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75% of those have enteropathic spondyloarthritis (5). Concordance for the development of axial SpA is as high as 63% in monozygotic HLA-B27-positive twins, but lower (24%) in dizygotic twin pairs (2). However, HLA-B27 is by no means the only allele involved, as confirmed by our HLA-B27-negative patients. Both twins carried the HLA-A2 allele, which confers susceptibility to axial SpA independently from HLA-B27 (6). Furthermore, genes involved in the IL-23 pathway are shared by patients with SpA and IBD (6). On a similar line, a recent study has shown that although the prevalence of HLA-B27 is higher in familial AS, the frequency of non-MHC risk alleles is not (7). Our cases reinforces the concept that HLA-B27 is not strictly required for the induction of SpA and that other genes may be involved.

2. Höhler T, Hug R, Schneider PM, Krummenauer F, GripenbergLerche C, Granfors K, et al. Ankylosing spondylitis in monozygotic twins: studies on immunological parameters. Ann Rheum Dis 1999;58:435–40. 3. Brown MA, Kennedy LG, MacGregor AJ, Darke C, Duncan E, Shatford JL, et al. Susceptibility to ankylosing spondylitis in twins. Arthritis Rheum 1997;40:1823–8. 4. Weber U, Pfirrmann CWA, Kissling RO, Mackenzie CR, Khan MA. Early spondyloarthritis in an HLA-B27-positive monozygotic twin pair: a highly concordant onset, sites of involvement, and disease course. J Rheumatol 2008;35;1464–6. 5. Khan MA. Update on spondyloarthropathies. Ann Intern Med 2002;136:896–907. 6. Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, Leo P, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 2013;45:730–8. 7. Joishi R, Reveille JD, Brown MA, Weisman MH, Ward MM, Gensler LS, et al. Is there a higher genetic load of susceptibility loci in familial ankylosing spondylitis? Arthritis Care Res 2012;64:780–4.

References

Leonardo Santo, Servizio di Reumatologia ASL BT, DSS 4 Barletta, Piazza Principe Umberto I, n.1, Barletta 76121, Italy. E-mail: [email protected]

1. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984;27:361–8.

Accepted 2 June 2014

Tocilizumab increases EPC regeneration in rheumatoid arthritis S Patschan1, K Nemirovsky1, E Henze1, J Scholze2, GA Müller1, D Patschan1 1

Department of Nephrology and Rheumatology, University Hospital of Göttingen, and 2Outpatient Clinic, Hypertension Excellence Centre, Humboldt-University, Charité, Berlin, Germany

Rheumatoid arthritis (RA) is associated with a significantly higher cardiovascular risk (1, 2) as compared to the general population. This results from the inflammatory activity of the disease itself but is also caused by drugs that are used for controlling the inflammatory process (3–5). Less is known about cardiovascular side-effects of newer, so-called disease-modifying antirheumatic drugs (DMARDs). This is particularly the case with biological agents, such as tumour necrosis factor (TNF)-α inhibitors or the B-cell depleting antibody rituximab. In recent years, several studies on endothelial progenitor cells (EPCs) in RA have been published. Some investigators have analysed EPC regeneration in relation to clinical characteristics, while others have evaluated the impact of anti-rheumatic drugs (glucocorticoids, antiTNF-α) on peripheral EPC numbers (6–8). Nevertheless, no study published so far has compared different RA treatment regimens in the context of EPC regeneration and vascular function. We prospectively analysed EPC numbers/regeneration and vascular stiffness in RA patients undergoing a 6-month treatment regimen with one of the following

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drugs: methotrexate (MTX), anti-TNF-α, tocilizumab, or rituximab. Clinical and laboratory findings were used for further clinical characterization. The results are expressed as mean  standard deviation (SD). Differences between three or more groups were assessed by an analysis of variance (ANOVA). Differences between two groups were analysed by the Mann–Whitney U test. This study included 63 patients with RA (18 males, 45 females). The mean age of the patients was 54  13 years and the mean overall duration of the disease was 10  9 years. In 29 patients, the disease showed low to no activity, 23 patients displayed moderate and 10 patients high activity, according to the Disease Activity Score using 28 joint counts (DAS28). DAS28 was not available in one patient. Seventeen patients were receiving MTX, 15 anti-TNF-α (eight adalimumab and seven etanercept), 14 tocilizumab, and 17 rituximab. Patient characteristics at baseline are summarized in Table 1. Statin therapy was being used in one patient receiving MTX, one receiving anti-TNF-α, and one rituximab. In these three patients, statins were given either because of a significantly increased cardiovascular risk in two patients (anti-

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Table 1. Patients’ characteristics and results from lipid analyses, EPC regeneration, haemodynamic measurements, and ELISAs. MTX 54  15 3.8  3.9 2.8  1.6 0.84  0.14 204  51 205  45 113  42 125  35 71  26 70  24 106  44 109  52 22  12 22  26 7.4  1.8 7.6  1.7 27  11 28  11 3.811  1993 5.431  1.288 3.573  1.750 2.738  1.052 398  248

Age (years) Duration of the disease (years) DAS28 Creatinine (mg/dL) Total cholesterol at start (mg/dL) Total cholesterol at 6 months (mg/dL) LDL at start (mg/dL) LDL at 6 months (mg/dL) HDL at start (mg/dL) HDL at 6 months (mg/dL) Triglycerides at start (mg/dL) Triglycerides at 6 months (mg/dL) CFU-ECs at start CFU-ECs at 6 months PWV (m/s) at start PWV (m/s) at 6 months AIx at start AIx at 6 months Ang-1 at start (pg/mL) Ang-1 at 6 months (pg/mL) Ang-2 at start (pg/mL) Ang-2 at 6 months (pg/mL) VEGF at start (pg/mL)

anti-TNF-α

Tocilizumab

Rituximab

p-value

53  7 12  9.6 3.1  1 0.84  0.13 218  42 222  43 129  25 142  34 71  25 67  23 138  106 115  78 15  10 18  11 7.3  2.3 8.4  2.1 27  12 30  8 4109  1040 5.798  1.538 2.993  1.164 2.696  1.462 360  225

52  9 10.6  7.8 4.6  1.2 0.9  0.19 215  44 233  46 130  35 154  41 54  22 57  20 189  158 189  95 11  11 22  10 8.7  3.6 9.1  3.1 29  11 27  9 3581  1387 3.959  1.233 3.118  1.203 2.915  1.368 419  299

57  14 16.2  10.5 3.7  1.6 0.8  0.18 237  35 237  44 146  30 151  33 77  26 71  25 142  68 130  66 14  8 13  8 9  3.1 9.6  2.9 32  12 29  10 3631  1182 4.125  1.190 4.333  1.994 3.306  1.187 464  490

0.69 0.0008 0.005 0.42 0.22 0.35 0.03 0.22 0.1 0.5 0.14 0.11 0.3 0.17 0.58 0.87 0.8 0.006 0.2 0.7 0.9

LDL, Low density lipoprotein; HDL, high density lipoprotein; CFU-ECs, endothelial cell colony-forming units; PWV, pulse wave velocity; AIx, augmentation index; Ang-2, Angiopoietin-2; VEGF, vascular endothelial growth factor. Values given as mean  SD. The mean age did not differ between the groups. Duration of the disease was significantly longer in patients treated with either antiTNF-α or rituximab compared to those receiving MTX. Patients treated with MTX showed the lowest disease activity while those receiving tocilizumab displayed the highest activity (p ¼ 0.005). p-values in bold are significant.

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Variable

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Figure 1. Endothelial progenitor cell (EPC) regeneration in rheumatoid arthritis (RA). The chart shows colonies per 10 view fields at the beginning of the study (start) and at month 6 after inclusion (6 m). (A) While patients receiving either methotrexate (MTX), anti-tumour necrosis factor (TNF)-α, or rituximab (RTX) did not show differences in the numbers of EPC colonies, those treated with tocilizumab (Toci) displayed higher colony numbers, reflecting increased EPC proliferation. (B–E) EPC regeneration reflected by the numbers of colonies formed in culture (CFU-ECs) in relation to the disease activity at 0 and 6 months. While EPC regeneration increased in Toci-treated patients, colony numbers remained stable in all other treatment groups. The DAS28 did not change in any of the four groups over time. (F) Colony formation in responders vs. non-responders. The differences were not statistically significant (data as mean  SEM, *p < 0.05).

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530

TNF-α and rituximab) or for hypercholesterolaemia (MTX). Three tocilizumab-treated patients were receiving statins on a regular basis. Treatment with MTX, antiTNF-α, or rituximab neither increased nor decreased EPC regeneration as reflected by the numbers of colonies appearing in culture after 5–7 days. By contrast, EPC regeneration was significantly increased in patients receiving tocilizumab [at start: 11  11 endothelial cell colony-forming units (CFU-ECs); at 6 months: 22  10 CFU-ECs, p ¼ 0.03] (Table 1 and Figure 1). Additional analysis did not show any significant changes in the DAS28 over the time course of 6 months in any of the four groups. Figure 1 shows EPC regeneration (number of CFU-ECs) in relation to the disease activity as reflected by DAS28. Finally, colony formation was evaluated in responders vs. non-responders. Response to treatment was defined as a 20-fold decrease in the DAS28 after 6 months. The differences were not statistically significant between the two groups (Figure 1). Pulse wave velocity (PWV) did not differ between the four groups at the start or at month 6. In addition, individual treatments did not result in increases and/or decreases of PWV (Table 1). Our particular interest in analysing the EPC system and vascular stiffness in RA was based on the fact that RA patients suffer from a higher-than-average cardiovascular risk. This problem has been extensively documented and discussed in the past (1, 2). Mechanisms involved in increasing the risk for cardiovascular events include, on the one hand, deleterious actions of drugs used for anti-inflammatory treatment and, on the other, the inflammatory activity of the disease itself (5, 9, 10). In recent years, the armamentarium of substances with disease-modifying activity has been expanded considerably. Thus, it has become of increasing interest to determine in which way such therapies also reduce cardiovascular risk in RA. By interfering with the interleukin (IL)-6 pathway, tocilizumab could serve as a potent antiatherosclerotic drug in the future. A recent study has suggested that IL-6 receptor signalling plays a causal role in coronary artery disease (11). Our data additionally suggest that the substance activates endogenous vascular repair mechanisms in an IL-6-independent manner. A

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Letters

limitation of the current study is the relatively low number of patients treated with tocilizumab. Acknowledgements This study was supported by the Heidenreich-von-Siebold programme.

References 1. Gkaliagkousi E, Gavriilaki E, Doumas M, Petidis K, Aslanidis S, Stella D. Cardiovascular risk in rheumatoid arthritis: pathogenesis, diagnosis, and management. J Clin Rheumatol 2012;18:422–30. 2. John H, Kitas G. Inflammatory arthritis as a novel risk factor for cardiovascular disease. Eur J Intern Med 2012;23:575–9. 3. Charles-Schoeman C. Cardiovascular disease and rheumatoid arthritis: an update. Curr Rheumatol Rep 2012;14:455–62. 4. Ng MK, Celermajer DS. Glucocorticoid treatment and cardiovascular disease. Heart 2004;90:829–30. 5. Strohmayer EA, Krakoff LR. Glucocorticoids and cardiovascular risk factors. Endocrinol Metab Clin North Am 2011;40:409–17, ix. 6. Ablin JN, Boguslavski V, Aloush V, Elkayam O, Paran D, Caspi D, et al. Effect of anti-TNFalpha treatment on circulating endothelial progenitor cells (EPCs) in rheumatoid arthritis. Life Sci 2006; 79:2364–9. 7. Grisar J, Aletaha D, Steiner CW, Kapral T, Steiner S, Saemann M, et al. Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy. Ann Rheum Dis 2007;66:1284–8. 8. Rodriguez-Carrio J, Prado C, de Paz B, Lopez P, Gomez J, AlperiLopez M, et al. Circulating endothelial cells and their progenitors in systemic lupus erythematosus and early rheumatoid arthritis patients. Rheumatology (Oxford) 2012;51:1775–84. 9. Boyer JF, Cantagrel A, Constantin A. Impact of traditional therapies and biologics on cardiovascular diseases in rheumatoid arthritis. Curr Vasc Pharmacol 2008;6:218–27. 10. Pimenta E, Wolley M, Stowasser M. Adverse cardiovascular outcomes of corticosteroid excess. Endocrinology 2012;153: 5137–42. 11. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Hingorani AD, Casas JP. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 2012;379:1214–42.

Daniel Patschan, Department of Nephrology and Rheumatology, University Medical Centre of Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany. E-mail: [email protected]

Tocilizumab increases EPC regeneration in rheumatoid arthritis.

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