Research ArticleArticle

Tuberculosis Risk in Patients Treated with Non-Anti-Tumor Necrosis Factor-α (TNF-α) Targeted Biologics and Recently Licensed TNF-α Inhibitors: Data from Clinical Trials and National Registries

Fabrizio Cantini, Laura Niccoli and Delia Goletti
The Journal of Rheumatology Supplement May 2014, 91 56-64; DOI: https://doi.org/10.3899/jrheum.140103

Abstract

This review aimed to evaluate the risk of active tuberculosis (TB) occurrence in patients with rheumatic disorders receiving non-anti-tumor necrosis factor (TNF) targeted biologics anakinra (ANK), tocilizumab (TCZ), rituximab (RTX), abatacept (ABA), and recently approved anti-TNF golimumab (GOL), and certolizumab pegol (CTP). In recent findings, no cases of active TB were recorded in patients with rheumatoid arthritis (RA) and other rheumatic conditions treated with anti-CD20+ RTX and anti-CD28 ABA. No patient receiving anti-interleukin 1 (IL-1) ANK developed active TB, and an increased risk was excluded in a Canadian database. In contrast, 8 active TB cases were observed in 21 trials of patients with RA receiving anti-IL-6 TCZ, while no increased TB risk resulted from Japanese postmarketing surveillance. Among GOL-treated and CTP-treated patients, 8 and 10 active TB cases occurred, respectively, while no data are available from registries. However, all but 1 TB case recorded in patients treated with TCZ, GOL, and CTP occurred in TB-endemic countries. No TB risk resulted for ANK, RTX, and ABA, suggesting pretreatment screening procedures for latent TB infection detection are unnecessary. Because all TB cases occurred in countries at high risk for TB, where TB exposure could have occurred during treatment, no definitive conclusions can be drawn for TCZ, GOL, and CTP.

Key Indexing Terms:

Anti-tumor necrosis factor-α (TNF-α) agents have ensured important efficacy advantages in the treatment of inflammatory rheumatic diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA). Moreover, wide off-label use of these drugs is made in other rheumatic disorders such as vasculitis, Behçet disease, and adult-onset Still disease. However, it has long been recognized that currently used TNF-α infliximab, etanercept, and adalimumab increase the risk of tuberculosis (TB) reactivation, and latent TB infection (LTBI) detection and TB prevention represent a current worldwide challenge for rheumatologists1. Indeed, anti-TNF-α agents facilitate the progression from LTBI to active TB by interfering with different steps of immune response against Mycobacterium tuberculosis such as chemokine secretion, downregulation of adhesion molecules, interferon-γ (IFN-γ) production and its effects on macrophage activation, and CD4+ and CD8+ T cell function2. Multiple biologics targeted to cytokines other than TNF-α, or to T and B cells of immune response, have been licensed over time, including anti-interleukin 1 (IL-1) anakinra (ANK), IL-6 inhibitor tocilizumab (TCZ), anti-CD20 rituximab (RTX), and anti-CD28 abatacept (ABA). Moreover, 2 new anti-TNF-α agents, golimumab (GOL) and certolizumab pegol (CTP), have recently been approved, the former for the treatment of RA, AS, and PsA, and the latter for RA only.

The aim of the present report was to assess TB risk in patients with rheumatic diseases exposed to currently available non-anti-TNF biologics and to the new anti-TNF drugs, through a review of safety results in clinical trials and, when available, data from national biologic registries. The literature search was extended to May 31, 2013.

Anakinra

ANK is a recombinant non-glycosylated homolog of the human IL-1 receptor antagonist (IL-1Ra) that competitively inhibits binding of IL-1 with its receptor3. The drug has been licensed for the treatment of RA at the dose of 100 mg/day by subcutaneous injection. In recent years ANK has also been used in the treatment of JIA, autoinflammatory diseases4, and gout5. IL-1 does not seem to be implicated in the control of TB infection6; this may explain the low or absent risk of TB in patients treated with ANK observed in clinical trials and real-life practice: Indeed, only 1 case of TB reactivation in a Greek female after 23 months of ANK therapy has been reported7. Of note, this patient was treated for active pulmonary TB 6 years before, and there is no information regarding correct adherence to TB therapy, and of TB recovery evaluation. Otherwise, no cases of TB were observed in 7964 patients with RA8,9,10,11,12,13,14,15,16,17,18,19, 35 patients with adult-onset Still disease20,21,22, and 216 with JIA23,24,25,26,27,28. In addition, data from a Canadian registry confirm no increased risk of TB in ANK-treated patients29. According to these data, ANK does not increase the risk of TB reactivation or new active TB cases.

Rituximab

RTX is a genetically engineered chimeric mouse-human monoclonal antibody that selectively depletes the CD20+ peripheral B cell subpopulation. CD20+ B cell depletion occurs through multiple mechanisms, including antibody-dependent cellular toxicity, complement-mediated lysis, and induction of apoptosis30. Because the immune response toward TB infection and reactivation is under the control of T lymphocytes31, as expected, no cases of active TB were recorded in 9 randomized controlled trials of RTX recruiting 3623 patients with RA32,33,34,35,36,37,38,39,40. In addition, no TB cases were observed in patients receiving RTX for the treatment of Sjögren syndrome41,42, mixed cryoglobulinemia43,44, antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis45,46, and systemic lupus erythematosus (SLE)47,48. Confirming the data from clinical trials, no cases of TB reactivation or new active TB were recorded in the French AutoImmunity and Rituximab registry, including 1681 patients with RA and SLE treated with RTX49,50. In keeping with these findings, none of 370 patients receiving RTX for the treatment of different autoimmune disorders included in the GRAID registry from Germany developed active TB over a longterm followup period51. Similar results were observed in 58 patients with ANCA-associated vasculitis in a recent report from the same registry52.

Hence, according to the Rituximab Consensus Expert Committee53, data from the literature indicate a negligible TB risk in patients with rheumatic diseases receiving RTX, and suggest that screening procedures for LTBI detection before starting therapy are unnecessary.

Tocilizumab

TCZ is a recombinant, humanized, monoclonal, anti-IL-6 receptor antibody competing for both the membrane-bound and soluble forms of human IL-6 receptor with inhibition of the binding of IL-6 to its receptors and its proinflammatory activity54. The drug is currently approved, combined or in monotherapy, for the treatment of RA. Our literature search disclosed 21 clinical trials of 10,281 patients with RA55-59,60-69,70-75, with clinical observation over 24 weeks in 8384 patients (81.5%) in 14 trials, during 1 year in 1754 patients (17%) in 3 trials, and during 5 years in 143 patients (1.5%) in 1 study. Of note, LTBI screening procedures and TB reactivation prophylaxis were included in the protocol as an inclusion criterion in only 2 studies59,63. Moreover, 4 clinical trials of TCZ in 205 patients with JIA76,77,78,79, 2 open clinical series of 31 patients with SLE80,81, 1 of 21 patients with spondyloarthritis82, and 3 open-label studies of 13 patients with large-vessel vasculitis and 3 patients with polymyalgia rheumatica83,84,85 were found.

Overall, no TB cases were recorded in any reported series, even if the short-term duration of clinical observation in most trials may have not exactly highlighted the topic, especially for worldwide multicenter studies involving countries at higher risk of TB infection. Confirming this issue, 8 patients with active TB were reported over time86, respectively, from Thailand, Spain, South Africa, Peru, Singapore, Brazil, and Mexico (Table 1).

View this table:
Table 1.

Reported cases of tuberculosis (TB) in patients receiving other than anti-tumor necrosis factor (TNF) biologics and recently licensed TNF inhibitors.

Owing to its recent use in clinical practice, there are no data on TCZ and TB risk from national registries. In published postmarketing surveillance from Japan87, 4 out of 3881 patients developed active TB at intervals ranging from 24 days to 4 months after starting TCZ therapy, with an incidence of 22/100,000/year, which was not higher than that reported by the World Health Organization in Japan, where TB incidence in the general population ranges from 15 to more than 30/100,000/year88.

Data from clinical trials suggest a very low risk of TB reactivation in patients receiving TCZ. However, although the reported frequency of active TB is low, LTBI screening procedures are suggested before starting TCZ.

Abatacept

ABA is a soluble fully human fusion protein consisting of the extracellular domain of human cytotoxic T lymphocyte-associated antigen 4-IgG1 fusion linked to the modified Fc (hinge CH2 and CH3 domains) portion of human immunoglobulin G1 (IgG1). ABA blocks activation of T cells by binding to costimulatory proteins present on antigen-presenting cells (APC; CD80/86 on APC and CD28 on T cells)89. The drug has been approved for the treatment of RA, and it is administered intravenously every 4 weeks at a dose of 10 mg/kg. Although CD8/CD28 T cell-reduced expression may interfere with the immune response against TB infection90, no cases of active TB were registered in 16 trials of ABA administered either intravenously or subcutaneously in 7530 patients with RA89,91-99,100,101,102, 103,104,105, with a followup extended up to 5 years106. Similarly, no TB cases were recorded in 1 trial of 175 patients with SLE107, 190 with JIA108, and 170 with PsA109. Data from real-life practice confirm the absence of ABA-related TB reactivation risk. Indeed, no TB cases were recorded in 682 patients included in the ORA French registry110, and to the best of our knowledge no single case description of TB occurrence in patients treated with ABA is reported.

This large body of evidence suggests that ABA does not increase the risk of TB reactivation, and although required by regulatory authorities, the screening procedures for LTBI detection seem unnecessary.

Golimumab

GOL is a human anti-TNF-α IgG1κ monoclonal antibody approved in 2009 for the treatment of RA, PsA, and AS at the dose of 50 mg, subcutaneously, monthly111. GOL safety data are available from 6 trials of 2626 patients with RA112,113,114,115,116,117, with a clinical observation extended up to 3 years118,119, 356 patients with AS followed for 2 years120,121, and 405 patients with PsA observed for 2 years122,123. Seven cases of TB were recorded in the trials of RA115,116,118,119, and 1 case in AS121. It should be noted that 7 out 8 TB cases occurred in TB-endemic countries, 1 case in Ukraine, 2 in Philippines115, 1 in Taiwan118, 1 each in Argentina, Mexico, and South Korea116,121, and 1 case in an unspecified country119. The estimated TB incidence in 2011 in these countries ranges between 50 and 299 cases per 100,000 inhabitants88, and at least in some of the previously mentioned cases, the possibility of primary TB infection cannot be ruled out. Moreover, some defective screening procedures were probably carried out in the cases recorded in Ukraine and in Philippines115. Indeed, a 64-year-old woman from Ukraine had back pain and radiologic abnormalities of the thoracic spine attributed to vertebral compression fracture before enrollment. She developed spinal TB 33 days after starting GOL, indicating a potentially unrecognized spinal TB at study entry. Similarly, the other 67-year-old woman from Philippines was enrolled despite interstitial lung disease demonstrated by chest radiography (attributed to RA). She developed pulmonary TB 1 month after receiving GOL.

No data are currently available from national registries and postmarketing surveillance, and there are no case reports of TB in patients treated with GOL in the literature.

A low number of TB cases have been recorded in patients treated with GOL, mostly in TB-endemic areas, and as underlined in a recent analysis124, 3 of these cases were presumed to be primary infections and 2 consistent with LTBI reactivation associated with unreliable screening procedures.

However, although the recorded active TB cases occurred in countries at high TB risk, similarly to the other anti-TNF-α agents, an accurate screening procedure for LTBI is recommended in candidates for GOL therapy.

Certolizumab pegol

CTP is an anti-TNF inhibitor composed by an engineered human anti-TNF-α antibody Fab9 fragment that is linked chemically to polyethylene glycol (PEG). The Fab9 fragment is made by microbial fermentation rather than in mammalian cell culture. The attachment of PEG increases the circulating half-life of Fab to about 14 days. The lack of an Fc portion may avoid potential Fc-mediated effects such as complement-dependent or antibody-dependent cell-mediated cytotoxicity125. CTP was approved by the US Food and Drug Administration in 2009 for adult patients with moderately to severely active RA. Six trials of CTP in 3167 patients with RA were published between 2002 and 2012126,127,128,129,130,131. As reported in Table 1, 10 patients developing active TB were observed in 2 trials127,129, all occurring in countries at high risk of TB, with 5 cases observed in Russia, and 1 each in Poland, Latvia, Estonia, Bulgaria, and Ukraine. As underlined for GOL-associated TB cases, also in these patients the possibility of some cases of primary TB infection cannot be excluded. Moreover, in both studies, defective LTBI screening procedures were reported in 6 patients developing active TB127,129, and 1 TB case occurred in a tuberculin skin test-negative worker in a TB clinic127. Notably, no active TB cases have been reported in CTP-exposed patients living in North America.

Because CTP was approved for the treatment of RA only recently, no data on TB cases in CTP-treated patients are available from national registries and postmarketing surveillance; and to the best of our knowledge, no case reports of CTP-associated TB have been published.

However, the consistent number of TB cases recorded in clinical trials, although occurring in high-risk countries, strongly suggest accurate screening for LTBI before starting CTP therapy.

Conclusion

Data from clinical trials seem to indicate increased risk of TB reactivation in patients treated with anti-TNF-α agents GOL and CTP with respect to non-anti-TNF targeted biologics (Table 1). This seems to confirm the class effect resulting from TNF inhibition, which leads to impaired TB granuloma formation2. However, the limited number of active TB cases, mostly occurring in countries at high risk of TB, and the lack of data from real-life practice do not allow definitive conclusions about TB risk associated with the recently licensed anti-TNF biologics GOL and CTP.

Regarding the non-anti-TNF-α targeted biologics, risk of TB associated with ANK and TCZ is negligible, whereas data from clinical trials and registries indicate the absence of TB risk in patients treated with RTX and ABA, thus suggesting LTBI detection procedures may be unnecessary.

Based on these findings, we suggest carefully taking into account host-related TB risks in patients with rheumatic disorders requiring biologic therapy, and to individualize the choice of therapy in view of the respective drug-related risk.

REFERENCES

  1. 1.↵
    1. Nacci F,
    2. Matucci Cerinic M
    . Tuberculosis and other infections in the anti-tumour necrosis factor-alpha (anti-TNF-alpha) era. Best Pract Res Clin Rheumatol 2011;25:375–88.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Harris J,
    2. Keane J
    . How tumour necrosis factor blockers interfere with tuberculosis immunity. Clin Exp Immunol 2010;161:1–9.
    OpenUrlPubMed
  3. 3.↵
    1. Zwerina J,
    2. Redlich K,
    3. Schett G,
    4. Smolen JS
    . Pathogenesis of rheumatoid arthritis: targeting cytokines. Ann N Y Acad Sci 2005;1051:716–29.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Goldbach-Mansky R
    . Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1. Clin Exp Immunol 2012;167:391–404.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Suresh E,
    2. Das P
    . Recent advances in management of gout. QJM 2012;105:407–17.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Zuñiga J,
    2. Torres-García D,
    3. Santos-Mendoza T,
    4. Rodriguez-Reyna TS,
    5. Granados J,
    6. Yunis EJ
    . Cellular and humoral mechanisms involved in the control of tuberculosis. Clin Dev Immunol 2012;2012:193923.
    OpenUrlPubMed
  7. 7.↵
    1. Settas LD,
    2. Tsimirikas G,
    3. Vosvotekas G,
    4. Triantafyllidou E,
    5. Nicolaides P
    . Reactivation of pulmonary tuberculosis in a patient with rheumatoid arthritis during treatment with IL-1 receptor antagonists (anakinra). J Clin Rheumatol 2007;13:219–20.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Campion GV,
    2. Lebsack ME,
    3. Lookabaugh J,
    4. Gordon G,
    5. Catalano M
    . Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group. Arthritis Rheum 1996;39:1092–101.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Bresnihan B,
    2. Alvaro-Gracia JM,
    3. Cobby M,
    4. Doherty M,
    5. Domljan Z,
    6. Emery P,
    7. et al.
    Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998;41:2196–204.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Jiang Y,
    2. Genant HK,
    3. Watt I,
    4. Cobby M,
    5. Bresnihan B,
    6. Aitchison R,
    7. et al.
    A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum 2000;43:1001–9.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Cohen S,
    2. Hurd E,
    3. Cush J,
    4. Schiff M,
    5. Weinblatt ME,
    6. Moreland LW,
    7. et al.
    Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:614–24.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Nuki G,
    2. Bresnihan B,
    3. Bear MB,
    4. McCabe D;
    5. European Group Of Clinical Investigators
    . Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:2838–46.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Fleischmann RM,
    2. Schechtman J,
    3. Bennett R,
    4. Handel ML,
    5. Burmester GR,
    6. Tesser J,
    7. et al.
    Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum 2003;48:927–34.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Cohen SB,
    2. Moreland LW,
    3. Cush JJ,
    4. Greenwald MW,
    5. Block S,
    6. Shergy WJ,
    7. et al.
    A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis 2004;63:1062–8.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Genovese MC,
    2. Cohen S,
    3. Moreland L,
    4. Lium D,
    5. Robbins S,
    6. Newmark R,
    7. et al.
    Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2004;50:1412–9.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Schiff MH,
    2. Di Vittorio G,
    3. Tesser J,
    4. Fleischmann R,
    5. Schechtman J,
    6. Hartman S,
    7. et al.
    The safety of anakinra in high-risk patients with active rheumatoid arthritis: six-month observations of patients with comorbid conditions. Arthritis Rheum 2004;50:1752–60.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. den Broeder AA,
    2. de Jong E,
    3. Franssen MJ,
    4. Jeurissen ME,
    5. Flendrie M,
    6. van den Hoogen FH
    . Observational study on efficacy, safety, and drug survival of anakinra in rheumatoid arthritis patients in clinical practice. Ann Rheum Dis 2006;65:760–2.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Fleischmann RM,
    2. Tesser J,
    3. Schiff MH,
    4. Schechtman J,
    5. Burmester GR,
    6. Bennett R,
    7. et al.
    Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 2006;65:1006–12.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Karanikolas G,
    2. Charalambopoulos D,
    3. Vaiopoulos G,
    4. Andrianakos A,
    5. Rapti A,
    6. Karras D,
    7. et al.
    Adjunctive anakinra in patients with active rheumatoid arthritis despite methotrexate, or leflunomide, or cyclosporin-A monotherapy: a 48-week, comparative, prospective study. Rheumatology 2008;47:1384–8.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Le Loët X,
    2. Nordström D,
    3. Rodriguez M,
    4. Rubbert A,
    5. Sarzi-Puttini P,
    6. Wouters JM,
    7. et al.
    Effect of anakinra on functional status in patients with active rheumatoid arthritis receiving concomitant therapy with traditional disease modifying antirheumatic drugs: evidence from the OMEGA Trial. J Rheumatol 2008;35:1538–44.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Georgiou PE,
    2. Antonopoulos IA,
    3. Andonopoulos AP,
    4. Liossis SN
    . Anakinra treatment in patients with adult-onset Still’s disease is fast, effective, safe and steroid sparing: experience from an uncontrolled trial. Ann Rheum Dis 2007;66:842–3.
    OpenUrlFREE Full Text
  22. 22.↵
    1. Naumann L,
    2. Feist E,
    3. Natusch A,
    4. Langen S,
    5. Krause A,
    6. Buttgereit F,
    7. et al.
    IL1-receptor antagonist anakinra provides long-lasting efficacy in the treatment of refractory adult-onset Still’s disease. Ann Rheum Dis 2010;69:466–7.
    OpenUrlFREE Full Text
  23. 23.↵
    1. Lequerré T,
    2. Quartier P,
    3. Rosellini D,
    4. Alaoui F,
    5. De Bandt M,
    6. Mejjad O,
    7. et al.
    Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 2008;67:302–8.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    1. Ohlsson V,
    2. Baildam E,
    3. Foster H,
    4. Jandial S,
    5. Pain C,
    6. Strike H,
    7. et al.
    Anakinra treatment for systemic onset juvenile idiopathic arthritis (SOJIA). Rheumatology 2008;47:555–6.
    OpenUrlFREE Full Text
  25. 25.↵
    1. Ilowite N,
    2. Porras O,
    3. Reiff A,
    4. Rudge S,
    5. Punaro M,
    6. Martin A,
    7. et al.
    Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Clin Rheumatol 2009;28:129–37.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Zeft A,
    2. Hollister R,
    3. LaFleur B,
    4. Sampath P,
    5. Soep J,
    6. McNally B,
    7. et al.
    Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J Clin Rheumatol 2009;15:161–4.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Quartier P,
    2. Allantaz F,
    3. Cimaz R,
    4. Pillet P,
    5. Messiaen C,
    6. Bardin C,
    7. et al.
    A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis 2011;70:747–54.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Nigrovic PA,
    2. Mannion M,
    3. Prince FH,
    4. Zeft A,
    5. Rabinovich CE,
    6. van Rossum MA,
    7. et al.
    Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum 2011;63:545–55.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Brassard P,
    2. Kezouh A,
    3. Suissa S
    . Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis 2006;43:717–22.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    1. Bingham CO III
    Emerging therapeutics for rheumatoid arthritis. Bull NYU Hosp Jt Dis 2008;66:210–5.
    OpenUrlPubMed
  31. 31.↵
    1. Shaler CR,
    2. Horvath C,
    3. Lai R,
    4. Xing Z
    . Understanding delayed T-cell priming, lung recruitment, and airway luminal T-cell responses in host defense against pulmonary tuberculosis. Clin Dev Immunol 2012;2012:628293.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Edwards JC,
    2. Szczepanski L,
    3. Szechinski J,
    4. Filipowicz-Sosnowska A,
    5. Emery P,
    6. Close DR,
    7. et al.
    Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572–81.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Mease PJ,
    2. Revicki DA,
    3. Szechinski J,
    4. Greenwald M,
    5. Kivitz A,
    6. Barile-Fabris L,
    7. et al.
    Improved health-related quality of life for patients with active rheumatoid arthritis receiving rituximab: Results of the Dose-Ranging Assessment: International Clinical Evaluation of Rituximab in Rheumatoid Arthritis (DANCER) Trial. J Rheumatol 2008;35:20–30.
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    1. Mease PJ,
    2. Cohen S,
    3. Gaylis NB,
    4. Chubick A,
    5. Kaell AT,
    6. Greenwald M,
    7. et al.
    Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. J Rheumatol 2010;37:917–27.
    OpenUrlAbstract/FREE Full Text
  35. 35.↵
    1. Emery P,
    2. Fleischmann R,
    3. Filipowicz-Sosnowska A,
    4. Schechtman J,
    5. Szczepanski L,
    6. Kavanaugh A,
    7. et al.
    The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390–400.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Cohen SB,
    2. Emery P,
    3. Greenwald MW,
    4. Dougados M,
    5. Furie RA,
    6. Genovese MC,
    7. et al.
    Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793–806.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Rubbert-Roth A,
    2. Tak PP,
    3. Zerbini C,
    4. Tremblay JL,
    5. Carreño L,
    6. Armstrong G,
    7. et al.
    Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR). Rheumatology 2010;49:1683–93.
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    1. Emery P,
    2. Deodhar A,
    3. Rigby WF,
    4. Isaacs JD,
    5. Combe B,
    6. Racewicz AJ,
    7. et al.
    Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab’s Efficacy in MTX iNadequate rEsponders (SERENE). Ann Rheum Dis 2010;69:1629–35.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Greenwald MW,
    2. Shergy WJ,
    3. Kaine JL,
    4. Sweetser MT,
    5. Gilder K,
    6. Linnik MD
    . Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Arthritis Rheum 2011;63:622–32.
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Tak PP,
    2. Rigby WF,
    3. Rubbert-Roth A,
    4. van Vollenhoven RF,
    5. Stohl W,
    6. Hessey E,
    7. et al.
    Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial. Ann Rheum Dis 2011;70:39–46.
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    1. Meijer JM,
    2. Meiners PM,
    3. Vissink A,
    4. Spijkervet FK,
    5. Abdulahad W,
    6. Kamminga N,
    7. et al.
    Effectiveness of rituximab treatment in primary Sjögren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:960–8.
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Mekinian A,
    2. Ravaud P,
    3. Hatron PY,
    4. Larroche C,
    5. Leone J,
    6. Gombert B,
    7. et al.
    Efficacy of rituximab in primary Sjogren’s syndrome with peripheral nervous system involvement: results from the AIR registry. Ann Rheum Dis 2012;71:84–7.
    OpenUrlAbstract/FREE Full Text
  43. 43.↵
    1. Sneller MC,
    2. Hu Z,
    3. Langford CA
    . A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis Rheum 2012;64:835–42.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. De Vita S,
    2. Quartuccio L,
    3. Isola M,
    4. Mazzaro C,
    5. Scaini P,
    6. Lenzi M,
    7. et al.
    A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum 2012;64:843–53.
    OpenUrlCrossRefPubMed
  45. 45.↵
    1. Jones RB,
    2. Tervaert JW,
    3. Hauser T,
    4. Luqmani R,
    5. Morgan MD,
    6. Peh CA,
    7. et al.
    Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211–20.
    OpenUrlCrossRefPubMed
  46. 46.↵
    1. Stone JH,
    2. Merkel PA,
    3. Spiera R,
    4. Seo P,
    5. Langford CA,
    6. Hoffman GS,
    7. et al.
    Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221–32.
    OpenUrlCrossRefPubMed
  47. 47.↵
    1. Rovin BH,
    2. Furie R,
    3. Latinis K,
    4. Looney RJ,
    5. Fervenza FC,
    6. Sanchez-Guerrero J,
    7. et al.
    Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012;64:1215–26.
    OpenUrlCrossRefPubMed
  48. 48.↵
    1. Fernández-Nebro A,
    2. de la Fuente JL,
    3. Carreño L,
    4. Izquierdo MG,
    5. Tomero E,
    6. Rúa-Figueroa I,
    7. et al.
    Multicenter longitudinal study of B-lymphocyte depletion in refractory systemic lupus erythematosus: the LESIMAB study. Lupus 2012;21:1063–76.
    OpenUrlAbstract/FREE Full Text
  49. 49.↵
    1. Gottenberg JE,
    2. Ravaud P,
    3. Bardin T,
    4. Cacoub P,
    5. Cantagrel A,
    6. Combe B,
    7. et al.
    AutoImmunity and Rituximab registry and French Society of Rheumatology. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 2010;62:2625–32.
    OpenUrlCrossRefPubMed
  50. 50.↵
    1. Terrier B,
    2. Amoura Z,
    3. Ravaud P,
    4. Hachulla E,
    5. Jouenne R,
    6. Combe B,
    7. et al.
    Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 2010;62:2458–66.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. Tony HP,
    2. Burmester G,
    3. Schulze-Koops H,
    4. Grunke M,
    5. Henes J,
    6. Kötter I,
    7. et al.
    Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID). Arthritis Res Ther 2011;13:R75.
    OpenUrlCrossRefPubMed
  52. 52.↵
    1. Roll P,
    2. Ostermeier E,
    3. Haubitz M,
    4. Lovric S,
    5. Unger L,
    6. Holle J,
    7. et al.
    Efficacy and safety of rituximab treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitides: results from a German registry (GRAID). J Rheumatol 2012;39:2153–6.
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    1. Buch MH,
    2. Smolen JS,
    3. Betteridge N,
    4. Breedveld FC,
    5. Burmester G,
    6. Dörner T,
    7. et al.
    Rituximab Consensus Expert Committee. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2011;70:909–20.
    OpenUrlAbstract/FREE Full Text
  54. 54.↵
    1. Schoels MM,
    2. van der Heijde D,
    3. Breedveld FC,
    4. Burmester GR,
    5. Dougados M,
    6. Emery P,
    7. et al.
    Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement. Ann Rheum Dis 2013;72:583–9.
    OpenUrlAbstract/FREE Full Text
  55. 55.↵
    1. Nishimoto N,
    2. Yoshizaki K,
    3. Miyasaka N,
    4. Yamamoto K,
    5. Kawai S,
    6. Takeuchi T,
    7. et al.
    Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo controlled trial. Arthritis Rheum 2004;50:1761–9.
    OpenUrlCrossRefPubMed
  56. 56.
    1. Maini RN,
    2. Taylor PC,
    3. Szechinski J,
    4. Pavelka K,
    5. Bröll J,
    6. Balint G,
    7. et al.
    Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006;54:2817–29.
    OpenUrlCrossRefPubMed
  57. 57.
    1. Nishimoto N,
    2. Hashimoto J,
    3. Miyasaka N,
    4. Yamamoto K,
    5. Kawai S,
    6. Takeuchi T,
    7. et al.
    Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis 2007;66:1162–7.
    OpenUrlAbstract/FREE Full Text
  58. 58.
    1. Smolen JS,
    2. Beaulieu A,
    3. Rubbert-Roth A,
    4. Ramos-Remus C,
    5. Rovensky J,
    6. Alecock E,
    7. et al.
    Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008;371:987–97.
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Emery P,
    2. Keystone E,
    3. Tony HP,
    4. Cantagrel A,
    5. van Vollenhoven R,
    6. Sanchez A,
    7. et al.
    IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008;67:1516–23.
    OpenUrlAbstract/FREE Full Text
  60. 60.↵
    1. Genovese MC,
    2. McKay JD,
    3. Nasonov EL,
    4. Mysler EF,
    5. da Silva NA,
    6. Alecock E,
    7. et al.
    Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008;58:2968–80.
    OpenUrlCrossRefPubMed
  61. 61.
    1. Nishimoto N,
    2. Miyasaka N,
    3. Yamamoto K,
    4. Kawai S,
    5. Takeuchi T,
    6. Azuma J,
    7. et al.
    Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol 2009;19:12–9.
    OpenUrlCrossRefPubMed
  62. 62.
    1. Nishimoto N,
    2. Miyasaka N,
    3. Yamamoto K,
    4. Kawai S,
    5. Takeuchi T,
    6. Azuma J
    . Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis 2009;68:1580–4.
    OpenUrlAbstract/FREE Full Text
  63. 63.↵
    1. Jones G,
    2. Sebba A,
    3. Gu J,
    4. Calvo A,
    5. Gomez-Reino JJ,
    6. Siri DA,
    7. et al.
    Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010;69:88–96.
    OpenUrlAbstract/FREE Full Text
  64. 64.
    1. Hirabayashi Y,
    2. Ishii T,
    3. Harigae H
    . Clinical efficacy of tocilizumab in patients with active rheumatoid arthritis in real clinical practice. Rheumatol Int 2010;30:1041–8.
    OpenUrlCrossRefPubMed
  65. 65.
    1. Yamanaka H,
    2. Tanaka Y,
    3. Inoue E,
    4. Hoshi D,
    5. Momohara S,
    6. Hanami K,
    7. et al.
    Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily clinical practice in Japan: results from a retrospective study (REACTION study). Mod Rheumatol 2011;21:122–33.
    OpenUrlCrossRefPubMed
  66. 66.
    1. Burmester GR,
    2. Feist E,
    3. Kellner H,
    4. Braun J,
    5. Iking-Konert C,
    6. Rubbert-Roth A
    . Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA). Ann Rheum Dis 2011;70:755–9.
    OpenUrlAbstract/FREE Full Text
  67. 67.
    1. Kremer JM,
    2. Blanco R,
    3. Brzosko M,
    4. Burgos-Vargas R,
    5. Halland AM,
    6. Vernon E,
    7. et al.
    Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum 2011;63:609–21.
    OpenUrlCrossRefPubMed
  68. 68.
    1. Takeuchi T,
    2. Tanaka Y,
    3. Amano K,
    4. Hoshi D,
    5. Nawata M,
    6. Nagasawa H,
    7. et al.
    Clinical, radiographic and functional effectiveness of tocilizumab for rheumatoid arthritis patients—REACTION 52-week study. Rheumatology 2011;50:1908–15.
    OpenUrlAbstract/FREE Full Text
  69. 69.↵
    1. Kume K,
    2. Amano K,
    3. Yamada S,
    4. Hatta K,
    5. Ohta H,
    6. Kuwaba N
    . Tocilizumab monotherapy reduces arterial stiffness as effectively as etanercept or adalimumab monotherapy in rheumatoid arthritis: an open-label randomized controlled trial. J Rheumatol 2011; 38:2169–71.
    OpenUrlAbstract/FREE Full Text
  70. 70.↵
    1. Yazici Y,
    2. Curtis JR,
    3. Ince A,
    4. Baraf H,
    5. Malamet RL,
    6. Teng LL,
    7. et al.
    Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis 2012;71:198–205.
    OpenUrlAbstract/FREE Full Text
  71. 71.
    1. Dougados M,
    2. Kissel K,
    3. Sheeran T,
    4. Tak PP,
    5. Conaghan PG,
    6. Mola EM,
    7. et al.
    Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis 2013;72:43–50.
    OpenUrlAbstract/FREE Full Text
  72. 72.
    1. Bykerk VP,
    2. Ostör AJ,
    3. Alvaro-Gracia J,
    4. Pavelka K,
    5. Ivorra JA,
    6. Graninger W,
    7. et al.
    Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. Ann Rheum Dis 2012;71:1950–4.
    OpenUrlAbstract/FREE Full Text
  73. 73.
    1. Strand V,
    2. Burmester GR,
    3. Ogale S,
    4. Devenport J,
    5. John A,
    6. Emery P
    . Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study. Rheumatology 2012;51:1860–9.
    OpenUrlAbstract/FREE Full Text
  74. 74.
    1. Weinblatt ME,
    2. Kremer J,
    3. Cush J,
    4. Rigby W,
    5. Teng LL,
    6. Devenport J,
    7. et al.
    Tocilizumab as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs: twenty-four-week results of an open-label, clinical practice study. Arthritis Care Res 2013;65:362–71.
    OpenUrlCrossRef
  75. 75.↵
    1. Gabay C,
    2. Emery P,
    3. van Vollenhoven R,
    4. Dikranian A,
    5. Alten R,
    6. Pavelka K,
    7. et al.
    Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 2013;381:1541–50.
    OpenUrlCrossRefPubMed
  76. 76.↵
    1. Woo P,
    2. Wilkinson N,
    3. Prieur AM,
    4. Southwood T,
    5. Leone V,
    6. Livermore P,
    7. et al.
    Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther 2005;7: R1281–8.
    OpenUrlCrossRefPubMed
  77. 77.↵
    1. Yokota S,
    2. Imagawa T,
    3. Mori M,
    4. Miyamae T,
    5. Aihara Y,
    6. Takei S,
    7. et al.
    Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008;371:998–1006.
    OpenUrlCrossRefPubMed
  78. 78.↵
    1. Imagawa T,
    2. Yokota S,
    3. Mori M,
    4. Miyamae T,
    5. Takei S,
    6. Imanaka H,
    7. et al.
    Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis. Mod Rheumatol 2012;22:109–15.
    OpenUrlCrossRefPubMed
  79. 79.↵
    1. De Benedetti F,
    2. Brunner HI,
    3. Ruperto N,
    4. Kenwright A,
    5. Wright S,
    6. Calvo I,
    7. et al.
    Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2385–95.
    OpenUrlCrossRefPubMed
  80. 80.↵
    1. Illei GG,
    2. Shirota Y,
    3. Yarboro CH,
    4. Daruwalla J,
    5. Tackey E,
    6. Takada K,
    7. et al.
    Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum 2010;62:542–52.
    OpenUrlCrossRefPubMed
  81. 81.↵
    1. Shirota Y,
    2. Yarboro C,
    3. Fischer R,
    4. Pham TH,
    5. Lipsky P,
    6. Illei GG
    . Impact of anti-interleukin-6 receptor blockade on circulating T and B cell subsets in patients with systemic lupus erythematosus. Ann Rheum Dis 2013;72:118–28.
    OpenUrlAbstract/FREE Full Text
  82. 82.↵
    1. Lekpa FK,
    2. Poulain C,
    3. Wendling D,
    4. Soubrier M,
    5. De Bandt M,
    6. Berthelot JM,
    7. et al.
    Is IL-6 an appropriate target to treat spondyloarthritis patients refractory to anti-TNF therapy? A multicentre retrospective observational study. Arthritis Res Ther 2012;14:R53.
    OpenUrlCrossRefPubMed
  83. 83.↵
    1. Salvarani C,
    2. Magnani L,
    3. Catanoso M,
    4. Pipitone N,
    5. Versari A,
    6. Dardani L,
    7. et al.
    Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology 2012;51:151–6.
    OpenUrlAbstract/FREE Full Text
  84. 84.↵
    1. Unizony S,
    2. Arias-Urdaneta L,
    3. Miloslavsky E,
    4. Arvikar S,
    5. Khosroshahi A,
    6. Keroack B,
    7. et al.
    Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res 2012;64:1720–9.
    OpenUrl
  85. 85.↵
    1. Macchioni P,
    2. Boiardi L,
    3. Catanoso M,
    4. Pulsatelli L,
    5. Pipitone N,
    6. Meliconi R,
    7. et al.
    Tocilizumab for polymyalgia rheumatica: Report of two cases and review of the literature. Semin Arthritis Rheum 2013;43:113–8.
    OpenUrlPubMed
  86. 86.↵
    1. Schiff MH,
    2. Kremer JM,
    3. Jahreis A,
    4. Vernon E,
    5. Isaacs JD,
    6. van Vollenhoven RF
    . Integrated safety in tocilizumab clinical trials. Arthritis Res Ther 2011;13:R141.
    OpenUrlCrossRefPubMed
  87. 87.↵
    1. Koike T,
    2. Harigai M,
    3. Inokuma S,
    4. Ishiguro N,
    5. Ryu J,
    6. Takeuchi T,
    7. et al.
    Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis 2011;70:2148–51.
    OpenUrlAbstract/FREE Full Text
  88. 88.↵
    1. World Health Organization Global Tuberculosis Report 2012
    . WHO Library Cataloguing-in-Publication Data. Geneva: Resource Centre HTM/STB World Health Organization; 2012.
  89. 89.↵
    1. Moreland LW,
    2. Alten R,
    3. Van den Bosch F,
    4. Appelboom T,
    5. Leon M,
    6. Emery P,
    7. et al.
    Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 2002;46:1470–9.
    OpenUrlCrossRefPubMed
  90. 90.↵
    1. Bernal-Fernandez G,
    2. Espinosa-Cueto P,
    3. Leyva-Meza R,
    4. Mancilla N,
    5. Mancilla R
    . Decreased expression of T-cell costimulatory molecule CD28 on CD4 and CD8 T cells of Mexican patients with pulmonary tuberculosis. Tuberc Res Treat 2010;2010:517547.
    OpenUrlPubMed
  91. 91.↵
    1. Kremer JM,
    2. Westhovens R,
    3. Leon M,
    4. Di Giorgio E,
    5. Alten R,
    6. Steinfeld S,
    7. et al.
    Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907–15.
    OpenUrlCrossRefPubMed
  92. 92.
    1. Kremer JM,
    2. Dougados M,
    3. Emery P,
    4. Durez P,
    5. Sibilia J,
    6. Shergy W,
    7. et al.
    Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase IIB, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:2263–71.
    OpenUrlCrossRefPubMed
  93. 93.
    1. Genovese MC,
    2. Becker JC,
    3. Schiff M,
    4. Luggen M,
    5. Sherrer Y,
    6. Kremer J,
    7. et al.
    Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005;353:1114–23.
    OpenUrlCrossRefPubMed
  94. 94.
    1. Westhovens R,
    2. Cole JC,
    3. Li T,
    4. Martin M,
    5. Maclean R,
    6. Lin P,
    7. et al.
    Improved health-related quality of life for rheumatoid arthritis patients treated with abatacept who have inadequate response to anti-TNF therapy in a double-blind, placebo-controlled, multicentre randomized clinical trial. Rheumatology 2006;45:1238–46.
    OpenUrlAbstract/FREE Full Text
  95. 95.
    1. Emery P,
    2. Kosinski M,
    3. Li T,
    4. Martin M,
    5. Williams GR,
    6. Becker JC,
    7. et al.
    Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-related quality of life. J Rheumatol 2006;33:681–9.
    OpenUrlAbstract/FREE Full Text
  96. 96.
    1. Kremer JM,
    2. Genant HK,
    3. Moreland LW,
    4. Russell AS,
    5. Emery P,
    6. Abud-Mendoza C,
    7. et al.
    Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144:865–76.
    OpenUrlCrossRefPubMed
  97. 97.
    1. Weinblatt M,
    2. Schiff M,
    3. Goldman A,
    4. Kremer J,
    5. Luggen M,
    6. Li T,
    7. et al.
    Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann Rheum Dis 2007;66:228–34.
    OpenUrlAbstract/FREE Full Text
  98. 98.
    1. Weinblatt M,
    2. Combe B,
    3. Covucci A,
    4. Aranda R,
    5. Becker JC,
    6. Keystone E
    . Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: a one-year randomized, placebo-controlled study. Arthritis Rheum 2006;54:2807–16.
    OpenUrlCrossRefPubMed
  99. 99.↵
    1. Schiff M,
    2. Keiserman M,
    3. Codding C,
    4. Songcharoen S,
    5. Berman A,
    6. Nayiager S,
    7. et al.
    Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 2008;67:1096–103.
    OpenUrlAbstract/FREE Full Text
  100. 100.↵
    1. Schiff M,
    2. Pritchard C,
    3. Huffstutter JE,
    4. Rodriguez-Valverde V,
    5. Durez P,
    6. Zhou X,
    7. et al.
    The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis 2009;68:1708–14.
    OpenUrlAbstract/FREE Full Text
  101. 101.↵
    1. Westhovens R,
    2. Robles M,
    3. Ximenes AC,
    4. Nayiager S,
    5. Wollenhaupt J,
    6. Durez P,
    7. et al.
    Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis 2009;68:1870–7.
    OpenUrlAbstract/FREE Full Text
  102. 102.↵
    1. Emery P,
    2. Durez P,
    3. Dougados M,
    4. Legerton CW,
    5. Becker JC,
    6. Vratsanos G,
    7. et al.
    Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial). Ann Rheum Dis 2010;69:510–6.
    OpenUrlAbstract/FREE Full Text
  103. 103.↵
    1. Genovese MC,
    2. Covarrubias A,
    3. Leon G,
    4. Mysler E,
    5. Keiserman M,
    6. Valente R,
    7. et al.
    Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate. Arthritis Rheum 2011;63:2854–64.
    OpenUrlCrossRefPubMed
  104. 104.↵
    1. Kaine J,
    2. Gladstein G,
    3. Strusberg I,
    4. Robles M,
    5. Louw I,
    6. Gujrathi S,
    7. et al.
    Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efficacy and safety (phase IIIB ALLOW study). Ann Rheum Dis 2012;71:38–44.
    OpenUrlAbstract/FREE Full Text
  105. 105.↵
    1. Keystone EC,
    2. Kremer JM,
    3. Russell A,
    4. Box J,
    5. Abud-Mendoza C,
    6. Elizondo MG,
    7. et al.
    Abatacept in subjects who switch from intravenous to subcutaneous therapy: results from the phase IIIB ATTUNE study. Ann Rheum Dis 2012;71:857–61.
    OpenUrlAbstract/FREE Full Text
  106. 106.↵
    1. Westhovens R,
    2. Kremer JM,
    3. Moreland LW,
    4. Emery P,
    5. Russell AS,
    6. Li T,
    7. et al.
    Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended phase IIB study. J Rheumatol 2009;36:736–42.
    OpenUrlAbstract/FREE Full Text
  107. 107.↵
    1. Merrill JT,
    2. Burgos-Vargas R,
    3. Westhovens R,
    4. Shanahan JC,
    5. Latinis KM,
    6. Oates JC,
    7. et al.
    The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:3077–87.
    OpenUrlCrossRefPubMed
  108. 108.↵
    1. Ruperto N,
    2. Lovell DJ,
    3. Quartier P,
    4. Paz E,
    5. Rubio-Pérez N,
    6. Silva CA,
    7. et al.
    Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet 2008;372:383–91.
    OpenUrlCrossRefPubMed
  109. 109.↵
    1. Mease P,
    2. Genovese MC,
    3. Gladstein G,
    4. Kivitz AJ,
    5. Ritchlin C,
    6. Tak PP,
    7. et al.
    Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheum 2011;63:939–48.
    OpenUrlCrossRefPubMed
  110. 110.↵
    1. Mariette X,
    2. Gottenberg JE,
    3. Ravaud P,
    4. Combe B
    . Registries in rheumatoid arthritis and autoimmune diseases: data from the French registries. Rheumatology 2011;50:222–9.
    OpenUrlAbstract/FREE Full Text
  111. 111.↵
    1. Mazumdar S,
    2. Greenwald D
    . Golimumab. MAbs 2009;1:422–31.
    OpenUrlPubMed
  112. 112.↵
    1. Kay J,
    2. Matteson EL,
    3. Dasgupta B,
    4. Nash P,
    5. Durez P,
    6. Hall S,
    7. et al.
    Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum 2008;58:964–75.
    OpenUrlCrossRefPubMed
  113. 113.↵
    1. Keystone EC,
    2. Genovese MC,
    3. Klareskog L,
    4. Hsia EC,
    5. Hall ST,
    6. Miranda PC,
    7. et al.
    Golimumab, a human antibody to tumour necrosis factor {alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis 2009;68:789–96.
    OpenUrlAbstract/FREE Full Text
  114. 114.↵
    1. Smolen JS,
    2. Kay J,
    3. Doyle MK,
    4. Landewé R,
    5. Matteson EL,
    6. Wollenhaupt J,
    7. et al.
    Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet 2009;374:210–21.
    OpenUrlCrossRefPubMed
  115. 115.↵
    1. Emery P,
    2. Fleischmann RM,
    3. Moreland LW,
    4. Hsia EC,
    5. Strusberg I,
    6. Durez P,
    7. et al.
    Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum 2009;60:2272–83.
    OpenUrlCrossRefPubMed
  116. 116.↵
    1. Kremer J,
    2. Ritchlin C,
    3. Mendelsohn A,
    4. Baker D,
    5. Kim L,
    6. Xu Z,
    7. et al.
    Golimumab, a new human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight-week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study. Arthritis Rheum 2010;62:917–28.
    OpenUrlCrossRefPubMed
  117. 117.↵
    1. Tanaka Y,
    2. Harigai M,
    3. Takeuchi T,
    4. Yamanaka H,
    5. Ishiguro N,
    6. Yamamoto K,
    7. et al.
    Golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis: results of the GO-FORTH study. Ann Rheum Dis 2012;71:817–24.
    OpenUrlAbstract/FREE Full Text
  118. 118.↵
    1. Keystone E,
    2. Genovese MC,
    3. Klareskog L,
    4. Hsia EC,
    5. Hall S,
    6. Miranda PC,
    7. et al.
    Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: 52-week results of the GO-FORWARD study. Ann Rheum Dis 2010;69:1129–35.
    OpenUrlAbstract/FREE Full Text
  119. 119.↵
    1. Smolen JS,
    2. Kay J,
    3. Landewé RB,
    4. Matteson EL,
    5. Gaylis N,
    6. Wollenhaupt J,
    7. et al.
    Golimumab in patients with active rheumatoid arthritis who have previous experience with tumour necrosis factor inhibitors: results of a long-term extension of the randomised, double-blind, placebo-controlled GO-AFTER study through week 160. Ann Rheum Dis 2012;71:1671–9.
    OpenUrlAbstract/FREE Full Text
  120. 120.↵
    1. Inman RD,
    2. Davis JC Jr,
    3. Heijde Dv,
    4. Diekman L,
    5. Sieper J,
    6. Kim SI,
    7. et al.
    Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 2008;58:3402–12.
    OpenUrlCrossRefPubMed
  121. 121.↵
    1. Braun J,
    2. Deodhar A,
    3. Inman RD,
    4. van der Heijde D,
    5. Mack M,
    6. Xu S,
    7. et al.
    Golimumab administered subcutaneously every 4 weeks in ankylosing spondylitis: 104-week results of the GO-RAISE study. Ann Rheum Dis 2012;71:661–7.
    OpenUrlAbstract/FREE Full Text
  122. 122.↵
    1. Kavanaugh A,
    2. McInnes I,
    3. Mease P,
    4. Krueger GG,
    5. Gladman D,
    6. Gomez-Reino J,
    7. et al.
    Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum 2009;60:976–86.
    OpenUrlCrossRefPubMed
  123. 123.↵
    1. Kavanaugh A,
    2. Mease P
    . Treatment of psoriatic arthritis with tumor necrosis factor inhibitors: longer-term outcomes including enthesitis and dactylitis with golimumab treatment in the Long term Extension of a Randomized, Placebo-controlled Study (GO-REVEAL). J Rheumatol Suppl. 2012 Jul;89:90–3.
    OpenUrlAbstract/FREE Full Text
  124. 124.↵
    1. Hsia EC,
    2. Cush JJ,
    3. Matteson EL,
    4. Beutler A,
    5. Doyle MK,
    6. Hsu B,
    7. et al.
    Comprehensive tuberculosis screening program in patients with inflammatory arthritides treated with golimumab, a human anti-tumor necrosis factor antibody, in Phase III clinical trials. Arthritis Care Res 2013;65:309–13.
    OpenUrlCrossRef
  125. 125.↵
    1. Nesbitt A,
    2. Fossati G,
    3. Bergin M,
    4. Stephens P,
    5. Stephens S,
    6. Foulkes R,
    7. et al.
    Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis 2007;13:1323–32.
    OpenUrlCrossRefPubMed
  126. 126.↵
    1. Choy EH,
    2. Hazleman B,
    3. Smith M,
    4. Moss K,
    5. Lisi L,
    6. Scott DG,
    7. et al.
    Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial. Rheumatology 2002;41:1133–7.
    OpenUrlAbstract/FREE Full Text
  127. 127.↵
    1. Keystone E,
    2. Heijde Dv,
    3. Mason D Jr,
    4. Landewé R,
    5. Vollenhoven RV,
    6. Combe B,
    7. et al.
    Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 2008;58:3319–29.
    OpenUrlCrossRefPubMed
  128. 128.↵
    1. Fleischmann R,
    2. Vencovsky J,
    3. van Vollenhoven RF,
    4. Borenstein D,
    5. Box J,
    6. Coteur G,
    7. et al.
    Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis 2009;68:805–11.
    OpenUrlAbstract/FREE Full Text
  129. 129.↵
    1. Smolen J,
    2. Landewé RB,
    3. Mease P,
    4. Brzezicki J,
    5. Mason D,
    6. Luijtens K,
    7. et al.
    Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis 2009;68:797–804.
    OpenUrlAbstract/FREE Full Text
  130. 130.↵
    1. Choy E,
    2. McKenna F,
    3. Vencovsky J,
    4. Valente R,
    5. Goel N,
    6. Vanlunen B,
    7. et al.
    Certolizumab pegol plus MTX administered every 4 weeks is effective in patients with RA who are partial responders to MTX. Rheumatology 2012;51:1226–34.
    OpenUrlAbstract/FREE Full Text
  131. 131.↵
    1. Weinblatt ME,
    2. Fleischmann R,
    3. Huizinga TW,
    4. Emery P,
    5. Pope J,
    6. Massarotti EM,
    7. et al.
    Efficacy and safety of certolizumab pegol in a broad population of patients with active rheumatoid arthritis: results from the REALISTIC phase IIIb study. Rheumatology 2012;51:2204–14.
    OpenUrlAbstract/FREE Full Text
View Abstract
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools

 Request Permissions

Bookmark this article

Jump to section

Keywords

GOLIMUMAB
CERTOLIZUMAB PEGOL
ANTI-TUMOR NECROSIS FACTOR
NON-ANTI-TNF BIOLOGICS
TUBERCULOSIS

Keywords