- Email: [email protected]
Hypertrigyceridemia during infliximab therapy
94
Letters to the editor / Joint Bone Spine 81 (2014) 93–101 lymphocyte depleting antibody alemtuzumab (CAMPATH-1H). Ann Rheum Dis 2008;67:1322–7. [10] Chee CE, Warrington KJ, Tefferi A. Chronic natural killer-cell lymphocytosis successfully treated with alemtuzumab. Blood 2009;114:3500–2.
Alexandra Audemard a,∗ Jonathan Boutemy a,b Philippe Guilpain c Rémi Sabatier d Nicolas Martin Silva a Boris Bienvenu a,b a CHU de Caen, Department of Internal Medicine, 14000 Caen, France b Université de Caen-Basse Normandie, Medical School, 14000 Caen, France c CHRU de Montpellier, hôpital Saint-Eloi, Department of Internal Medicine A, 34000 Montpellier, France d CHU de Caen, Department of Cardiology, 14000 Caen, France ∗ Corresponding author. Department of Internal Medicine, CHU Côte-de-Nacre, BP 95182, 14033 Caen cedex 9, France. Tel.: +33 2 31 06 45 84; fax: +33 2 31 06 49 54. E-mail address: [email protected] (A. Audemard)
Fig. 2. Coronary angiograph: stabilization of triple-vessel coronary vasculitis after alemtuzumab therapy.
[10]. In our patient, alemtuzumab could have been effective on coronary vasculitis, illustrated by the absence of additional coronary lesions. Absence of lesion’s regression could be linked with fixed damage. Alemtuzumab could be proposed in the context of hematological malignancy-associated vasculitis.
Accepted 16 April 2013 Available online 31 May 2013 doi:10.1016/j.jbspin.2013.04.007
Disclosure of interest
Hypertrigyceridemia during infliximab therapy
The authors declare that they have no conflicts of interest concerning this article.
a r t i c l e
Authorship contributions A. Audemard, J. Boutemy, and B. Bienvenu analyzed the data and wrote the paper. P. Guilpain wrote the paper. R. Sabatier, T. Le Gallou, N. Martin Silva and M. Macro analyzed the data. Acknowledgments Mr Erwan Floch, from Newmed Company, provided drafts and editorial assistance to the authors during preparation of this manuscript. References [1] Fain O, Hamidou M, Cacoub P, et al. Vasculitides associated with malignancies: analysis of sixty patients. Arthritis Rheum 2007;57:1473–80. [2] Jennette JC, Falk RJ, Bacon PA. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65: 1–11. [3] Behn A, Sykes H. Polyarteritis nodosa and hairy cell leukaemia. Rheumatol Rehabil 1982;21:164–6. [4] Buhl T, Bertsch HP, Raab BW, et al. Fulminant polyarteritis nodosa associated with acute myeloid leukaemia resulted in bilateral lower leg amputation. Rheumatology (Oxford) 2009;48:1170–2. [5] Leroy P, Villee C, Lefebvre C, et al. Multiple myeloma-associated polyarteritis nodosa. Br J Haematol 2010;5:634. [6] Barrier J, Grolleau JY, Gaillard F, et al. Waldenström’s disease and periarteritis nodosa: fortuitous association? Sem Hop 1981;57:1212–4. [7] Mizutani H, Asahi K, Shimizu M. Complete remission of recalcitrant polyarteritis nodosa after combination chemotherapy for accompanying B-cell non-Hodgkin lymphoma. Int J Dermatol 1998;37:398–9. [8] Dearden CE, Matutes E, Cazin B, et al. Hight remission rate in T cell prolymphocytic leukemia with campath. Blood 2001;98:1721–6. [9] Walsh M, Chaudhry A, Jayne D. Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the
i n f o
Keywords: Hypertriglyceridemia Anti-TNF Biotherapy
Tumor necrosis factor (TNF) antagonists are largely prescribed for the treatment of inflammatory rheumatic diseases. Herein, we report a series of three patients who experienced hypertriglyceridemia during infliximab therapy. 1. Case reports 1.1. Case 1 A 28-year-old man (body mass index [BMI] 20.5) without a history of dyslipidemia and alcoholism started receiving infliximab infusion for ankylosing spondylitis. After four infusions, triglyceride (TG) levels increased to 4.55 g/L and remained high during infliximab continuation (10 years), ranging from 1.47 to 6.41 g/L, whereas total cholesterol (TC) ranged from 1.44 to 2.02 g/L (Table 1). 1.2. Case 2 A 44-year-old man (BMI 29.3) with a history of moderate hypertriglyceridemia but no history of alcoholism started receiving infliximab infusion for psoriatic arthritis. The first infusion was poorly tolerated with asthenia, vomiting, and chest pain. Before the third infusion, TGs increased to 7.17 g/L. Infliximab was continued and fenofibrate treatment was initiated (160 mg/day). Because of
Letters to the editor / Joint Bone Spine 81 (2014) 93–101
95
Table 1 Characteristics and lipid profiles of the three reported cases.
Sex/Age BMI Disease Infliximab dosage Baseline TGs Highest TGs Baseline TC Highest TC HyperTG delay of onset Anti-TNF duration Anti-TNF discontinuation Lipid lowering therapy TG outcome
Patient 1
Patient 2
Patient 3
M/28 20.5 Ankylosing spondylitis 5 mg/kg 1.26 g/L 4.55 g/L 1.15 g/L 1.25 g/L 9 months (4 infusions) 10 years (still ongoing) No None Still increased
M/44 29.3 Psoriatic arthritis 5 mg/kg 1.16 to 4.59 g/L 7.17 g/L 2.24 to 3.05 g/L 2.58 g/L 1.5 months (2 infusions) 5 months Yes Fibrate Unknown
F/52 22.6 Rheumatoid arthritis 3 mg/kg 1.50 g/L 4.90 g/L 1.88 g/L 2.55 g/L 4 months (3 infusions) 10 years (still ongoing) No HMG-COa reductase inhibitor Decreased but abnormal
TGs: Triglycerides; TC: Total cholesterol.
Table 2 Cases of hypertriglyceridemia induced by anti-TNF therapy: literature review.
Sex/Age Disease Anti-TNF Anti-TNF dosage Baseline TGs Highest TGs Baseline TC Highest TC HyperTG delay of onset Lipid lowering therapy Anti-TNF discontinuation Anti-TNF duration TG outcome
Antoniou et al. [5]
Stinco et al. [6]
Haroon et al. [7]
M/35 Psoriatic arthritis and psoriasis vulgaris Infliximab 5 mg/kg 3.97 g/L 11.29 g/L Normal “Mild elevation” 0.5 month (1 infusion) None Yes 0.5 month Return to baseline values
M/39 Psoriatic arthritis Adalimumab 40 mg Normal 6.89 g/L Normal 2.64 g/L 2 months (4 infusions) None Yes 3 months Decreased but abnormal
M/38 Psoriatic arthritis Etanercept 20 mg 5.03 g/L 18.07 g/L 1.78 g/L 2.60 g/L 3 months (–) HMG-Coa reductase inhibitor No 18 months Return to baseline values
TGs: Triglycerides; TC: Total cholesterol.
muscle pain and creatine phosphokinase elevation (5 N), fenofibrate was stopped quickly. At the fifth infusion, TGs decreased to 4.64 g/L, but myalgia persisted. Infliximab was replaced with methotrexate. 1.3. Case 3 A 52-year-old woman (BMI 22.6) without a history of dyslipidemia, alcoholism, and cardiovascular disease started receiving infliximab infusion for refractory rheumatoid arthritis. Hypertriglyceridemia occurred from the third infusion, reaching 4.90 g/L. Infliximab was continued and trimestrial lipid monitoring showed that TG levels were still elevated (3.90 and 4.90 g/L). She further experienced right central retinal vein thrombosis without obvious vascular etiology (sixth infusion), and two acute myocardial infarctions (AMIs) at the 21st (TGs = 2.94 g/L and TC = 2.60 g/L) and the 69th infusion (TGs and TC unknown at this date). HMG-COa reductase inhibitor therapy was started after the first AMI. TGs ranged from 1.05 to 2.13 g/L during the 10 following years of anti-TNF treatment. These cases have been registered by the regional pharmacovigilance center with a dubious imputability score (C1S1) [1]. 2. Discussion Recent studies have suggested that immunosuppression with anti-TNF in patients suffering from inflammatory rheumatic disease is associated with a reduced risk of cardiovascular events. However, there are conflicting results about the effects of antiTNF on lipid profiles: some studies have shown an increase in TGs (up to 125%) and/or in TC, whereas other studies have reported no significant modifications [2–4].
To date, only three case reports of hypertriglyceridemia without pancreatitis (highest reported TG level, 18.07 g/L) during anti-TNF biotherapy have been described [5–7] (Table 2). Both monoclonal antibodies and fusion proteins were involved. According to Chen et al. [8], TNF may affect plasma TG metabolism by: • suppressing free fatty acid uptake and promoting lipogenesis; • stimulating lipolysis in adipocytes; • inhibiting lipoprotein lipase and regulating adipocyte triglyceride lipase and acetyl-CoA carboxylase; • regulating adipokines. If so, then TNF should reduce TG plasmatic clearance, and anti-TNF therapy should decrease TG levels. However, this is inconsistent with the present and previous observations of hypertriglyceridemia during anti-TNF therapy. Such side effects could result from a paradoxical biological mechanism. In practice, lipid profile monitoring during anti-TNF therapy should be recommended for all patients. Disclosure of interest L.J., P.P., I.G., N.P., P.G. declare no conflicts of interest. L.P-B. receives consulting and lecture fees for Merck and Abbott. References [1] Moore N, Biour M, Paux G, et al. Adverse drug reaction monitoring: doing it the French way. Lancet 1985;2:1056–8. [2] Pollono EN, Lopez-Olivo MA, Martinez Lopez JA, et al. A systematic review of the effect of TNF-␣ antagonists on lipid profiles in patients with rheumatoid arthritis. Clin Rheumatol 2010;29:947–55.
96
Letters to the editor / Joint Bone Spine 81 (2014) 93–101
[3] Soubrier M, Jouanel P, Mathieu S, et al. Effects of anti-tumor necrosis factor therapy on lipid profile in patients with rheumatoid arthritis. Joint Bone Spine 2008;75:22–4. [4] Castro KR, Aikawa NE, Saad CG, et al. Infliximab induces increase in triglyceride levels in psoriatic arthritis patients. Clin Dev Immunol 2011;2011:352686. [5] Antoniou C, Dessinioti C, Katsambas A, et al. Elevated triglyceride and cholesterol levels after intravenous antitumour necrosis factor-␣ therapy in a patient with psoriatic arthritis and psoriasis vulgaris. Br J Dermatol 2007;156:1090–1. [6] Stinco G, Piccirillo F, Patrone P. Hypertriglyceridaemia during treatment with adalimumab in psoriatic arthritis. Br J Dermatol 2007;157:1267–304. [7] Haroon M, Devlin J. Marked hypertriglyceridemia upon treatment with etanercept. Joint Bone Spine 2009;76:570–6. [8] Chen X, Xun K, Chen L, et al. TNF-␣, a potent lipid metabolism regulator. Cell Biochem Funct 2009;27:407–16.
Lucie Javot a,∗,1 Patrice Pere b Isabelle Got c Nadine Petitpain a Laurent Peyrin-Biroulet d Pierre Gillet a,e a University Hospital of Nancy, Regional Pharmacovigilance Center, 54035 Nancy, France b University Hospital of Nancy, Department of Rheumatology, 54511 Vandœuvre-les-Nancy, France c University Hospital of Nancy, Department of Diabetology, Metabolic Diseases and Nutrition, 54511 Vandœuvre-les-Nancy, France d University Hospital of Nancy, Department of Hepatogastroenterology, 54511 Vandœuvre-les-Nancy, France e University Hospital of Nancy, Department of Pharmacology and Toxicology, 54035 Nancy, France ∗ Corresponding
author. University Hospital of Nancy, Regional Pharmacovigilance Center, University Hospital of Nancy, 29, avenue du Maréchal-de-Lattre-de-Tassigny, CO 60034, 54035 Nancy cedex, France. Tel.: +33 3 83 85 27 60; fax: ++33 3 83 32 33 44. E-mail address: [email protected] (L. Javot) 1
The corresponding author certifies that all the authors approved the entirety of the submitted material and contributed actively to the study. Accepted 27 April 2013 Available online 21 June 2013
doi:10.1016/j.jbspin.2013.04.018
25-Hydroxyvitamin D status does not affect the clinical rituximab response in rheumatoid arthritis
a r t i c l e
i n f o
Keywords: Rheumatoid arthritis Vitamin D Rituximab
Rheumatoid arthritis (RA) has been associated with inadequate vitamin D stores. In vitro, vitamin D inhibits pro-inflammatory cytokines involved in RA pathogenesis [1], inhibits Th17 polarization [2,3], and diminishes B-cell proliferation and IgG and IgM production [4]. Circulating 25(OH)D levels may be inversely associated with RA activity in cross-sectional studies from the USA [5–7] and Europe [8,9]. We hypothesized that inadequate vitamin D stores would stimulate B-cell response and consequently, hamper the efficacy of
biologics targeting B-cells used to control the inflammatory process in RA. In order to assess this hypothesis, we evaluated whether baseline vitamin D status in a cohort of patients with RA was associated with the 6-month rituximab response using the delta DAS (DAS) between baseline and month 6 (primary end point). Clinical response according to seasonal variation (sun exposure) was also evaluated (secondary end point). We established a prospective cohort of 111 RA patients (Table 1) scheduled for treatment with the anti-CD20 antibody rituximab as part of standard care. Baseline serum samples were obtained to assay 25(OH)D and 1.25(OH)2 D using a commercial ELISA (IDS, Paris, France) at the time when treatment was initiated and was not repeated after 6 months. RA activity and severity were assessed by collecting the data in Table 1 at baseline and after 6 months of rituximab therapy. The DAS 28 change (DAS 28) during the 6month rituximab treatment period was computed. The treatment response was categorized according to the European League against Rheumatism (EULAR) classification scheme based on DAS 28 at M6 and DAS 28. Patients currently on steroids (85%) and vitamin D supplementation at baseline (64%) remained on a stable daily dose during the 6-month period. Baseline serum 25(OH)D was normal in 33 (30%) patients, insufficient (<20 ng/mL) in 55 (49.5%), and deficient (<10 ng/mL) in 23 patients (20.7%). No correlation was found between baseline 25(OH)D and DAS 28 (P = 0.3218, Pearson test). 1.25(OH)2D Table 1 Baseline characteristics of the 111 patients with rheumatoid arthritis scheduled for rituximab therapy. Characteristics Demographics Age in years (mean ± SD) Women, n (%) Caucasians, n (%) Smokers (current or past), n (%) BMI (mean ± SD)
53.3 ± 10.3 92 (82.9) 96 (86.5) 38 (45.2) 27.2 ± 6.6
Disease characteristics Disease duration in years (mean ± SD) RF-positive, n (%) ACPA-positive, n (%) Swollen joint count (mean ± SD) Tender joint count (mean ± SD) Global health VAS (mean ± SD) CRP (mg/L) (mean ± SD) ESR (mm/h) (mean ± SD) DAS 28 (mean ± SD)
12.1 ± 9.7 95 (85.6) 88 (80.0) 6.9 (5.3) 8.1 (6.8) 6.0 ± 6.3 18.9 ± 19.3 34.2 ± 24.1 5.2 ± 1.3
Current and previous drug use N previous chemical DMARDs Mean ± SD Median (inter-quartile range) Current chemical DMARDs, n (%) None Methotrexate Other Previous biologics, n (%) None Anti-TNF (n = 1) Anti-TNF (n = 2) Anti-TNF (n = 3) Anti-TNF plus others Current steroids, n (%) Daily steroid dose in mg (mean ± SD) Vitamin D supplementation at baseline and during the study period (800 UI/d) n/N (%) Season of enrolment: number of patients Autumn Winter Spring Summer
2.6 ± 1.5 2.0 (1.0–3.0) 31 (28.2) 57 (51.8) 22 (20.0) 30 (27.0) 29 (26.1) 39 (35.1) 9 (8.1) 4 (3.6) 94 (84.7) 8.6 ± 7.7 69/108 (63.9)
23 33 31 24
Letters to the editor / Joint Bone Spine 81 (2014) 93–101 lymphocyte depleting antibody alemtuzumab (CAMPATH-1H). Ann Rheum Dis 2008;67:1322–7. [10] Chee CE, Warrington KJ, Tefferi A. Chronic natural killer-cell lymphocytosis successfully treated with alemtuzumab. Blood 2009;114:3500–2.
Alexandra Audemard a,∗ Jonathan Boutemy a,b Philippe Guilpain c Rémi Sabatier d Nicolas Martin Silva a Boris Bienvenu a,b a CHU de Caen, Department of Internal Medicine, 14000 Caen, France b Université de Caen-Basse Normandie, Medical School, 14000 Caen, France c CHRU de Montpellier, hôpital Saint-Eloi, Department of Internal Medicine A, 34000 Montpellier, France d CHU de Caen, Department of Cardiology, 14000 Caen, France ∗ Corresponding author. Department of Internal Medicine, CHU Côte-de-Nacre, BP 95182, 14033 Caen cedex 9, France. Tel.: +33 2 31 06 45 84; fax: +33 2 31 06 49 54. E-mail address: [email protected] (A. Audemard)
Fig. 2. Coronary angiograph: stabilization of triple-vessel coronary vasculitis after alemtuzumab therapy.
[10]. In our patient, alemtuzumab could have been effective on coronary vasculitis, illustrated by the absence of additional coronary lesions. Absence of lesion’s regression could be linked with fixed damage. Alemtuzumab could be proposed in the context of hematological malignancy-associated vasculitis.
Accepted 16 April 2013 Available online 31 May 2013 doi:10.1016/j.jbspin.2013.04.007
Disclosure of interest
Hypertrigyceridemia during infliximab therapy
The authors declare that they have no conflicts of interest concerning this article.
a r t i c l e
Authorship contributions A. Audemard, J. Boutemy, and B. Bienvenu analyzed the data and wrote the paper. P. Guilpain wrote the paper. R. Sabatier, T. Le Gallou, N. Martin Silva and M. Macro analyzed the data. Acknowledgments Mr Erwan Floch, from Newmed Company, provided drafts and editorial assistance to the authors during preparation of this manuscript. References [1] Fain O, Hamidou M, Cacoub P, et al. Vasculitides associated with malignancies: analysis of sixty patients. Arthritis Rheum 2007;57:1473–80. [2] Jennette JC, Falk RJ, Bacon PA. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65: 1–11. [3] Behn A, Sykes H. Polyarteritis nodosa and hairy cell leukaemia. Rheumatol Rehabil 1982;21:164–6. [4] Buhl T, Bertsch HP, Raab BW, et al. Fulminant polyarteritis nodosa associated with acute myeloid leukaemia resulted in bilateral lower leg amputation. Rheumatology (Oxford) 2009;48:1170–2. [5] Leroy P, Villee C, Lefebvre C, et al. Multiple myeloma-associated polyarteritis nodosa. Br J Haematol 2010;5:634. [6] Barrier J, Grolleau JY, Gaillard F, et al. Waldenström’s disease and periarteritis nodosa: fortuitous association? Sem Hop 1981;57:1212–4. [7] Mizutani H, Asahi K, Shimizu M. Complete remission of recalcitrant polyarteritis nodosa after combination chemotherapy for accompanying B-cell non-Hodgkin lymphoma. Int J Dermatol 1998;37:398–9. [8] Dearden CE, Matutes E, Cazin B, et al. Hight remission rate in T cell prolymphocytic leukemia with campath. Blood 2001;98:1721–6. [9] Walsh M, Chaudhry A, Jayne D. Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the
i n f o
Keywords: Hypertriglyceridemia Anti-TNF Biotherapy
Tumor necrosis factor (TNF) antagonists are largely prescribed for the treatment of inflammatory rheumatic diseases. Herein, we report a series of three patients who experienced hypertriglyceridemia during infliximab therapy. 1. Case reports 1.1. Case 1 A 28-year-old man (body mass index [BMI] 20.5) without a history of dyslipidemia and alcoholism started receiving infliximab infusion for ankylosing spondylitis. After four infusions, triglyceride (TG) levels increased to 4.55 g/L and remained high during infliximab continuation (10 years), ranging from 1.47 to 6.41 g/L, whereas total cholesterol (TC) ranged from 1.44 to 2.02 g/L (Table 1). 1.2. Case 2 A 44-year-old man (BMI 29.3) with a history of moderate hypertriglyceridemia but no history of alcoholism started receiving infliximab infusion for psoriatic arthritis. The first infusion was poorly tolerated with asthenia, vomiting, and chest pain. Before the third infusion, TGs increased to 7.17 g/L. Infliximab was continued and fenofibrate treatment was initiated (160 mg/day). Because of
Letters to the editor / Joint Bone Spine 81 (2014) 93–101
95
Table 1 Characteristics and lipid profiles of the three reported cases.
Sex/Age BMI Disease Infliximab dosage Baseline TGs Highest TGs Baseline TC Highest TC HyperTG delay of onset Anti-TNF duration Anti-TNF discontinuation Lipid lowering therapy TG outcome
Patient 1
Patient 2
Patient 3
M/28 20.5 Ankylosing spondylitis 5 mg/kg 1.26 g/L 4.55 g/L 1.15 g/L 1.25 g/L 9 months (4 infusions) 10 years (still ongoing) No None Still increased
M/44 29.3 Psoriatic arthritis 5 mg/kg 1.16 to 4.59 g/L 7.17 g/L 2.24 to 3.05 g/L 2.58 g/L 1.5 months (2 infusions) 5 months Yes Fibrate Unknown
F/52 22.6 Rheumatoid arthritis 3 mg/kg 1.50 g/L 4.90 g/L 1.88 g/L 2.55 g/L 4 months (3 infusions) 10 years (still ongoing) No HMG-COa reductase inhibitor Decreased but abnormal
TGs: Triglycerides; TC: Total cholesterol.
Table 2 Cases of hypertriglyceridemia induced by anti-TNF therapy: literature review.
Sex/Age Disease Anti-TNF Anti-TNF dosage Baseline TGs Highest TGs Baseline TC Highest TC HyperTG delay of onset Lipid lowering therapy Anti-TNF discontinuation Anti-TNF duration TG outcome
Antoniou et al. [5]
Stinco et al. [6]
Haroon et al. [7]
M/35 Psoriatic arthritis and psoriasis vulgaris Infliximab 5 mg/kg 3.97 g/L 11.29 g/L Normal “Mild elevation” 0.5 month (1 infusion) None Yes 0.5 month Return to baseline values
M/39 Psoriatic arthritis Adalimumab 40 mg Normal 6.89 g/L Normal 2.64 g/L 2 months (4 infusions) None Yes 3 months Decreased but abnormal
M/38 Psoriatic arthritis Etanercept 20 mg 5.03 g/L 18.07 g/L 1.78 g/L 2.60 g/L 3 months (–) HMG-Coa reductase inhibitor No 18 months Return to baseline values
TGs: Triglycerides; TC: Total cholesterol.
muscle pain and creatine phosphokinase elevation (5 N), fenofibrate was stopped quickly. At the fifth infusion, TGs decreased to 4.64 g/L, but myalgia persisted. Infliximab was replaced with methotrexate. 1.3. Case 3 A 52-year-old woman (BMI 22.6) without a history of dyslipidemia, alcoholism, and cardiovascular disease started receiving infliximab infusion for refractory rheumatoid arthritis. Hypertriglyceridemia occurred from the third infusion, reaching 4.90 g/L. Infliximab was continued and trimestrial lipid monitoring showed that TG levels were still elevated (3.90 and 4.90 g/L). She further experienced right central retinal vein thrombosis without obvious vascular etiology (sixth infusion), and two acute myocardial infarctions (AMIs) at the 21st (TGs = 2.94 g/L and TC = 2.60 g/L) and the 69th infusion (TGs and TC unknown at this date). HMG-COa reductase inhibitor therapy was started after the first AMI. TGs ranged from 1.05 to 2.13 g/L during the 10 following years of anti-TNF treatment. These cases have been registered by the regional pharmacovigilance center with a dubious imputability score (C1S1) [1]. 2. Discussion Recent studies have suggested that immunosuppression with anti-TNF in patients suffering from inflammatory rheumatic disease is associated with a reduced risk of cardiovascular events. However, there are conflicting results about the effects of antiTNF on lipid profiles: some studies have shown an increase in TGs (up to 125%) and/or in TC, whereas other studies have reported no significant modifications [2–4].
To date, only three case reports of hypertriglyceridemia without pancreatitis (highest reported TG level, 18.07 g/L) during anti-TNF biotherapy have been described [5–7] (Table 2). Both monoclonal antibodies and fusion proteins were involved. According to Chen et al. [8], TNF may affect plasma TG metabolism by: • suppressing free fatty acid uptake and promoting lipogenesis; • stimulating lipolysis in adipocytes; • inhibiting lipoprotein lipase and regulating adipocyte triglyceride lipase and acetyl-CoA carboxylase; • regulating adipokines. If so, then TNF should reduce TG plasmatic clearance, and anti-TNF therapy should decrease TG levels. However, this is inconsistent with the present and previous observations of hypertriglyceridemia during anti-TNF therapy. Such side effects could result from a paradoxical biological mechanism. In practice, lipid profile monitoring during anti-TNF therapy should be recommended for all patients. Disclosure of interest L.J., P.P., I.G., N.P., P.G. declare no conflicts of interest. L.P-B. receives consulting and lecture fees for Merck and Abbott. References [1] Moore N, Biour M, Paux G, et al. Adverse drug reaction monitoring: doing it the French way. Lancet 1985;2:1056–8. [2] Pollono EN, Lopez-Olivo MA, Martinez Lopez JA, et al. A systematic review of the effect of TNF-␣ antagonists on lipid profiles in patients with rheumatoid arthritis. Clin Rheumatol 2010;29:947–55.
96
Letters to the editor / Joint Bone Spine 81 (2014) 93–101
[3] Soubrier M, Jouanel P, Mathieu S, et al. Effects of anti-tumor necrosis factor therapy on lipid profile in patients with rheumatoid arthritis. Joint Bone Spine 2008;75:22–4. [4] Castro KR, Aikawa NE, Saad CG, et al. Infliximab induces increase in triglyceride levels in psoriatic arthritis patients. Clin Dev Immunol 2011;2011:352686. [5] Antoniou C, Dessinioti C, Katsambas A, et al. Elevated triglyceride and cholesterol levels after intravenous antitumour necrosis factor-␣ therapy in a patient with psoriatic arthritis and psoriasis vulgaris. Br J Dermatol 2007;156:1090–1. [6] Stinco G, Piccirillo F, Patrone P. Hypertriglyceridaemia during treatment with adalimumab in psoriatic arthritis. Br J Dermatol 2007;157:1267–304. [7] Haroon M, Devlin J. Marked hypertriglyceridemia upon treatment with etanercept. Joint Bone Spine 2009;76:570–6. [8] Chen X, Xun K, Chen L, et al. TNF-␣, a potent lipid metabolism regulator. Cell Biochem Funct 2009;27:407–16.
Lucie Javot a,∗,1 Patrice Pere b Isabelle Got c Nadine Petitpain a Laurent Peyrin-Biroulet d Pierre Gillet a,e a University Hospital of Nancy, Regional Pharmacovigilance Center, 54035 Nancy, France b University Hospital of Nancy, Department of Rheumatology, 54511 Vandœuvre-les-Nancy, France c University Hospital of Nancy, Department of Diabetology, Metabolic Diseases and Nutrition, 54511 Vandœuvre-les-Nancy, France d University Hospital of Nancy, Department of Hepatogastroenterology, 54511 Vandœuvre-les-Nancy, France e University Hospital of Nancy, Department of Pharmacology and Toxicology, 54035 Nancy, France ∗ Corresponding
author. University Hospital of Nancy, Regional Pharmacovigilance Center, University Hospital of Nancy, 29, avenue du Maréchal-de-Lattre-de-Tassigny, CO 60034, 54035 Nancy cedex, France. Tel.: +33 3 83 85 27 60; fax: ++33 3 83 32 33 44. E-mail address: [email protected] (L. Javot) 1
The corresponding author certifies that all the authors approved the entirety of the submitted material and contributed actively to the study. Accepted 27 April 2013 Available online 21 June 2013
doi:10.1016/j.jbspin.2013.04.018
25-Hydroxyvitamin D status does not affect the clinical rituximab response in rheumatoid arthritis
a r t i c l e
i n f o
Keywords: Rheumatoid arthritis Vitamin D Rituximab
Rheumatoid arthritis (RA) has been associated with inadequate vitamin D stores. In vitro, vitamin D inhibits pro-inflammatory cytokines involved in RA pathogenesis [1], inhibits Th17 polarization [2,3], and diminishes B-cell proliferation and IgG and IgM production [4]. Circulating 25(OH)D levels may be inversely associated with RA activity in cross-sectional studies from the USA [5–7] and Europe [8,9]. We hypothesized that inadequate vitamin D stores would stimulate B-cell response and consequently, hamper the efficacy of
biologics targeting B-cells used to control the inflammatory process in RA. In order to assess this hypothesis, we evaluated whether baseline vitamin D status in a cohort of patients with RA was associated with the 6-month rituximab response using the delta DAS (DAS) between baseline and month 6 (primary end point). Clinical response according to seasonal variation (sun exposure) was also evaluated (secondary end point). We established a prospective cohort of 111 RA patients (Table 1) scheduled for treatment with the anti-CD20 antibody rituximab as part of standard care. Baseline serum samples were obtained to assay 25(OH)D and 1.25(OH)2 D using a commercial ELISA (IDS, Paris, France) at the time when treatment was initiated and was not repeated after 6 months. RA activity and severity were assessed by collecting the data in Table 1 at baseline and after 6 months of rituximab therapy. The DAS 28 change (DAS 28) during the 6month rituximab treatment period was computed. The treatment response was categorized according to the European League against Rheumatism (EULAR) classification scheme based on DAS 28 at M6 and DAS 28. Patients currently on steroids (85%) and vitamin D supplementation at baseline (64%) remained on a stable daily dose during the 6-month period. Baseline serum 25(OH)D was normal in 33 (30%) patients, insufficient (<20 ng/mL) in 55 (49.5%), and deficient (<10 ng/mL) in 23 patients (20.7%). No correlation was found between baseline 25(OH)D and DAS 28 (P = 0.3218, Pearson test). 1.25(OH)2D Table 1 Baseline characteristics of the 111 patients with rheumatoid arthritis scheduled for rituximab therapy. Characteristics Demographics Age in years (mean ± SD) Women, n (%) Caucasians, n (%) Smokers (current or past), n (%) BMI (mean ± SD)
53.3 ± 10.3 92 (82.9) 96 (86.5) 38 (45.2) 27.2 ± 6.6
Disease characteristics Disease duration in years (mean ± SD) RF-positive, n (%) ACPA-positive, n (%) Swollen joint count (mean ± SD) Tender joint count (mean ± SD) Global health VAS (mean ± SD) CRP (mg/L) (mean ± SD) ESR (mm/h) (mean ± SD) DAS 28 (mean ± SD)
12.1 ± 9.7 95 (85.6) 88 (80.0) 6.9 (5.3) 8.1 (6.8) 6.0 ± 6.3 18.9 ± 19.3 34.2 ± 24.1 5.2 ± 1.3
Current and previous drug use N previous chemical DMARDs Mean ± SD Median (inter-quartile range) Current chemical DMARDs, n (%) None Methotrexate Other Previous biologics, n (%) None Anti-TNF (n = 1) Anti-TNF (n = 2) Anti-TNF (n = 3) Anti-TNF plus others Current steroids, n (%) Daily steroid dose in mg (mean ± SD) Vitamin D supplementation at baseline and during the study period (800 UI/d) n/N (%) Season of enrolment: number of patients Autumn Winter Spring Summer
2.6 ± 1.5 2.0 (1.0–3.0) 31 (28.2) 57 (51.8) 22 (20.0) 30 (27.0) 29 (26.1) 39 (35.1) 9 (8.1) 4 (3.6) 94 (84.7) 8.6 ± 7.7 69/108 (63.9)
23 33 31 24