- Email: [email protected]
25-Hydroxyvitamin D status does not affect the clinical rituximab response in rheumatoid arthritis
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
97
Table 2 Comparisons of the DAS28 at M0, DAS28 at M6 and DAS28 according to the vitamin D status. Variable
Disease activity score at M0 Median (IQR) Mean (Std) Disease activity score at M6 Median (IQR) Mean (Std) DAS (DASM6-DASM0) Median (IQR) Mean (Std) *
Total (n = 111)
Vitamin D status
P value
Normal (n = 33)
Insufficient (n = 55)
Deficient (n = 23)
5.2 (4.4–6.2) 5.2 (1.3)
5.2 (3.6–6.1) 5.1 (1.5)
5.1 (4.6–6.3) 5.3 (1.2)
5.3 (4.3–6.3) 5.1 (1.3)
4.1 (3.0–5.0) 4.0 (1.5)
3.8 (2.5–5.0) 3.9 (1.6)
4.1 (3.0–4.9) 3.9 (1.5)
4.3 (3.8–5.4) 4.4 (1.2)
−1.2 (−1.9 – −0.2) −1.2 (1.3)
−1.2 (−1.9 – −0.5) −1.2 (1.3)
−1.4 (−2.6 − −0.4) −1.4 (1.3)
−0.9 (−1.4–0.1) −0.7 (1.2)
(S)* P = 0.7346
(S)* P = 0.3161
(S)* P = 0.1162
(S): variance analysis.
was normal in 98 (88.3%) and deficient in 13 patients (11.7%). In the overall population, the mean DAS 28 after 6 months was −1.2 (95% CI: −1.9 to −0.2). According to EULAR criteria, 24.3% of the patients were good responders and 38.7% moderate responders. Disease remission was achieved by 20.7% of the patients. Baseline serum 25(OH)D and 1.25(OH)2D (Table 2) (data not shown) did not correlate significantly with DAS 28 (P = 0.7807, Pearson test). The non-response rate was somewhat higher in the group with baseline vitamin D deficiency (52.2%) than in the groups with insufficient (32.7%) or normal (33.3%) 25(OH)D levels (P = 0.1667, Fisher exact test). By ordinal multinomial logistic regression, only season of enrolment was significantly associated with the response rate: enrolment in the fall was associated with a higher response rate (global P value = 0.0166). Our finding of inadequate 25(OH)D levels in 70% of RA patients is consistent with previous studies [5,6,8,9]. In contrast to the previous studies, we were unable to find an inverse correlation between serum 25(OH)D concentration and DAS28 at baseline, irrespective of standard vitamin D supplementation [6,8,9]. Sixtyfour percent of the studied population received vitamin D supplies during the 6-month period, which might represent a major confounding factor. However, the mean 25(OH)D level did not statistically differ between those who received vitamin D supplies and those who did not. Despite a possible in vitro immunomodulating effect of 1,25(OH)2 D on B-cell activity[4], and in accordance with data obtained by Baker et al. using golimumab [10], we failed to detect any correlation between serum 25(OH)D levels and rituximab efficacy assessed based on the 6-month EULAR response.
[7] Kerr GS, Sabahi I, Richards JS, et al. Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol 2011;38:53–9. [8] Rossini M, Maddali Bongi S, La Montagna G, et al. Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with disease activity and disability. Arthritis Res Ther 2010;12:R216. [9] Patel S, Farragher T, Berry J, et al. Association between serum vitamin D metabolite levels and disease activity in patients with early inflammatory polyarthritis. Arthritis Rheum 2007;56:2143–9. [10] Baker JF, Baker DG, Toedter G, et al. Associations between vitamin D, disease activity, and clinical response to therapy in rheumatoid arthritis. Clin Exp Rheumatol 2012;30:658–64.
Rim Ben M’Barek a Thierry Dupré b Florence Tubach c,d,e Philippe Dieudé a,e Elisabeth Palazzo a Gilles Hayem a Karen Dawidowicz a Sébastien Ottaviani a Tony Alfaiate c,d Véronique Lec¸on-Malais b Anne Boutten b Olivier Meyer a,e,∗ a Rheumatology, AP–HP, Hôpital Bichat, Paris, France b Biochemistry, AP–HP, Hôpital Bichat, Paris, France c Département d’Epidémiologie et Recherche Clinique, AP–HP, Hôpital Bichat, Paris, France d Inserm, CIE801 Paris, France e Université Paris-Diderot, Sorbonne Paris Cité, Paris, France ∗ Corresponding
author. Rheumatology, Hôpital Bichat, 75018 Paris, France. E-mail address: [email protected] (O. Meyer)
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Accepted 30 April 2013 Available online 21 June 2013
References doi:10.1016/j.jbspin.2013.04.017 [1] Manolagas SC, Werntz DA, Tsoukas CD, et al. 1,25-Dihydroxyvitamin D3 receptors in lymphocytes from patients with rheumatoid arthritis. J Lab Clin Med 1986;108:596–600. [2] Colin EM, Asmawidjaja PS, van Hamburg JP, et al. 1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis Rheum 2010;62:132–42. [3] Peelen E, Knippenberg S, Muris AH, et al. Effects of vitamin D on the peripheral adaptive immune system: a review. Autoimmun Rev 2011;10: 733–43. [4] Chen S, Sims GP, Chen XX, et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007;179:1634–47. [5] Craig SM, Yu F, Curtis JR, et al. Vitamin D status and its associations with disease activity and severity in African Americans with recent-onset rheumatoid arthritis. J Rheumatol 2010;37:275–81. [6] Haque UJ, Bartlett SJ. Relationships among vitamin D, disease activity, pain and disability in rheumatoid arthritis. Clin Exp Rheumatol 2010;28:745–7.
IgA deficiency in primary antiphospholipid syndrome
a r t i c l e
i n f o
Keywords: IgA deficiency Immunodeficiency Antiphospholipid syndrome Antiphospholipid antibodies
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
97
Table 2 Comparisons of the DAS28 at M0, DAS28 at M6 and DAS28 according to the vitamin D status. Variable
Disease activity score at M0 Median (IQR) Mean (Std) Disease activity score at M6 Median (IQR) Mean (Std) DAS (DASM6-DASM0) Median (IQR) Mean (Std) *
Total (n = 111)
Vitamin D status
P value
Normal (n = 33)
Insufficient (n = 55)
Deficient (n = 23)
5.2 (4.4–6.2) 5.2 (1.3)
5.2 (3.6–6.1) 5.1 (1.5)
5.1 (4.6–6.3) 5.3 (1.2)
5.3 (4.3–6.3) 5.1 (1.3)
4.1 (3.0–5.0) 4.0 (1.5)
3.8 (2.5–5.0) 3.9 (1.6)
4.1 (3.0–4.9) 3.9 (1.5)
4.3 (3.8–5.4) 4.4 (1.2)
−1.2 (−1.9 – −0.2) −1.2 (1.3)
−1.2 (−1.9 – −0.5) −1.2 (1.3)
−1.4 (−2.6 − −0.4) −1.4 (1.3)
−0.9 (−1.4–0.1) −0.7 (1.2)
(S)* P = 0.7346
(S)* P = 0.3161
(S)* P = 0.1162
(S): variance analysis.
was normal in 98 (88.3%) and deficient in 13 patients (11.7%). In the overall population, the mean DAS 28 after 6 months was −1.2 (95% CI: −1.9 to −0.2). According to EULAR criteria, 24.3% of the patients were good responders and 38.7% moderate responders. Disease remission was achieved by 20.7% of the patients. Baseline serum 25(OH)D and 1.25(OH)2D (Table 2) (data not shown) did not correlate significantly with DAS 28 (P = 0.7807, Pearson test). The non-response rate was somewhat higher in the group with baseline vitamin D deficiency (52.2%) than in the groups with insufficient (32.7%) or normal (33.3%) 25(OH)D levels (P = 0.1667, Fisher exact test). By ordinal multinomial logistic regression, only season of enrolment was significantly associated with the response rate: enrolment in the fall was associated with a higher response rate (global P value = 0.0166). Our finding of inadequate 25(OH)D levels in 70% of RA patients is consistent with previous studies [5,6,8,9]. In contrast to the previous studies, we were unable to find an inverse correlation between serum 25(OH)D concentration and DAS28 at baseline, irrespective of standard vitamin D supplementation [6,8,9]. Sixtyfour percent of the studied population received vitamin D supplies during the 6-month period, which might represent a major confounding factor. However, the mean 25(OH)D level did not statistically differ between those who received vitamin D supplies and those who did not. Despite a possible in vitro immunomodulating effect of 1,25(OH)2 D on B-cell activity[4], and in accordance with data obtained by Baker et al. using golimumab [10], we failed to detect any correlation between serum 25(OH)D levels and rituximab efficacy assessed based on the 6-month EULAR response.
[7] Kerr GS, Sabahi I, Richards JS, et al. Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol 2011;38:53–9. [8] Rossini M, Maddali Bongi S, La Montagna G, et al. Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with disease activity and disability. Arthritis Res Ther 2010;12:R216. [9] Patel S, Farragher T, Berry J, et al. Association between serum vitamin D metabolite levels and disease activity in patients with early inflammatory polyarthritis. Arthritis Rheum 2007;56:2143–9. [10] Baker JF, Baker DG, Toedter G, et al. Associations between vitamin D, disease activity, and clinical response to therapy in rheumatoid arthritis. Clin Exp Rheumatol 2012;30:658–64.
Rim Ben M’Barek a Thierry Dupré b Florence Tubach c,d,e Philippe Dieudé a,e Elisabeth Palazzo a Gilles Hayem a Karen Dawidowicz a Sébastien Ottaviani a Tony Alfaiate c,d Véronique Lec¸on-Malais b Anne Boutten b Olivier Meyer a,e,∗ a Rheumatology, AP–HP, Hôpital Bichat, Paris, France b Biochemistry, AP–HP, Hôpital Bichat, Paris, France c Département d’Epidémiologie et Recherche Clinique, AP–HP, Hôpital Bichat, Paris, France d Inserm, CIE801 Paris, France e Université Paris-Diderot, Sorbonne Paris Cité, Paris, France ∗ Corresponding
author. Rheumatology, Hôpital Bichat, 75018 Paris, France. E-mail address: [email protected] (O. Meyer)
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Accepted 30 April 2013 Available online 21 June 2013
References doi:10.1016/j.jbspin.2013.04.017 [1] Manolagas SC, Werntz DA, Tsoukas CD, et al. 1,25-Dihydroxyvitamin D3 receptors in lymphocytes from patients with rheumatoid arthritis. J Lab Clin Med 1986;108:596–600. [2] Colin EM, Asmawidjaja PS, van Hamburg JP, et al. 1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis Rheum 2010;62:132–42. [3] Peelen E, Knippenberg S, Muris AH, et al. Effects of vitamin D on the peripheral adaptive immune system: a review. Autoimmun Rev 2011;10: 733–43. [4] Chen S, Sims GP, Chen XX, et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007;179:1634–47. [5] Craig SM, Yu F, Curtis JR, et al. Vitamin D status and its associations with disease activity and severity in African Americans with recent-onset rheumatoid arthritis. J Rheumatol 2010;37:275–81. [6] Haque UJ, Bartlett SJ. Relationships among vitamin D, disease activity, pain and disability in rheumatoid arthritis. Clin Exp Rheumatol 2010;28:745–7.
IgA deficiency in primary antiphospholipid syndrome
a r t i c l e
i n f o
Keywords: IgA deficiency Immunodeficiency Antiphospholipid syndrome Antiphospholipid antibodies