http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(3): 511–516 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.843743
ORIGINAL ARTICLE
Immune response to influenza vaccine and pneumococcal polysaccharide vaccine under IL-6 signal inhibition therapy with tocilizumab Tomomi Tsuru1, Kimio Terao2, Miho Murakami3,4,5, Takaji Matsutani3, Midori Suzaki1, Toshiaki Amamoto1, Hitoshi Nakashima6, Azusa Akiyama7, and Norihiro Nishimoto3,4,5 1Medical Co. LTA PS clinic, Fukuoka, Japan, 2Chugai Pharmaceutical Co., LTD., Tokyo, Japan, 3Department of Immune Regulation, Wakayama Medical University, Wakayama, Japan, 4Department of Molecular Regulation for Intractable Diseases, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan, 5Osaka Rheumatology Clinic, Osaka, Japan, 6Division of Nephrology and Rheumatology, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan, and 7Chugai Clinical Research Center Co., LTD. Tokyo, Japan
Abstract
Keywords
Objectives. To evaluate humoral immune response to influenza vaccine and polysaccharide pneumococcal vaccine in patients with rheumatoid arthritis (RA) or Castleman’s disease (CD) during tocilizumab therapy. Methods. Thirty-eight patients (28 RA and 10 CD) receiving tocilizumab and 39 RA patients receiving TNF inhibitors and/or synthetic DMARDs subcutaneously received a single dose of a split-virion inactivated influenza vaccine containing A(New Caledonia (NC):H1N1), A(Hiroshima (HIR):H3N2) and B(Malaysia (MAL)) strains. Twenty-one RA patients using tocilizumab also received 23-valent polysaccharide pneumococcal vaccine. Antibody titers were measured every 4 weeks for a total of 12 weeks after vaccination. Results. In the tocilizumab group, seroprotective titers (40-fold or more) were obtained in 36/38(95%) for A(NC), 35/38(92%) for A(HIR) and 32/38(84%) for B(MAL). In the patients with baseline antibody titer ⬍ 40-fold, 11/11(100%), 7/8(88%) and 18/20(90%) patients showed fourfold or more increase in the titer from baseline to A(NC), A(HIR) and B(MAL), respectively. Patients using TNF inhibitors and/or DMARDs showed similar responses. Pneumococcal antibody titers increased at least two-fold in more than 9 of 12 serotypes, which continued for longer than 12 weeks in all the patients. Conclusion. Interleukin-6 (IL-6) blocking therapy with tocilizumab did not affect the humoral immune response to both influenza and pneumococcal vaccines.
Castleman’s disease, Humoral immune response, Influenza vaccine, Rheumatoid arthritis, Tocilizumab
Introduction Interleukin-6 (IL-6) is a multifunctional cytokine with a wide range of biological activities on various target cells, and it regulates the immune responses, acute phase reactions, hematopoiesis and bone metabolism [for reviews see refs 1,2]. It was originally identified as a T cell-derived factor that induced B cells to differentiate to immunoglobulin-producing cells [3]. Because of this activity, in vivo overproduction of IL-6 results in plasmacytosis [4]. IL-6 also induces T-cell proliferation and cytotoxic-T-cell differentiation [5,6]. Thus IL-6 plays an important role in host defense against infectious microorganisms such as virus and bacteria. In an IL-6 knockout mouse model, the antiviral antibody response was decreased more than 90% at a challenge of vesicular virus with a vesicular stomatitis virus in comparison with wild type mice, thus confirming that IL-6 is essential for the humoral immune response [7]. Despite important physiological roles of IL-6, deregulated overproduction of IL-6 has been shown to be pathologically Correspondence to: Norihiro Nishimoto, M.D., Osaka Rheumatology Clinic, Tatsuno-Sinsaibashi-Building 5th Floor 4-4-10 Minamisenba Chuo-ku, Osaka, 542-0081 Japan. Tel: ⫹ 81-6-4708-8852. Fax: ⫹ 81-64708-8853. E-mail: [email protected]
History Received 20 August 2012 Accepted 10 May 2013 Published online 31 October 2013
involved in various immune inflammatory diseases including rheumatoid arthritis (RA), Castleman’s disease (CD) and juvenile idiopathic arthritis (JIA) [8–11]. Thus the blockade of IL-6 actions can be a therapeutical approach for these diseases. Tocilizumab is a humanized anti-human IL-6 receptor (IL-6R) antibody which binds to the IL-6-binding site of IL-6R and competitively inhibits IL-6 actions [12]. A series of clinical studies have shown that tocilizumab is therapeutically effective for patients with RA, CD, systemic-onset JIA, poly arthritic JIA and Crohn’s disease [13–17]. Tocilizumab ameliorates the inflammatory manifestations of these diseases and normalizes acute phase protein levels including C-reactive proteins (CRP). In the tocilizumab therapy, various kinds of infections were observed similarly to TNF inhibitors [18–20]. Moreover, inflammatory symptoms of infection are often masked during IL-6 blockade therapy with tocilizumab [21]. Therefore, it is important to prevent the patients from possible infections and to diagnose the infectious diseases as early as possible. Vaccination is one of the effective methods to prevent the patients from possible infections. However, since IL-6 plays an important role in host defense by stimulating B cell differentiation and by inducing T-cell proliferation and cytotoxic-T-cell differentiation, it is concerned that humoral immune response to pathogens may be affected under IL-6 inhibition therapy using tocilizumab.
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This study aims to evaluate humoral immune response to influenza vaccine in patients with RA or CD during tocilizumab treatment, as well as to 23-vallent polysaccharide pneumococcal vaccine in patients with RA.
Materials and methods Patients For seasonal influenza vaccine, 38 patients (28 RA and 10 CD) were treated with tocilizumab therapy, 15 RA patients treated with TNF inhibitors in combination with methotrexate (MTX) and 24 patients treated with synthetic DMARDs were enrolled in this open-label study after informed consent was obtained. All the 67 patients with RA fulfilled the American college of Rheumatology (ACR; formerly, the American Rheumatism Association) 1987 revised criteria for the classification of RA [22]. CD was diagnosed both clinically and pathologically. An independent pathologist examined the histological feature of the biopsied lymph nodes from the patients and confirmed the histological diagnosis of the plasma cell type or mixed type variant [14]. Patients receiving oral corticosteroids (10 mg equivalent of prednisolone daily maximum) were eligible if the dosage had not been increased throughout the study in all treatment groups. Twenty-one RA patients from the tocilizumab group also received pneumococcal vaccine. Patients with RA essentially received tocilizumab (8 mg/kg, every 4 weeks) for at least 11 months before influenza vaccination. Patients with CD received tocilizumab 8 mg/kg, every 2 weeks for at least 3 months before influenza vaccination. In the TNF inhibitor group, six patients received etanercept at 50 mg/week in combination with 8 mg/week MTX, and nine patients received infliximab at 3 mg/kg of body weight in combination with 8 mg/ week MTX. In the synthetic DMARDs group, patients received one to four kinds of synthetic DMARDs (MTX, salazosulfapyridine, ciclosporin and bucillamine). The study was approved by the local ethics committees and all the patients gave written informed consent. Vaccines and vaccinations The seasonal influenza and pneumovax vaccines were administered to the patients on the same day as anti-rheumatic treatment (e.g. same day as TCZ, anti TNF drug or synthetic DMARD). Seasonal influenza vaccine A split-virion inactivated influenza vaccine (The research foundation for microbial diseases of Osaka University, Osaka, Japan) containing 15 μg hemagglutinin each of A(New Caledonia (NC):H1N1), A(Hiroshima (HIR):H3N2) and B(Malaysia (MAL)) strains [23], was administered subcutaneously in the upper arm. Pneumovax vaccine Pneumovax® II consisting of 23-valent serotypes of the capsular polysaccharide mixture (Merck & Co., inc., Whitehouse Station, NJ, USA) widely used in the world was subcutaneously administered in the upper arm with 0.5 mL of the vaccine containing 25 μg of each serotype [24].
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were drawn and the separated sera were stored below ⫺ 20°C until they were tested. To remove non-specific inhibitors or agglutinins, serum samples were filtrated and treated with Turkey red blood cells, sequentially. Then the antibody titers in the serum samples were measured by HI test against the antigens of three serotypes influenza strains contained in this vaccine (NC, HIR and MAL). Upper quantification limit is defined as 1280-fold. For pneumococcal vaccine, immunoglobulin G (IgG) antibody to the polyvalent Pneumococcal vaccines was measured at IBT Reference Laboratory (Kansas City, KS, USA). The serum samples were analyzed using Fluoroimmunoassay Luminex® Multiplex Platform measuring responses to 12 major serotypes: 1 (1), 8 (8), 19 (19F), 3 (3), 9 (9N), 23 (23F), 4 (4), 12 (12F), 51 (7F), 26 (6B), 14 (14) and 56 (18C). Polystyrene microspheres impregnated with paired fluorescent dyes in a unique ratio were covalently coated with a specific pneumoccocal capsular polysaccharide serotype. Twelve microsphere preparations, each coated with the 12 pneumoccocal capsular polysaccharide serotypes, were combined (multiplexed) in optimized proportions. When antipneumococcal IgG standards, control sera or test sera are mixed with the multiplexed microspheres in a filter-bottom microwell, anti-pneumoccocal capsular polysaccharide IgG in the sample will be captured by the pneumoccocal capsular polysaccharide-coated microspheres. After the microspheres were washed, r-phycoerythrin-conjugated anti-human IgG was added to the well to detect IgG captured on the microsphere surface. After a brief incubation, the multiplexed microspheres were passed through a flow cell in the Bio-Plex™ reader. The IgG concentration was calculated from a standard curve and the result was assigned to the correct pneumoccocal capsular polysaccharide serotype. Anti-pneumococcal IgG quantification was performed via the IBT Bioplex Array Reader, and data acquisition and integration were performed by means of the Accent Lab v. 3.0 LIMS System. Serological responses and statistical analysis Seropositive response was defined as the HI titer at the post-vaccination ⱖ 4-fold increase from the baseline titer against influenza antigen [25,26]. For influenza vaccine, seroprotective titer was defined as HI titer at the post-vaccination ⱖ 1:40, and the seroconversion was also defined as HI titer changed from negative (pre-vaccination titer ⬍ 1:10) to positive (post-vaccination HI titer ⱖ 1:40) [25,26]. For pneumococcal vaccine, seropositive response was defined as ⱖ 2-fold increase in antibody concentration from the baseline antibody levels in 6 out of 12 serotypes of pneumococcal vaccine [27]. To compare the serological responses to influenza vaccine among the three groups, the geometric means (GMT) of HI titer were obtained. Comparison among the treatment groups was performed using the log transformed value with ANOVA and p values ⬍ 0.05 were considered significant. Differences of response rate between the tocilizumab group and either TNF inhibitor group or synthetic DMARDs group were examined by Fisher’s exact test. All statistical analyses were performed using WinNonlin® (ver.6.1).
Results Demographic characterization of patients
Measurement of anti-vaccine antibody titers Antibody titers were measured every 4 weeks, for a total of 12 weeks after vaccination. The serological response to the influenza vaccine was investigated by the hemagglutination inhibition (HI) test. The titer was measured at the Research foundation for microbial diseases of Osaka University (Kannonji, Ehime, Japan). HI test was conducted and met a standard WHO procedure. Blood samples
Demographics and baseline disease characteristics of the patients were shown in Table 1. Mean disease duration was 9.2 years for influenza vaccine, 9.0 years for pneumococcal vaccine in the tocilizumab group, 14.7 years in the TNF inhibitor group and 10.2 years in the synthetic DMARDs group. Mean age of patients was 52 years for influenza vaccine, 54 years for pneumococcal vaccine in the tocilizumab group, 52 years in the TNF inhibitor group
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Table 1. Demographic data of the patients. Influenza vaccine
Vaccine Treatment Number of patients Gender (M/F) Age (years) Mean (range) Corticosteroid Dose (mg) Mean/median (range) Disease duration (years) Mean (range) Functional Assessment* Class (I/II/III/IV) RA stage† Stage (I/II/III/IV)
Tocilizumab All 38 8/30 52(28–68) 3.4/1(0–20) 9.5(3–23)
RA 28 5/23 49(32–63) 2.6/1(0–10) 9.2(3–23)
TNF inhibitor RA 15 3/12 52(22–72) 5.2/5.0(0–10) 14.7(4–34)
DMARDs RA 24 4/20 54(25–77) 2.8/1.5(0–10) 10.2(1–32)
Pneumovax vaccine Tocilizumab RA 21 4/17 54(28–67) 2.2/0(0–10) 9.0(3–23)
NA
3/20/5/0
4/9/2/0
16/8/0/0
1/17/3/0
NA
0/16/4/8
0/7/4/4
12/7/5/0
0/12/2/7
NA, not applicable. *RA functional status determined by American College of Rheumatology criteria. †RA stage determined by Steinbrocker criteria.
and 54 years in the synthetic DMARDs group. Mean concomitant treatment of corticosteroid dose was 3.4 (range: 0–20) mg for influenza vaccine, 2.2 (0–10) mg for pneumococcal vaccine in the tocilizumab group, 5.2 (0–10) mg in the TNF inhibitor group and 2.8 (0–10) mg years in the synthetic DMARDs group. CRP was normalized by tocilizumab in the patients both with RA and with CD throughout this vaccination study (Figure 1). Serological response to vaccines After vaccination, GMT of antibody titers markedly increased compared with the baseline titer in all the treatment groups (Figure 2). Serological responses to influenza vaccine are summarized in Table 2. In the tocilizumab group, seroprotective levels of HI titer were achieved in 36/38 (95%) for A(NC), 35/38 (92%) for A(HIR) and 32/38 (84%) for B(MAL); seropositive responses in 17/38 (45%) for A(NC), 18/38 (47%) for A(HIR) and 24/38 (63%) for B(MAL); and seroconversion in 9/11 (82%), 4/8 (50%) and 14/20 (70%) for A(NC), A(HIR) and B(MAL), respectively. In the TNF inhibitor group, seroprotective levels of HI titer were achieved in 11/15 (73%) for A(NC), 12/15 (80%) for A(HIR) and 8/15 (53%) for B(MAL); seropositive responses in 6/15 (40%) for
A(NC), 8/15 (53%) for A(HIR) and 4/15 (27%) for B(MAL); and seroconversion rates in 3/7 (43%), 6/9 (67%) and 3/10 (30%) for A(NC), A(HIR) and B(MAL), respectively. In the DMARDs group, seroprotective levels of HI titer were achieved in 22/24 (92%) for A(NC), 23/24 (96%) for A(HIR) and 21/24 (88%) for B(MAL); seropositive responses in 18/24 (75%) for A(NC), 13/24 (54%) for A(HIR) and 19/24 (79%) for B(MAL); and seroconversion rates were 10/12 (83%), 10/11(91%) and 13/16 (81%) to A(NC), A(HIR) and B(MAL), respectively. The seropositive response, seroprotective level after vaccination and seroconversion rate were similar among these treatment groups. Seropositive response to pneumococcal vaccine was observed in all the 21 patients and the antibody levels were at least twofold increase for at least 9 of 12 serotypes which continued for longer than 12 weeks. Especially, all the patients showed positive response against serotypes 1, 8, 19 (19F) and 56. Monovariate analysis for the relationship of concomitant prednisolone dosage, gender, duration of disease and IgG levels with antibody response did not show any significant correlation of these factors and the antibody responses for both influenza vaccine and pneumococcal vaccine. No patients suffered from influenza and pneumonia in this season. Safety After influenza vaccination, no systemic or injection-site reaction related to the vaccination were observed in this study. On the other hand, after pneumococcal vaccination, injection related systemic reaction was reported: fever above 38°C in 2/21 (9.5%) and injection site reaction in 12/21 (57%). In addition, injection site redness over 10 cm in diameter were reported in 8/21 (38%). and two of them showed both systemic and local injection site reactions. All these reactions spontaneously disappeared.
Discussion
Figure 1. IgG, rheumatoid factor (RF), CRP levels and DAS28 before tocilizumab therapy and at the day of vaccinations in patients with RA under tocilizumab therapy. (a) IgG, (b) RF, (c) CRP and (d) DAS28 of each patient were demonstrated. At the vaccination, IgG were within normal range and CRP was normalized. DAS28 also improved by tocilizumab therapy. *: before tocilizumab therapy.
The result of this study showed that the humoral immune response to seasonal influenza vaccine during IL-6 inhibition therapy with tocilizumab was comparable to those of the patients treated with TNF inhibitors and/or DMARDs in terms of seropositive response rate, seroprotective response rate and seroconversion rate. Although the number of patients enrolled in this study is limited, it is noteworthy that most patients achieved all the three types of serological responses. This study supports the findings reported recently by Dr. Shinoki et al. that influenza vaccination is safe and effective at a dose of 8 mg/kg every 2 weeks in patients with systemic-onset JIA, and by Dr. Mori et al. at a dose of 8 mg/kg every 4 weeks in patients with RA [28,29]. Our study also clarified that, (1) the serological response of influenza vaccine is comparable in patients with RA at a dose of
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Figure 2. GMT changes of antibody titers. GMT changes of HI titers and antibody concentrations after vaccinations were plotted. (a) A(NC), (b) A(HIR) and (c) B(MAL) of influenza vaccine: solid with closed circle shows tocilizumab, broken line with closed square shows TNF inhibitors and dotted line with closed triangle shows synthetic DMARDs. Vertical bar shows standard deviation. (d) antibody concentrations against 12 serotypes (1 [1], 8 [8], 19 [19F], 3 [3], 9 [9N], 23 [23F], 4 [4], 12 [12F], 51 [7F], 26 [6B], 14 [14] and 56 [18C]) from pneumovax vaccine.
8 mg/kg every 4 weeks to a dose of 8 mg/kg every 2 weeks in patients with CD, (2) serological response to influenza vaccine in patients with RA under tocilizumab treatment was similar to the response in patients with RA receiving TNF inhibitors or synthetic DMARD and (3) the pneumovax vaccine was tolerated and effective in patients with RA. At baseline, 47, 43 and 31 patients showed seroprotective levels of antibody titers against A(NC), A(HIR) and B(MAL), respectively, indicating that these patients were immuninized with previously received influenza vaccine or with naturally infected viruses and maintained the immunity even under the treatment using biologic and/or synthetic DMARDs. Even in such patients, a further increase in the titers was observed more than upper limit of quantification (1280-folds). In addition, in the patients whose baseline titer was ⬍ 40-fold, 9 out of 11, 4 out of 8 and 14 out of 20
patients showed seroconversion and obtained seroprotective levels of antibodies against A(NC), A(HIR) and B(MAL), respectively. These data again confirmed the benefit of influenza vaccination in these patients. The response to pneumococcal vaccine was also comparable to the previously reported data [30,31]. Regarding the pneumococcal vaccine, however, the seroconversion rate by pneumococcal vaccine could not be discussed in this study, because precise seroprotective levels of antibody titers quantified by ELISA method has not been established for pneumococcal infection yet [32]. The mechanisms of immunological responses are different between influenza vaccine and pneumococcal vaccine. The antibody production induced by purified or mixed protein and/or peptide such as influenza vaccine has been reported to be regulated
Table 2. Numbers of patients with seropositive response, seroprotective levels of antibody, seroconversion after influenza vaccine and seropositive response after pneumococcal vaccine. Influenza vaccine
Vaccine Treatment Number of patients Seropositive response A(NC) A(HIR) B(MAL) Seroprotective level after vaccination A(NC) A(HIR) B(MAL) Seroconversion A(NC) A(HIR) B(MAL) All: RA ⫹ CD. TNF inhibitors: infliximab and etanercept.
Tocilizumab All RA 38 28
TNF inhibitor RA 15
DMARDs RA 24
17/38 18/38 24/38
10/28 13/28 18/28
6/15 8/15 4/15
18/24 13/24 19/24
36/38 35/38 32/38
26/28 25/28 22/28
11/15 12/15 8/15
22/24 23/24 21/24
9/11 4/8 14/20
5/7 3/6 10/16
3/7 6/9 3/10
10/12 10/11 13/16
Seropositive response
Pneumovax vaccine Tocilizumab RA 21 21/21
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by B-cell and memory T-cell responses [33] but the antibody production by B cells against polysaccharide vaccine such as pneumococcal vaccine is T cell independent [34]. This study clearly demonstrated that tocilizumab treatment did not affect the immune response to both types of vaccines. We emphasize that this study found vaccination is safe and effective on the same day as tocilizumab infusion. We need to address the difference in the humoral immune response between IL-6 knockout mice and patients treated with tocilizumab. In contrast to the IL-6 knockout mice of which antiviral antibody response is decreased more than 90% [7], patients receiving tocilizumab treatment showed sufficient humoral response to the vaccines. This difference may be because tocilizumab concentration is not enough to inhibit fully IL-6 action required for the immune response to vaccination in the local skin lesion where antigen presenting cells such as dendritic cells are dominant, while IL-6 is systemically and completely abolished in IL-6 knockout mice. Indeed, we observed a mild redness and itching in the injection site in our patients, indicating that some local inflammatory responses occurred although tocilizumab treatment normalized CRP levels. Further study will be required to know the difference in the mechanisms of IL-6 action on antibody production and CRP production. In this study, vaccinations for influenza and pneumococcus appeared to be relatively safe, but this is not applicable to live vaccines such as rubella vaccine. We should not give live vaccines to patients receiving biologic DMARDs including tocilizumab because safety has not been established for live vaccines. Our data clearly indicate that humoral immune response to influenza and pneumococcal vaccines is not significantly affected by tocilizumab treatment, and the patients are able to obtain seroprotective antibody titers. Since IL-6 blockade therapy with tocilizumab may mask the inflammatory symptoms of infections, and consequently may delay diagnosis of the infectious diseases, we highly recommend patients to receive these vaccines during tocilizumab treatment.
Acknowledgements
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The author would like to thank Mr. Nobuhiro Takagi for advice on preparing manuscript. 19.
Conflict of interest K.T. and A.A. are employees of Chugai Pharmaceutical Co., Ltd., whose product (tocilizumab) was studied in the present work. N.N., as a medical advisor, received a consulting fee and royalty for a soJIA patent from Chugai Pharmaceutical Co., Ltd.. He also works on the scientific advisory board of Hoffmann-La Roche who developed TCZ in collaboration with Chugai Pharmaceutical Co., Ltd. T.T., M.M., T.M., M.S., T.A. and H.N. declare no competing financial interests.
20.
Funding
22.
21.
This study was financially supported by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
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ORIGINAL ARTICLE
Immune response to influenza vaccine and pneumococcal polysaccharide vaccine under IL-6 signal inhibition therapy with tocilizumab Tomomi Tsuru1, Kimio Terao2, Miho Murakami3,4,5, Takaji Matsutani3, Midori Suzaki1, Toshiaki Amamoto1, Hitoshi Nakashima6, Azusa Akiyama7, and Norihiro Nishimoto3,4,5 1Medical Co. LTA PS clinic, Fukuoka, Japan, 2Chugai Pharmaceutical Co., LTD., Tokyo, Japan, 3Department of Immune Regulation, Wakayama Medical University, Wakayama, Japan, 4Department of Molecular Regulation for Intractable Diseases, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan, 5Osaka Rheumatology Clinic, Osaka, Japan, 6Division of Nephrology and Rheumatology, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan, and 7Chugai Clinical Research Center Co., LTD. Tokyo, Japan
Abstract
Keywords
Objectives. To evaluate humoral immune response to influenza vaccine and polysaccharide pneumococcal vaccine in patients with rheumatoid arthritis (RA) or Castleman’s disease (CD) during tocilizumab therapy. Methods. Thirty-eight patients (28 RA and 10 CD) receiving tocilizumab and 39 RA patients receiving TNF inhibitors and/or synthetic DMARDs subcutaneously received a single dose of a split-virion inactivated influenza vaccine containing A(New Caledonia (NC):H1N1), A(Hiroshima (HIR):H3N2) and B(Malaysia (MAL)) strains. Twenty-one RA patients using tocilizumab also received 23-valent polysaccharide pneumococcal vaccine. Antibody titers were measured every 4 weeks for a total of 12 weeks after vaccination. Results. In the tocilizumab group, seroprotective titers (40-fold or more) were obtained in 36/38(95%) for A(NC), 35/38(92%) for A(HIR) and 32/38(84%) for B(MAL). In the patients with baseline antibody titer ⬍ 40-fold, 11/11(100%), 7/8(88%) and 18/20(90%) patients showed fourfold or more increase in the titer from baseline to A(NC), A(HIR) and B(MAL), respectively. Patients using TNF inhibitors and/or DMARDs showed similar responses. Pneumococcal antibody titers increased at least two-fold in more than 9 of 12 serotypes, which continued for longer than 12 weeks in all the patients. Conclusion. Interleukin-6 (IL-6) blocking therapy with tocilizumab did not affect the humoral immune response to both influenza and pneumococcal vaccines.
Castleman’s disease, Humoral immune response, Influenza vaccine, Rheumatoid arthritis, Tocilizumab
Introduction Interleukin-6 (IL-6) is a multifunctional cytokine with a wide range of biological activities on various target cells, and it regulates the immune responses, acute phase reactions, hematopoiesis and bone metabolism [for reviews see refs 1,2]. It was originally identified as a T cell-derived factor that induced B cells to differentiate to immunoglobulin-producing cells [3]. Because of this activity, in vivo overproduction of IL-6 results in plasmacytosis [4]. IL-6 also induces T-cell proliferation and cytotoxic-T-cell differentiation [5,6]. Thus IL-6 plays an important role in host defense against infectious microorganisms such as virus and bacteria. In an IL-6 knockout mouse model, the antiviral antibody response was decreased more than 90% at a challenge of vesicular virus with a vesicular stomatitis virus in comparison with wild type mice, thus confirming that IL-6 is essential for the humoral immune response [7]. Despite important physiological roles of IL-6, deregulated overproduction of IL-6 has been shown to be pathologically Correspondence to: Norihiro Nishimoto, M.D., Osaka Rheumatology Clinic, Tatsuno-Sinsaibashi-Building 5th Floor 4-4-10 Minamisenba Chuo-ku, Osaka, 542-0081 Japan. Tel: ⫹ 81-6-4708-8852. Fax: ⫹ 81-64708-8853. E-mail: [email protected]
History Received 20 August 2012 Accepted 10 May 2013 Published online 31 October 2013
involved in various immune inflammatory diseases including rheumatoid arthritis (RA), Castleman’s disease (CD) and juvenile idiopathic arthritis (JIA) [8–11]. Thus the blockade of IL-6 actions can be a therapeutical approach for these diseases. Tocilizumab is a humanized anti-human IL-6 receptor (IL-6R) antibody which binds to the IL-6-binding site of IL-6R and competitively inhibits IL-6 actions [12]. A series of clinical studies have shown that tocilizumab is therapeutically effective for patients with RA, CD, systemic-onset JIA, poly arthritic JIA and Crohn’s disease [13–17]. Tocilizumab ameliorates the inflammatory manifestations of these diseases and normalizes acute phase protein levels including C-reactive proteins (CRP). In the tocilizumab therapy, various kinds of infections were observed similarly to TNF inhibitors [18–20]. Moreover, inflammatory symptoms of infection are often masked during IL-6 blockade therapy with tocilizumab [21]. Therefore, it is important to prevent the patients from possible infections and to diagnose the infectious diseases as early as possible. Vaccination is one of the effective methods to prevent the patients from possible infections. However, since IL-6 plays an important role in host defense by stimulating B cell differentiation and by inducing T-cell proliferation and cytotoxic-T-cell differentiation, it is concerned that humoral immune response to pathogens may be affected under IL-6 inhibition therapy using tocilizumab.
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This study aims to evaluate humoral immune response to influenza vaccine in patients with RA or CD during tocilizumab treatment, as well as to 23-vallent polysaccharide pneumococcal vaccine in patients with RA.
Materials and methods Patients For seasonal influenza vaccine, 38 patients (28 RA and 10 CD) were treated with tocilizumab therapy, 15 RA patients treated with TNF inhibitors in combination with methotrexate (MTX) and 24 patients treated with synthetic DMARDs were enrolled in this open-label study after informed consent was obtained. All the 67 patients with RA fulfilled the American college of Rheumatology (ACR; formerly, the American Rheumatism Association) 1987 revised criteria for the classification of RA [22]. CD was diagnosed both clinically and pathologically. An independent pathologist examined the histological feature of the biopsied lymph nodes from the patients and confirmed the histological diagnosis of the plasma cell type or mixed type variant [14]. Patients receiving oral corticosteroids (10 mg equivalent of prednisolone daily maximum) were eligible if the dosage had not been increased throughout the study in all treatment groups. Twenty-one RA patients from the tocilizumab group also received pneumococcal vaccine. Patients with RA essentially received tocilizumab (8 mg/kg, every 4 weeks) for at least 11 months before influenza vaccination. Patients with CD received tocilizumab 8 mg/kg, every 2 weeks for at least 3 months before influenza vaccination. In the TNF inhibitor group, six patients received etanercept at 50 mg/week in combination with 8 mg/week MTX, and nine patients received infliximab at 3 mg/kg of body weight in combination with 8 mg/ week MTX. In the synthetic DMARDs group, patients received one to four kinds of synthetic DMARDs (MTX, salazosulfapyridine, ciclosporin and bucillamine). The study was approved by the local ethics committees and all the patients gave written informed consent. Vaccines and vaccinations The seasonal influenza and pneumovax vaccines were administered to the patients on the same day as anti-rheumatic treatment (e.g. same day as TCZ, anti TNF drug or synthetic DMARD). Seasonal influenza vaccine A split-virion inactivated influenza vaccine (The research foundation for microbial diseases of Osaka University, Osaka, Japan) containing 15 μg hemagglutinin each of A(New Caledonia (NC):H1N1), A(Hiroshima (HIR):H3N2) and B(Malaysia (MAL)) strains [23], was administered subcutaneously in the upper arm. Pneumovax vaccine Pneumovax® II consisting of 23-valent serotypes of the capsular polysaccharide mixture (Merck & Co., inc., Whitehouse Station, NJ, USA) widely used in the world was subcutaneously administered in the upper arm with 0.5 mL of the vaccine containing 25 μg of each serotype [24].
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were drawn and the separated sera were stored below ⫺ 20°C until they were tested. To remove non-specific inhibitors or agglutinins, serum samples were filtrated and treated with Turkey red blood cells, sequentially. Then the antibody titers in the serum samples were measured by HI test against the antigens of three serotypes influenza strains contained in this vaccine (NC, HIR and MAL). Upper quantification limit is defined as 1280-fold. For pneumococcal vaccine, immunoglobulin G (IgG) antibody to the polyvalent Pneumococcal vaccines was measured at IBT Reference Laboratory (Kansas City, KS, USA). The serum samples were analyzed using Fluoroimmunoassay Luminex® Multiplex Platform measuring responses to 12 major serotypes: 1 (1), 8 (8), 19 (19F), 3 (3), 9 (9N), 23 (23F), 4 (4), 12 (12F), 51 (7F), 26 (6B), 14 (14) and 56 (18C). Polystyrene microspheres impregnated with paired fluorescent dyes in a unique ratio were covalently coated with a specific pneumoccocal capsular polysaccharide serotype. Twelve microsphere preparations, each coated with the 12 pneumoccocal capsular polysaccharide serotypes, were combined (multiplexed) in optimized proportions. When antipneumococcal IgG standards, control sera or test sera are mixed with the multiplexed microspheres in a filter-bottom microwell, anti-pneumoccocal capsular polysaccharide IgG in the sample will be captured by the pneumoccocal capsular polysaccharide-coated microspheres. After the microspheres were washed, r-phycoerythrin-conjugated anti-human IgG was added to the well to detect IgG captured on the microsphere surface. After a brief incubation, the multiplexed microspheres were passed through a flow cell in the Bio-Plex™ reader. The IgG concentration was calculated from a standard curve and the result was assigned to the correct pneumoccocal capsular polysaccharide serotype. Anti-pneumococcal IgG quantification was performed via the IBT Bioplex Array Reader, and data acquisition and integration were performed by means of the Accent Lab v. 3.0 LIMS System. Serological responses and statistical analysis Seropositive response was defined as the HI titer at the post-vaccination ⱖ 4-fold increase from the baseline titer against influenza antigen [25,26]. For influenza vaccine, seroprotective titer was defined as HI titer at the post-vaccination ⱖ 1:40, and the seroconversion was also defined as HI titer changed from negative (pre-vaccination titer ⬍ 1:10) to positive (post-vaccination HI titer ⱖ 1:40) [25,26]. For pneumococcal vaccine, seropositive response was defined as ⱖ 2-fold increase in antibody concentration from the baseline antibody levels in 6 out of 12 serotypes of pneumococcal vaccine [27]. To compare the serological responses to influenza vaccine among the three groups, the geometric means (GMT) of HI titer were obtained. Comparison among the treatment groups was performed using the log transformed value with ANOVA and p values ⬍ 0.05 were considered significant. Differences of response rate between the tocilizumab group and either TNF inhibitor group or synthetic DMARDs group were examined by Fisher’s exact test. All statistical analyses were performed using WinNonlin® (ver.6.1).
Results Demographic characterization of patients
Measurement of anti-vaccine antibody titers Antibody titers were measured every 4 weeks, for a total of 12 weeks after vaccination. The serological response to the influenza vaccine was investigated by the hemagglutination inhibition (HI) test. The titer was measured at the Research foundation for microbial diseases of Osaka University (Kannonji, Ehime, Japan). HI test was conducted and met a standard WHO procedure. Blood samples
Demographics and baseline disease characteristics of the patients were shown in Table 1. Mean disease duration was 9.2 years for influenza vaccine, 9.0 years for pneumococcal vaccine in the tocilizumab group, 14.7 years in the TNF inhibitor group and 10.2 years in the synthetic DMARDs group. Mean age of patients was 52 years for influenza vaccine, 54 years for pneumococcal vaccine in the tocilizumab group, 52 years in the TNF inhibitor group
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Table 1. Demographic data of the patients. Influenza vaccine
Vaccine Treatment Number of patients Gender (M/F) Age (years) Mean (range) Corticosteroid Dose (mg) Mean/median (range) Disease duration (years) Mean (range) Functional Assessment* Class (I/II/III/IV) RA stage† Stage (I/II/III/IV)
Tocilizumab All 38 8/30 52(28–68) 3.4/1(0–20) 9.5(3–23)
RA 28 5/23 49(32–63) 2.6/1(0–10) 9.2(3–23)
TNF inhibitor RA 15 3/12 52(22–72) 5.2/5.0(0–10) 14.7(4–34)
DMARDs RA 24 4/20 54(25–77) 2.8/1.5(0–10) 10.2(1–32)
Pneumovax vaccine Tocilizumab RA 21 4/17 54(28–67) 2.2/0(0–10) 9.0(3–23)
NA
3/20/5/0
4/9/2/0
16/8/0/0
1/17/3/0
NA
0/16/4/8
0/7/4/4
12/7/5/0
0/12/2/7
NA, not applicable. *RA functional status determined by American College of Rheumatology criteria. †RA stage determined by Steinbrocker criteria.
and 54 years in the synthetic DMARDs group. Mean concomitant treatment of corticosteroid dose was 3.4 (range: 0–20) mg for influenza vaccine, 2.2 (0–10) mg for pneumococcal vaccine in the tocilizumab group, 5.2 (0–10) mg in the TNF inhibitor group and 2.8 (0–10) mg years in the synthetic DMARDs group. CRP was normalized by tocilizumab in the patients both with RA and with CD throughout this vaccination study (Figure 1). Serological response to vaccines After vaccination, GMT of antibody titers markedly increased compared with the baseline titer in all the treatment groups (Figure 2). Serological responses to influenza vaccine are summarized in Table 2. In the tocilizumab group, seroprotective levels of HI titer were achieved in 36/38 (95%) for A(NC), 35/38 (92%) for A(HIR) and 32/38 (84%) for B(MAL); seropositive responses in 17/38 (45%) for A(NC), 18/38 (47%) for A(HIR) and 24/38 (63%) for B(MAL); and seroconversion in 9/11 (82%), 4/8 (50%) and 14/20 (70%) for A(NC), A(HIR) and B(MAL), respectively. In the TNF inhibitor group, seroprotective levels of HI titer were achieved in 11/15 (73%) for A(NC), 12/15 (80%) for A(HIR) and 8/15 (53%) for B(MAL); seropositive responses in 6/15 (40%) for
A(NC), 8/15 (53%) for A(HIR) and 4/15 (27%) for B(MAL); and seroconversion rates in 3/7 (43%), 6/9 (67%) and 3/10 (30%) for A(NC), A(HIR) and B(MAL), respectively. In the DMARDs group, seroprotective levels of HI titer were achieved in 22/24 (92%) for A(NC), 23/24 (96%) for A(HIR) and 21/24 (88%) for B(MAL); seropositive responses in 18/24 (75%) for A(NC), 13/24 (54%) for A(HIR) and 19/24 (79%) for B(MAL); and seroconversion rates were 10/12 (83%), 10/11(91%) and 13/16 (81%) to A(NC), A(HIR) and B(MAL), respectively. The seropositive response, seroprotective level after vaccination and seroconversion rate were similar among these treatment groups. Seropositive response to pneumococcal vaccine was observed in all the 21 patients and the antibody levels were at least twofold increase for at least 9 of 12 serotypes which continued for longer than 12 weeks. Especially, all the patients showed positive response against serotypes 1, 8, 19 (19F) and 56. Monovariate analysis for the relationship of concomitant prednisolone dosage, gender, duration of disease and IgG levels with antibody response did not show any significant correlation of these factors and the antibody responses for both influenza vaccine and pneumococcal vaccine. No patients suffered from influenza and pneumonia in this season. Safety After influenza vaccination, no systemic or injection-site reaction related to the vaccination were observed in this study. On the other hand, after pneumococcal vaccination, injection related systemic reaction was reported: fever above 38°C in 2/21 (9.5%) and injection site reaction in 12/21 (57%). In addition, injection site redness over 10 cm in diameter were reported in 8/21 (38%). and two of them showed both systemic and local injection site reactions. All these reactions spontaneously disappeared.
Discussion
Figure 1. IgG, rheumatoid factor (RF), CRP levels and DAS28 before tocilizumab therapy and at the day of vaccinations in patients with RA under tocilizumab therapy. (a) IgG, (b) RF, (c) CRP and (d) DAS28 of each patient were demonstrated. At the vaccination, IgG were within normal range and CRP was normalized. DAS28 also improved by tocilizumab therapy. *: before tocilizumab therapy.
The result of this study showed that the humoral immune response to seasonal influenza vaccine during IL-6 inhibition therapy with tocilizumab was comparable to those of the patients treated with TNF inhibitors and/or DMARDs in terms of seropositive response rate, seroprotective response rate and seroconversion rate. Although the number of patients enrolled in this study is limited, it is noteworthy that most patients achieved all the three types of serological responses. This study supports the findings reported recently by Dr. Shinoki et al. that influenza vaccination is safe and effective at a dose of 8 mg/kg every 2 weeks in patients with systemic-onset JIA, and by Dr. Mori et al. at a dose of 8 mg/kg every 4 weeks in patients with RA [28,29]. Our study also clarified that, (1) the serological response of influenza vaccine is comparable in patients with RA at a dose of
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Figure 2. GMT changes of antibody titers. GMT changes of HI titers and antibody concentrations after vaccinations were plotted. (a) A(NC), (b) A(HIR) and (c) B(MAL) of influenza vaccine: solid with closed circle shows tocilizumab, broken line with closed square shows TNF inhibitors and dotted line with closed triangle shows synthetic DMARDs. Vertical bar shows standard deviation. (d) antibody concentrations against 12 serotypes (1 [1], 8 [8], 19 [19F], 3 [3], 9 [9N], 23 [23F], 4 [4], 12 [12F], 51 [7F], 26 [6B], 14 [14] and 56 [18C]) from pneumovax vaccine.
8 mg/kg every 4 weeks to a dose of 8 mg/kg every 2 weeks in patients with CD, (2) serological response to influenza vaccine in patients with RA under tocilizumab treatment was similar to the response in patients with RA receiving TNF inhibitors or synthetic DMARD and (3) the pneumovax vaccine was tolerated and effective in patients with RA. At baseline, 47, 43 and 31 patients showed seroprotective levels of antibody titers against A(NC), A(HIR) and B(MAL), respectively, indicating that these patients were immuninized with previously received influenza vaccine or with naturally infected viruses and maintained the immunity even under the treatment using biologic and/or synthetic DMARDs. Even in such patients, a further increase in the titers was observed more than upper limit of quantification (1280-folds). In addition, in the patients whose baseline titer was ⬍ 40-fold, 9 out of 11, 4 out of 8 and 14 out of 20
patients showed seroconversion and obtained seroprotective levels of antibodies against A(NC), A(HIR) and B(MAL), respectively. These data again confirmed the benefit of influenza vaccination in these patients. The response to pneumococcal vaccine was also comparable to the previously reported data [30,31]. Regarding the pneumococcal vaccine, however, the seroconversion rate by pneumococcal vaccine could not be discussed in this study, because precise seroprotective levels of antibody titers quantified by ELISA method has not been established for pneumococcal infection yet [32]. The mechanisms of immunological responses are different between influenza vaccine and pneumococcal vaccine. The antibody production induced by purified or mixed protein and/or peptide such as influenza vaccine has been reported to be regulated
Table 2. Numbers of patients with seropositive response, seroprotective levels of antibody, seroconversion after influenza vaccine and seropositive response after pneumococcal vaccine. Influenza vaccine
Vaccine Treatment Number of patients Seropositive response A(NC) A(HIR) B(MAL) Seroprotective level after vaccination A(NC) A(HIR) B(MAL) Seroconversion A(NC) A(HIR) B(MAL) All: RA ⫹ CD. TNF inhibitors: infliximab and etanercept.
Tocilizumab All RA 38 28
TNF inhibitor RA 15
DMARDs RA 24
17/38 18/38 24/38
10/28 13/28 18/28
6/15 8/15 4/15
18/24 13/24 19/24
36/38 35/38 32/38
26/28 25/28 22/28
11/15 12/15 8/15
22/24 23/24 21/24
9/11 4/8 14/20
5/7 3/6 10/16
3/7 6/9 3/10
10/12 10/11 13/16
Seropositive response
Pneumovax vaccine Tocilizumab RA 21 21/21
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by B-cell and memory T-cell responses [33] but the antibody production by B cells against polysaccharide vaccine such as pneumococcal vaccine is T cell independent [34]. This study clearly demonstrated that tocilizumab treatment did not affect the immune response to both types of vaccines. We emphasize that this study found vaccination is safe and effective on the same day as tocilizumab infusion. We need to address the difference in the humoral immune response between IL-6 knockout mice and patients treated with tocilizumab. In contrast to the IL-6 knockout mice of which antiviral antibody response is decreased more than 90% [7], patients receiving tocilizumab treatment showed sufficient humoral response to the vaccines. This difference may be because tocilizumab concentration is not enough to inhibit fully IL-6 action required for the immune response to vaccination in the local skin lesion where antigen presenting cells such as dendritic cells are dominant, while IL-6 is systemically and completely abolished in IL-6 knockout mice. Indeed, we observed a mild redness and itching in the injection site in our patients, indicating that some local inflammatory responses occurred although tocilizumab treatment normalized CRP levels. Further study will be required to know the difference in the mechanisms of IL-6 action on antibody production and CRP production. In this study, vaccinations for influenza and pneumococcus appeared to be relatively safe, but this is not applicable to live vaccines such as rubella vaccine. We should not give live vaccines to patients receiving biologic DMARDs including tocilizumab because safety has not been established for live vaccines. Our data clearly indicate that humoral immune response to influenza and pneumococcal vaccines is not significantly affected by tocilizumab treatment, and the patients are able to obtain seroprotective antibody titers. Since IL-6 blockade therapy with tocilizumab may mask the inflammatory symptoms of infections, and consequently may delay diagnosis of the infectious diseases, we highly recommend patients to receive these vaccines during tocilizumab treatment.
Acknowledgements
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14. 15.
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18.
The author would like to thank Mr. Nobuhiro Takagi for advice on preparing manuscript. 19.
Conflict of interest K.T. and A.A. are employees of Chugai Pharmaceutical Co., Ltd., whose product (tocilizumab) was studied in the present work. N.N., as a medical advisor, received a consulting fee and royalty for a soJIA patent from Chugai Pharmaceutical Co., Ltd.. He also works on the scientific advisory board of Hoffmann-La Roche who developed TCZ in collaboration with Chugai Pharmaceutical Co., Ltd. T.T., M.M., T.M., M.S., T.A. and H.N. declare no competing financial interests.
20.
Funding
22.
21.
This study was financially supported by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
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Copyright of Modern Rheumatology is the property of Springer Science & Business Media B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of Modern Rheumatology (Informa Healthcare) is the property of Informa Healthcare and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
