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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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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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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]