death. †Prescription data were only available for dispensings between 2005 and 2012. TNFi, tumour necrosis factor inhibitor.

The corresponding IR in the general population was 8.6 (95% CI 7.1 to 10.3) (table 2). Previous studies have shown using ICD discharge diagnoses for ALS is reasonably accurate,8 9 but some ALS cases may have been misclassified. In a sensitivity analysis, the use of a more strict definition of ALS (requiring diagnoses to be listed in internal medicine or neurology departments) resulted in similar IRs, demonstrating that our results were not sensitive to the ALS definition used. We adjusted for age and sex, but information was unavailable for other potential confounders such as smoking. Confounding due to smoking would drive the observed rates higher in the RA population compared with the general population than the true rates, which was not observed.

Table 2 Crude and age-standardised and sex-standardised incidence rates of amyotrophic lateral sclerosis (ALS) in general population comparators, TNFi-naïve and TNFi-exposed individuals with rheumatoid arthritis (RA) Study population General population RA population (TNFi-naïve and TNFi-exposed) TNFi-naive RA TNFi-exposed RA

ALS cases*

Person-years

SIR† (95% CI) per 100 000py

116 23

1 311 104 293 220

8.6 (7.1 to 10.3) 7.8 (5.0 to 11.8)

18 5

237 284 70 037

7.1 (4.2 to 11.5) 7.8 (2.5 to 41.2)

*Defined as at least 2 ICD codes for ALS listed in one of the following sources: inpatient register, outpatient register or cause of death register. 139 (86%) cases had at least 1 inpatient visit, 130 (80%) cases had at least 1 outpatient visit and 93 (57%) had ALS listed as cause of death. 13 (8%) cases were identified with only 1 inpatient or outpatient visit and ALS as cause of death. †Incidence rate standardised to the age and sex distribution in the overall RA population. SIR, standardised incidence rate; TNFi, tumour necrosis factor inhibitor.

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Letters The rate of ALS in the RA population was similar to the rate in a general population comparator sample taking age and sex into account. The rate was also similar to a national estimate among individuals with the same age distribution (60–80 years old: 6–8 per 100 000).10 No increased rate of ALS was seen in TNFi-exposed patients with RA, although the wide CIs should be taken into consideration. Our findings indicate that ALS and RA are likely separate entities with only modest, if any, aetiological overlap. Whether treatment with TNFi modifies the presentation or clinical course of ALS once it has occurred remains unknown. Elizabeth V Arkema,1 Nils Feltelius,2,3 Tomas Olsson,4 Johan Askling,1,2 on behalf of the ARTIS study group 1

Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden 3 Medical Products Agency, Uppsala, Sweden 4 Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

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Dziadzio M, Reddy V, Rahman S, et al. Is TNFalpha really a good therapeutic target in motoneuronal degeneration? A case of amyotrophic lateral sclerosis in a patient with RA receiving infliximab. Rheumatology 2006;45:1445–6. Padovan M, Caniatti LM, Trotta F, et al. Concomitant rheumatoid arthritis and amyotrophic lateral sclerosis: report of two new cases and review of literature. Rheumatol Int 2011;31:715–19. Borjesson A, Grundmark B, Olaisson H, et al. Is there a link between amyotrophic lateral sclerosis and treatment with TNF-alpha inhibitors? Ups J Med Sci 2013;118:199–200. Pisa FE, Verriello L, Deroma L, et al. The accuracy of discharge diagnosis coding for Amyotrophic Lateral Sclerosis in a large teaching hospital. Eur J Epidemiol 2009;24:635–40. St Germaine-Smith C, Metcalfe A, Pringsheim T, et al. Recommendations for optimal ICD codes to study neurologic conditions: a systematic review. Neurology 2012;79:1049–55. Fang F, Valdimarsdottir U, Bellocco R, et al. Amyotrophic lateral sclerosis in Sweden, 1991–2005. Arch Neurol 2009;66:515–19.

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Correspondence to Dr Elizabeth V Arkema, Clinical Epidemiology Unit, Department of Medicine, T2, Karolinska Institutet, Stockholm 17176, Sweden; [email protected] Collaborators The ARTIS Study Group: JA, NF, Eva Baecklund, Helena Forsblad, Pierre Geborek, Lennart Jacobsson, Alf Kastbom, Lars Klarskog, Lars-Erik Kristensen, Staffan Lindblad, Solbritt Rantapää-Dahlqvist, Ronald van Vollenhoven. Contributors All authors contributed to the study’s conception and design. EVA performed the analysis and drafted the manuscript. All authors provided critical revision and final approval. The views presented are those of the authors and do not represent an official position of the Medical Products Agency to which one of the authors (NF) is affiliated. Funding The ARTIS Study Group conducts scientific analyses using data from the Swedish biologics register (ARTIS) run by the Swedish Society for Rheumatology. For this register, the Swedish Society for Rheumatology has received funding, independent of the conduct of these scientific analyses, from Merck, BMS, Pfizer, Abbott Laboratories, SOBI, UCB and Roche. These entities were allowed to comment on the findings before submission, although all final decisions resided with the investigators. This specific study further received funding from the Swedish Medical Research Council, the Swedish Foundation for Strategic Research, and from the Swedish public-private COMBINE research consortium. These entities had no influence on the data collection, statistical analyses, manuscript preparation, or decision to submit. Competing interests None. Ethics approval Obtained from Karolinska Institutet. Provenance and peer review Not commissioned; externally peer reviewed.

To cite Arkema EV, Feltelius N, Olsson T, et al. Ann Rheum Dis 2014;73:2061– 2062. Received 25 March 2014 Revised 24 June 2014 Accepted 20 July 2014 Published Online First 5 August 2014 Ann Rheum Dis 2014;73:2061–2062. doi:10.1136/annrheumdis-2014-205622

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Ghatak NR, Hirano A, Zimmerman HM. Rheumatoid arthritis with arteritis and neuropathy masking amyotrophic lateral sclerosis. Rinsho Shinkeigaku 1972;12:401–10. Kohler W. [Amyotrophic lateral sclerosis following polyarthritis]. Dtsch Med Wochenschr 1950;75:1070–2. Schady W, Metcalfe RA, Holt PJ. Rheumatoid arthritis and motor neurone disease— an association? Br J Rheumatol 1989;28:70–3. M’Bappe P, Moguilevski A, Arnal C, et al. Concomitant rheumatoid arthritis and amyotrophic lateral sclerosis. A puzzle illustrated by a new case. Joint Bone Spine 2000;67:242–4.

Ann Rheum Dis November 2014 Vol 73 No 11

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No association between rheumatoid arthritis, amyotrophic lateral sclerosis, and tumour necrosis factor inhibitor treatment Elizabeth V Arkema, Nils Feltelius, Tomas Olsson and Johan Askling Ann Rheum Dis 2014 73: 2061-2062 originally published online August 5, 2014

doi: 10.1136/annrheumdis-2014-205622 Updated information and services can be found at: http://ard.bmj.com/content/73/11/2061

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No association between rheumatoid arthritis, amyotrophic lateral sclerosis, and tumour necrosis factor inhibitor treatment.

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