Letters to the Editor / Joint Bone Spine 82 (2015) 66–73 Table 1 Clinical characteristics and comparison of patient and control group serum IMA, TAS, MDA, TOS and OSI levels. BD (n = 35) mean ± SD
Control (n = 31) mean ± SD
P
Age (years)
38.1 ± 10.2
37.6 ± 8.6
0.926
IMA
0.63 ± 0.25
0.42 ± 0.12
0.0001
MDA (nmol/dL)
0.31 ± 0.18
0.14 ± 0.12
0.0001
TAS (mol TroloxEq/L)
1.31 ± 0.56
1.86 ± 1.03
0.002
TOS (mol TroloxEq/L)
28.20 ± 22.54
6.17 ± 1.55
0.0001
2.52 ± 1.99
0.37 ± 0.15
0.0001
OSI
BD: Behc¸et’s disease; IMA: ischemia-modified albumin; TAS: total antioxidative status; TOS: total oxidative status; OSI: oxidative stress index; SD: standard deviation; MDA: malondialdehyde.
Table 2 Oxidative status in patients with and without vascular involvement. Vascular involvement Positive (n = 11)
Negative (n = 24)
P value
IMA (ABSU)
0.78 ± 0.37
0.56 ± 0.14
0.016
MDA (nmol/dL)
0.33 ± 0.22
0.29 ± 0.16
0.072
TAS (mol TroloxEq/L)
1.18 ± 0.52
1.58 ± 0.57
0.072
TOS (mol TroloxEq/L)
28.6 ± 21.4
28 ± 23.4
0.070
OSI
2.05 ± 1.56
2.7 ± 2.08
0.283
ESR (mm/st)
39.8 ± 17.8
28.6 ± 17.8
0.046
CRP (ng/dL)
1.3 ± 1.1
0.7 ± 0.6
0.178
References [1] Hatemi G, Yazici Y, Yazici H. Behc¸et’s syndrome. Rheum Dis Clin North Am 2013;39:245–61. [2] Taysi S, Gul M, Sari RA, et al. Serum oxidant/antioxidant status in serum of patients with systemic lupus erythematosus. Clin Chem Lab Med 2002;40:684–8. [3] Karkucak M, Capkin E, Alver A, et al. The effect of anti-TNF agent on oxidation status in patients with ankylosing spondylitis. Clin Rheum 2010;29:303–7. [4] Taysi S, Kocer I, Memisogullari R, et al. Serum oxidant/antioxidant status in patients with Behc¸et’s disease. Ann Clin Lab Sci 2002;32:377–82. [5] Collinson PO, Gaze DC. Ischaemia-modified albumin: clinical utility and pitfalls in measurement. J Clin Pathol 2008;61:1025–8. [6] Mentese A, Mentese U, Turedi S, et al. Effect of deep vein thrombosis on ischaemia-modified albumin levels. Emerg Med J 2008;25:81–4. [7] Turk A, Nuhoglu I, Mentese A, et al. The relationship between diabetic retinopathy and serum levels of ischemia-modified albumin and malondialdehyde. Retina 2011;31:602–8. [8] Ozsu S, Gulsoy A, Karahan SC, et al. Diagnostic value of pleural effusion ischaemia-modified albumin in patients with cardiac failure. Ann Clin Biochem 2011;48:45–50. [9] Niwa Y, Miyake S, Sakane T, et al. Auto-oxidative damage in Behc¸et’s disease endothelial cell damage following the elevated oxygen radicals generated by stimulated neutrophils. Clin Exp Immunol 1982;49:247–55. [10] Chambers JC, Haskard DO, Kooner JS. Vascular endothelial function and oxidative stress mechanisms in patients with Behc¸et’s syndrome. J Am Coll Cardiol 2001;37:517–20.
Erhan Capkin a,∗ Murat Karkucak a Mehmet Kola b Adem Karaca a Arzu Aydin Capkin d Suleyman Caner Karahan c a Department of PM&R and Rheumatology, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey b Department of Eyes disease, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey c Department of Medical Biochemistry, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey d Department of Dermatology, Fatih state hospital, Trabzon, Turkey
IMA: ischemia-modified albumin; TAS: total antioxidative status; TOS: total oxidative status; OSI: oxidative stress index; MDA: malondialdehyde; ESR: erythrocyte sedimentation rate; CRP: c-reactive protein.
oxidative stress (higher serum MDA, TOS and OSI) and decreased antioxidant capacity (lower TAS level) in patients with BD. We determined significantly higher serum IMA levels compared to those in the control group. Studies have demonstrated that many conditions may elevate IMA levels, including ischemia and deep vein thrombosis [6–8]. To the best of our knowledge, this study is the first to analyze the relationship between serum IMA levels and BD. Vascular involvement is common in BD patients. Endothelial dysfunction is mediated by increased oxidative stress. Oxidative stress is a key factor in vascular injury [9,10]. Although the number of patients with vascular involvement was lower than that of patients without, IMA levels were statistically significantly higher in patients with vascular involvement. The limitation to this study is the low patient numbers involved, and that the type of vascular involvement was not determined. Our results demonstrate increased oxidative stress and decreased antioxidant capacity in patients with BD. IMA is an important marker of oxidative stress in BD patients and can be used as a significant tool in distinguishing vascular involvement in particular. Further clinical studies are now required to evaluate this issue. Disclosure of interest
69
∗ Corresponding
author. Tel.: +90 46 23 77 10 93/90 50 52 34 42 58. E-mail address: [email protected] (E. Capkin) Accepted 16 June 2014 Available online 30 July 2014 http://dx.doi.org/10.1016/j.jbspin.2014.06.007
Toxidermia under treatment with tocilizumab for rheumatoid arthritis
a r t i c l e
i n f o
Keywords: Tocilizumab Rheumatoid arthritis Biotherapy Anti-IL6 Cutaneous eruption Toxidermia
The authors declare that they have no conflicts of interest concerning this article.
1. Introduction
Ethical approval: the study approved by Karadeniz Technical University ethics committee, ethics number: 2009/56.
The development of TNF inhibitors represents a major advancement in the treatment of rheumatoid arthritis (RA). TNF inhibitors
70
Letters to the Editor / Joint Bone Spine 82 (2015) 66–73
the production of antibodies to TCZ may predispose to hypersensitivity reactions [7]. This dosage was not made in our case. With TCZ, Izquierdo et al. reported a case of acute generalized exanthematous pustulosis. Lesions began two weeks after the first infusion and decreased with oral and topic steroid. TCZ was not stopped [8]. A second case of cutaneous toxidermia was described for a 57-year-old woman with a RA associated with a secondary Sjogren’s syndrome. After the first infusion of TCZ, she complained of a lichenoid toxidermia that resolved with topic treatment [9]. 4. Conclusion We here reported a case of toxidermia after treatment with TCZ for RA. To our knowledge, this is the third case described. This side effect seems to appear rarely and without any fatal consequence. Further case reports should be necessary to confirm their low side effect impact. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References
Fig. 1. Cutaneous lesions after infusion of tocilizumab.
may have potential side effects. Here, we are reporting a case of a cutaneous eruption in a patient treated with tocilizumab (TCZ). 2. Clinical vignette A 34-year-old woman with a RA (anti-CCP and rheumatoid factor positives) diagnosed in 1999 was treated with TCZ. TCZ monotherapy (8 mg/kg) was introduced after failure of several TNF inhibitors. Clinical remission was fastly obtained and she was then treated during twenty-six months. Three days after the last two monthly intravenous infusions, the patient noticed a vesiculopustular erythematous rash on the same side of the infusion arm, without any fever or other symptoms (Fig. 1). Lesions decreased without any treatment in ten days. Her initial laboratory results showed normal levels of leukocytes (11,300/mm3 ), neutrophils (8927/mm3 ), eosinophils and normal liver function tests. Cutaneous biospy was not realized since the patient had been seen after the decrease of the cutaneous lesions. Hepatitis, HIV, Epstein Barr, cytomegalovirus, Parvovirus B19 tests were negatives. After a drug safety analysis and despite a lack of reference, this eruption was correlated with TCZ. 3. Discussion In case of inadequate response or contraindication to conventional synthetic disease-modifying antirheumatic drugs, TCZ is a possibility and may be used in monotherapy [1]. The rate of infusions reactions reported varies between 10 to 50%. Haematoma, red benign lesions are described near the infusion site. Studies reported clinically significant hypersensitivity reactions as anaphylaxia at the ninth week or at the second or third infusion [2,3]. Other symptoms included rash, urticaria, itching or dermatitis [4,5]. The rate of anaphylactic reaction in pooled results from five phase III trials was 0.1/100 patients-years in patient randomised and treated with TCZ 8 mg/kg [6]. Some studies seem to show that
[1] Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological diseasemodifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492– 509. [2] Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008;371: 987–97. [3] Kremer JM, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebocontrolled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum 2011;63:609–21. [4] Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008;58:2968–80. [5] Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010;69:88–96. [6] Schiff MH, Kremer JM, Jahreis A, et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther 2011;13:R141. [7] Jones G, Ding C. Tocilizumab: a review of its safety and efficacy in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord 2010;3: 81–9. [8] Izquierdo JH, Bonilla-Abadia F, Ochoa CD, et al. Acute generalized exanthematous pustulosis due to tocilizumab in a rheumatoid arthritis patient. Case Rep Rheumatol 2012;2012:517424. [9] Latourte A, Viguier M, Dallot A, et al. Un cas de toxidermie lichenoïde survenue sous tocilizumab dans le traitement de la polyarthrite rhumatoïde. Rev Rhum 2012;79:A13–352.
Marie Fechtenbaum ∗ Christopher Banse Pauline Boyard-Lasselin Vincent Goëb Service de Rhumatologie, EA 4666, CHU d’Amiens, Université de Picardie-Jules-Verne, 80054 Amiens, France ∗ Corresponding author. E-mail address: [email protected] (M. Fechtenbaum)
Accepted 13 June 2014 Available online 19 July 2014 http://dx.doi.org/10.1016/j.jbspin.2014.06.006
Control (n = 31) mean ± SD
P
Age (years)
38.1 ± 10.2
37.6 ± 8.6
0.926
IMA
0.63 ± 0.25
0.42 ± 0.12
0.0001
MDA (nmol/dL)
0.31 ± 0.18
0.14 ± 0.12
0.0001
TAS (mol TroloxEq/L)
1.31 ± 0.56
1.86 ± 1.03
0.002
TOS (mol TroloxEq/L)
28.20 ± 22.54
6.17 ± 1.55
0.0001
2.52 ± 1.99
0.37 ± 0.15
0.0001
OSI
BD: Behc¸et’s disease; IMA: ischemia-modified albumin; TAS: total antioxidative status; TOS: total oxidative status; OSI: oxidative stress index; SD: standard deviation; MDA: malondialdehyde.
Table 2 Oxidative status in patients with and without vascular involvement. Vascular involvement Positive (n = 11)
Negative (n = 24)
P value
IMA (ABSU)
0.78 ± 0.37
0.56 ± 0.14
0.016
MDA (nmol/dL)
0.33 ± 0.22
0.29 ± 0.16
0.072
TAS (mol TroloxEq/L)
1.18 ± 0.52
1.58 ± 0.57
0.072
TOS (mol TroloxEq/L)
28.6 ± 21.4
28 ± 23.4
0.070
OSI
2.05 ± 1.56
2.7 ± 2.08
0.283
ESR (mm/st)
39.8 ± 17.8
28.6 ± 17.8
0.046
CRP (ng/dL)
1.3 ± 1.1
0.7 ± 0.6
0.178
References [1] Hatemi G, Yazici Y, Yazici H. Behc¸et’s syndrome. Rheum Dis Clin North Am 2013;39:245–61. [2] Taysi S, Gul M, Sari RA, et al. Serum oxidant/antioxidant status in serum of patients with systemic lupus erythematosus. Clin Chem Lab Med 2002;40:684–8. [3] Karkucak M, Capkin E, Alver A, et al. The effect of anti-TNF agent on oxidation status in patients with ankylosing spondylitis. Clin Rheum 2010;29:303–7. [4] Taysi S, Kocer I, Memisogullari R, et al. Serum oxidant/antioxidant status in patients with Behc¸et’s disease. Ann Clin Lab Sci 2002;32:377–82. [5] Collinson PO, Gaze DC. Ischaemia-modified albumin: clinical utility and pitfalls in measurement. J Clin Pathol 2008;61:1025–8. [6] Mentese A, Mentese U, Turedi S, et al. Effect of deep vein thrombosis on ischaemia-modified albumin levels. Emerg Med J 2008;25:81–4. [7] Turk A, Nuhoglu I, Mentese A, et al. The relationship between diabetic retinopathy and serum levels of ischemia-modified albumin and malondialdehyde. Retina 2011;31:602–8. [8] Ozsu S, Gulsoy A, Karahan SC, et al. Diagnostic value of pleural effusion ischaemia-modified albumin in patients with cardiac failure. Ann Clin Biochem 2011;48:45–50. [9] Niwa Y, Miyake S, Sakane T, et al. Auto-oxidative damage in Behc¸et’s disease endothelial cell damage following the elevated oxygen radicals generated by stimulated neutrophils. Clin Exp Immunol 1982;49:247–55. [10] Chambers JC, Haskard DO, Kooner JS. Vascular endothelial function and oxidative stress mechanisms in patients with Behc¸et’s syndrome. J Am Coll Cardiol 2001;37:517–20.
Erhan Capkin a,∗ Murat Karkucak a Mehmet Kola b Adem Karaca a Arzu Aydin Capkin d Suleyman Caner Karahan c a Department of PM&R and Rheumatology, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey b Department of Eyes disease, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey c Department of Medical Biochemistry, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey d Department of Dermatology, Fatih state hospital, Trabzon, Turkey
IMA: ischemia-modified albumin; TAS: total antioxidative status; TOS: total oxidative status; OSI: oxidative stress index; MDA: malondialdehyde; ESR: erythrocyte sedimentation rate; CRP: c-reactive protein.
oxidative stress (higher serum MDA, TOS and OSI) and decreased antioxidant capacity (lower TAS level) in patients with BD. We determined significantly higher serum IMA levels compared to those in the control group. Studies have demonstrated that many conditions may elevate IMA levels, including ischemia and deep vein thrombosis [6–8]. To the best of our knowledge, this study is the first to analyze the relationship between serum IMA levels and BD. Vascular involvement is common in BD patients. Endothelial dysfunction is mediated by increased oxidative stress. Oxidative stress is a key factor in vascular injury [9,10]. Although the number of patients with vascular involvement was lower than that of patients without, IMA levels were statistically significantly higher in patients with vascular involvement. The limitation to this study is the low patient numbers involved, and that the type of vascular involvement was not determined. Our results demonstrate increased oxidative stress and decreased antioxidant capacity in patients with BD. IMA is an important marker of oxidative stress in BD patients and can be used as a significant tool in distinguishing vascular involvement in particular. Further clinical studies are now required to evaluate this issue. Disclosure of interest
69
∗ Corresponding
author. Tel.: +90 46 23 77 10 93/90 50 52 34 42 58. E-mail address: [email protected] (E. Capkin) Accepted 16 June 2014 Available online 30 July 2014 http://dx.doi.org/10.1016/j.jbspin.2014.06.007
Toxidermia under treatment with tocilizumab for rheumatoid arthritis
a r t i c l e
i n f o
Keywords: Tocilizumab Rheumatoid arthritis Biotherapy Anti-IL6 Cutaneous eruption Toxidermia
The authors declare that they have no conflicts of interest concerning this article.
1. Introduction
Ethical approval: the study approved by Karadeniz Technical University ethics committee, ethics number: 2009/56.
The development of TNF inhibitors represents a major advancement in the treatment of rheumatoid arthritis (RA). TNF inhibitors
70
Letters to the Editor / Joint Bone Spine 82 (2015) 66–73
the production of antibodies to TCZ may predispose to hypersensitivity reactions [7]. This dosage was not made in our case. With TCZ, Izquierdo et al. reported a case of acute generalized exanthematous pustulosis. Lesions began two weeks after the first infusion and decreased with oral and topic steroid. TCZ was not stopped [8]. A second case of cutaneous toxidermia was described for a 57-year-old woman with a RA associated with a secondary Sjogren’s syndrome. After the first infusion of TCZ, she complained of a lichenoid toxidermia that resolved with topic treatment [9]. 4. Conclusion We here reported a case of toxidermia after treatment with TCZ for RA. To our knowledge, this is the third case described. This side effect seems to appear rarely and without any fatal consequence. Further case reports should be necessary to confirm their low side effect impact. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References
Fig. 1. Cutaneous lesions after infusion of tocilizumab.
may have potential side effects. Here, we are reporting a case of a cutaneous eruption in a patient treated with tocilizumab (TCZ). 2. Clinical vignette A 34-year-old woman with a RA (anti-CCP and rheumatoid factor positives) diagnosed in 1999 was treated with TCZ. TCZ monotherapy (8 mg/kg) was introduced after failure of several TNF inhibitors. Clinical remission was fastly obtained and she was then treated during twenty-six months. Three days after the last two monthly intravenous infusions, the patient noticed a vesiculopustular erythematous rash on the same side of the infusion arm, without any fever or other symptoms (Fig. 1). Lesions decreased without any treatment in ten days. Her initial laboratory results showed normal levels of leukocytes (11,300/mm3 ), neutrophils (8927/mm3 ), eosinophils and normal liver function tests. Cutaneous biospy was not realized since the patient had been seen after the decrease of the cutaneous lesions. Hepatitis, HIV, Epstein Barr, cytomegalovirus, Parvovirus B19 tests were negatives. After a drug safety analysis and despite a lack of reference, this eruption was correlated with TCZ. 3. Discussion In case of inadequate response or contraindication to conventional synthetic disease-modifying antirheumatic drugs, TCZ is a possibility and may be used in monotherapy [1]. The rate of infusions reactions reported varies between 10 to 50%. Haematoma, red benign lesions are described near the infusion site. Studies reported clinically significant hypersensitivity reactions as anaphylaxia at the ninth week or at the second or third infusion [2,3]. Other symptoms included rash, urticaria, itching or dermatitis [4,5]. The rate of anaphylactic reaction in pooled results from five phase III trials was 0.1/100 patients-years in patient randomised and treated with TCZ 8 mg/kg [6]. Some studies seem to show that
[1] Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological diseasemodifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492– 509. [2] Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008;371: 987–97. [3] Kremer JM, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebocontrolled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum 2011;63:609–21. [4] Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008;58:2968–80. [5] Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010;69:88–96. [6] Schiff MH, Kremer JM, Jahreis A, et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther 2011;13:R141. [7] Jones G, Ding C. Tocilizumab: a review of its safety and efficacy in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord 2010;3: 81–9. [8] Izquierdo JH, Bonilla-Abadia F, Ochoa CD, et al. Acute generalized exanthematous pustulosis due to tocilizumab in a rheumatoid arthritis patient. Case Rep Rheumatol 2012;2012:517424. [9] Latourte A, Viguier M, Dallot A, et al. Un cas de toxidermie lichenoïde survenue sous tocilizumab dans le traitement de la polyarthrite rhumatoïde. Rev Rhum 2012;79:A13–352.
Marie Fechtenbaum ∗ Christopher Banse Pauline Boyard-Lasselin Vincent Goëb Service de Rhumatologie, EA 4666, CHU d’Amiens, Université de Picardie-Jules-Verne, 80054 Amiens, France ∗ Corresponding author. E-mail address: [email protected] (M. Fechtenbaum)
Accepted 13 June 2014 Available online 19 July 2014 http://dx.doi.org/10.1016/j.jbspin.2014.06.006
