CPD 9: Rheumatoid Arthritis 29 Continuing Professional Development
CPD
Biography - Sandra Ryan is a Freelance Medical Writer with numerous experience writing both healthcare professional-facing and patient-facing materials. In her previous role as Clinical Communications Executive she has worked with pharmaceutical companies, patient organisations, charities, hospitals and individual healthcare professionals on a variety of communications projects. She is familiar with IPHA guidelines and best practice policy, as well as standard Industry protocol. Her specialist areas include oncology, cardiology, respiratory, biopharmaceuticals, biosimilars, pain medicine and neurology.
60 Second Summary
1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice.
Since their widespread introduction, biologic therapies have changed the treatment of rheumatoid arthritis (RA), improving many patients’ lives and representing a breakthrough in managing this debilitating condition. Biologics have been proven to slow disease progression in RA, leading to better quality of life and less work-related disability for patients.
2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area.
There are five anti-tumour necrosis factor (TNF) biologic agents approved for the treatment of RA: etanercept, adalimumab, infliximab, golimumab and certolizumab. We know that all biologics are immunogenic - i.e. they have the ability to induce an immune response in the treated patient. Five studies regarding the use of infliximab or adalimumab analysed EULAR treatment responses from 12 to 192 weeks, and looked at the association of ADAs with treatment response in infliximab, adalimumab, golimumab, abatacept, and rituximab. Of these, one study of adalimumab showed a lower treatment response in patients who had measurable ADAs. Two studies reported an increased risk of infusion reactions in patients with ADAs. Seventeen studies reported on an increased risk of hypersensitivity reactions in patients who had ADAs. In patients who receive biologics subcutaneously, local injection reactions are frequently seen; the relation to antibody formation is, however, unclear. In some patients treated subcutaneously with biologicals a systemic response is observed1, but little information is available on the clinical effects of chronic immune-complex formation in these patients. 1. Bartelds GM, Wolbink GJ, Stapel S, et al. High levels of human antihuman antibodies to adalimumab in a patient not responding to adalimumab treatment. Ann Rheum Dis 2006; 65:1249-1250.
3. PLAN - If I have identified a knowledge gap - will this article
satisfy those needs - or will more reading be required? 4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result? Have I identified further learning needs? 5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the 4 previous steps, log and record your findings.
Sandra Ryan
Published by HPN, sponsored by Pfizer Healthcare Ireland. Copies can be downloaded from www.irishpharmacytraining.ie Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author. Pfizer Healthcare Ireland has no editorial oversight of the CPD programmes included in these modules.
The impact of immunogenicity in rheumatoid arthritis Since their widespread introduction, biologic therapies have changed the treatment of rheumatoid arthritis (RA), improving many patients’ lives and representing a breakthrough in managing this debilitating condition. Biologics have been proven to slow disease progression in RA, leading to better quality of life and less workrelated disability for patients1,2. RA predominantly affects individuals of working age: about 75 per cent of new diagnoses are in people who are working at the time of diagnosis . Research by Arthritis Ireland in 2008 estimated the annual indirect cost of lost production time due to all forms of arthritis in Ireland to be ¤1.6 billion, and found that 70 per cent of individuals diagnosed with RA in Ireland were not able to work outside their home4. As research continues into the long-term use and effects of biologic therapies in RA, better understanding has emerged of the difference between each drug, which can help when choosing the
right treatment for the right patient. This article will outline recommendations for choosing the right biologic for the right patient, where possible; how this can be achieved, and why it is important. BIOLOGIC THERAPIES AND IMMUNOGENICITY Biologics can be native proteins like hormones, cytokines, and growth factors or engineered molecules such as therapeutic antibodies, antibody fragments or protein constructs. Monoclonal antibodies are one of the fastest growing class of human pharmaceuticals - several hundred are being investigated in clinical trials in various therapeutic indications, including oncology and autoimmune disease5. There are five anti-tumour necrosis factor (TNF) biologic agents approved for the treatment of RA: etanercept, adalimumab, infliximab, golimumab and certolizumab. We know that all biologics are immunogenic - i.e. they have the ability to induce an
immune response in the treated patient. We also know that although traditional disease modifying antirheumatic (DMARD) treatments for RA broadly impact the patient’s immune system, biologics are designed to target the specific components that play a key role in inflammation and subsequent pain and joint damage in RA6. Immunogenicity occurs when biologic anti-TNFs trigger the body’s immune system into forming antibodies that can impact treatment progress7,8. These anti-drug antibodies (ADAs) are either neutralising or non-neutralising. Neutralising antibodies can prevent biologic therapies from working effectively, potentially leading to further progression of RA disease and symptoms9,10,11,12. In contrast, non-neutralising antibodies bind to the therapeutic protein but do not neutralise it, and in many cases appear to have no biologic effect; though there is some evidence that non-
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neutralising antibodies may affect the bioavailability of the medicine in question13. Since the presence of anti-drug antibodies may influence the levels and function of the drug in the body, this immune response can alter the efficacy of the biologic treatment and even its safety profile, depending on the mechanism of action (neutralising or non-neutralising) and/or an accelerated clearance of the drug14. The three anti-TNF agents approved for use in RA, etanercept, adalimumab and infliximab, differ slightly with regard to their immunogenicity. There are important molecular distinctions between all these agents that can help when deciding which to use in which patient. Etanercept is a fully human, soluble TNF receptor, while the other two are monoclonal antibodies (MAbs). Immunogenicity will vary depending on whether the biologic agent is a fusion protein or a chimeric, humanised, or fully human antibody. In chimeric antibodies, such as infliximab, 25 per cent of the protein is of murine origin, and it is these sequences that are the main target of the anti-drug antibodies produced by the immune system. However, research has shown that ADAs develop in response to treatment with all types of biologics, including humanised monoclonal antibodies (> 90 per cent human), fusion proteins (etanercept), and even fully human antibodies such as adalimumab, which contain no murine proteins16. A large JAMA review17 published last year examined the effect of immunogenicity on treatment outcomes, and the differences
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between each biologic therapy. The primary endpoint of the analysis was the association of ADAs with treatment outcomes. The secondary endpoint concerned the association of ADAs with safety. The review captured 10,728 articles and abstracts. By hand and reverse search, 31 articles were additionally included. After evaluation of the full reports, 60 references were selected. They included 59 studies of anti-TNF monoclonal antibodies: One with etanercept, two with rituximab, and two with abatacept. Five studies regarding the use of infliximab or adalimumab analysed EULAR treatment responses from 12 to 192 weeks, and looked at the association of ADAs with treatment response in infliximab, adalimumab, golimumab, abatacept, and rituximab. Of these, one study of adalimumab showed a lower treatment response in patients who had measurable ADAs. Two studies reported an increased risk of infusion reactions in patients with ADAs. Seventeen studies reported on an increased risk of hypersensitivity reactions in patients who had ADAs. The review found that significantly better responses were seen in patients who did not develop ADAs, and concluded that the presence of antibodies against anti-TNF monoclonal antibodies confers a risk of discontinuation of treatment in RA.
non-biologic DMARDs on ADA formation18,19,20. Thirty studies suggested that patients receiving treatment with monoclonal anti-TNF agents plus a DMARD were less likely to form ADAs than patients receiving anti-TNF monotherapy. The bulk of these studies related to monoclonal antiTNF therapies with limited data available on etanercept and agents with alternative mechanisms of action. In RA, methotrexate was the most effective companion agent. In addition to its effect on ADA formation, the concurrent use of methotrexate with monoclonal anti-TNF agents has a direct affect on the serum concentration and half-life of the agent. For example, the concurrent use of methotrexate with adalimumab results in a 38 per cent increase in the serum concentration of the adalimumab. This effect has also been demonstrated with infliximab. Another study21 compared the effectiveness and dose escalation rates of etanercept, adalimumab, and infliximab in a community setting. This found that fewer etanercept patients escalated dose than infliximab or adalimumab patients, but improvements in functional disability were similar. These differences may have been influenced by package labeling, mode of administration, or other factors, the authors wrote. THE IMPACT OF ADAS ON TREATMENT EFFICACY
IMPACT OF CONCOMITANT TREATMENT WITH NONBIOLOGIC DMARDS ON ADA FORMATION
As we have seen, immunogenicity therefore impacts the clinical management of RA in various ways.
The JAMA review also included studies on the impact of concomitant treatment with
The dose and/or frequency of the biologic therapy or coadministered RA therapy may
need to be increased (dose escalation), and a new medicine may need to be initiated, in order to avoid the effects of neutralising antibodies22,23,24,25. While dose escalation is possible and recommended for certain therapies, in some cases, even dose increases may not always lead to improved treatment responses26,27. Studies have shown that highdose treatment can also lead to an increase in treatment-related side effects, such as infections and injection site reactions28,29. ALLERGIC REACTIONS Patients who develop antibodies to biologics are more likely to show infusion-related reactions, research shows. Acute infusion reactions, including anaphylaxis, develop in a close temporal relationship to an infusion. The acute reactions can be truly allergic, namely IgE-mediated type I reactions, including hypotension, bronchospasm, laryngeal or pharyngeal oedema, wheezing and/or urticaria. In a small study using infliximab it was demonstrated that in addition to the quantity of anti-infliximab, the quality of the response is related to infusion reactions30. Many of the anti-infliximab antibodies are of the IgG4 and IgG1 isotype. IgG4 antibodies are considered to be less inflammatory as they do not activate the complement system. In a study of 19 patients with infusion reactions to infliximab, an association with the level of anti-infliximab antibodies was observed. However, no protective effect of specific IgG4 was found31.
31
In patients who receive biologics subcutaneously, local injection reactions are frequently seen; the relation to antibody formation is, however, unclear. In some patients treated subcutaneously with biologicals a systemic response is observed32, but little information is available on the clinical effects of chronic immune-complex formation in these patients. COMPARING TREATMENTS The soluble TNF receptor etanercept mimics the action of naturally occurring TNF receptors and is not associated with neutralising antibodies34,35, offering a sustainable clinical response. This therefore potentially reduces the need for dose escalation with etanercept. Studies36,37 have demonstrated that anti-infliximab formation is lower in RA patients receiving higher doses of infliximab. Patients treated with 10 mg/kg infliximab had significantly less antibody formation compared with patients treated with 3 or 1 mg/kg (7, 21, 53 per cent, respectively). A further reduction of anti-infliximab formation was seen in patients receiving low-dose methotrexate. In the ATTRACT study38 two years of follow-up did not reveal clinically significant anti-infliximab formation in RA patients. For the fully human antibody adalimumab earlier studies reported differently on the clinical significance of immunogenicity. The Armada trial did not find any clinically significant effect of anti-adalimumab formation in RA patients treated with adalimumab39. Another study40 reported that 12 per cent of adalimumab-treated patients tested positive for antibodies
against adalimumab. No differences in adverse events were found. However, the response rate was numerically lower for patients who were positive for adalimumab. In a study41 investigating the relation between clinical response pharmacokinetics and anti-adalimumab formation, it was shown that formation of anti-adalimumab is associated with lower serum adalimumab concentrations and non-response. ADDRESSING IMMUNOGENICITY IN CLINICAL PRACTICE When making prescribing decisions for RA patients to achieve long-term disease remission, all factors influencing long-term outcomes, including the immunogenic profile of the drug and potential for dose escalation, should be considered42 prior to the initiation of treatment. Choosing a treatment option that is less immunogenic may reduce the need for dose escalation, as shown above43. Immunogenicity testing can help identify or confirm treatment failure in patients44. Despite the sensitivity and specificity problems of currently available ADA detection assays, detection kits will probably soon be available for use in routine clinical practice45.
Where possible, the priority should be to measure drug concentrations, as serum drug levels are the most reliable sign that immunogenicity or other factors are not interfering with the treatment strategy.
Patients who respond well to treatment with a first anti-TNF agent but then lose efficacy are likely to respond well to a second anti-TNF agent, as the efficacy of the TNF inhibition has already been validated for that patient47.
IMPLICATIONS OF IMMUNOGENICITY OF BIOLOGIC DMARDS ON THE TREATMENT OF RA46
In choosing a second anti-TNF agent in the presence of ADAs to the first anti-TNF agent: 1) When possible use a less immunogenic agent (i.e. etanercept); 2) Optimise dose of companion DMARD or if first drug was given as monotherapy, give the second drug in combination with DMARD; 3) Optimise dosing intervals to avoid low trough levels.
Patients should be closely monitored for loss of efficacy after they have achieved target treatment goals. The initial treatment plan should focus on achieving shortterm clinical targets with an eye towards maximising the chance of long-term efficacy of the treatment by taking the steps to reduce the likelihood of ADAs forming. Loss of efficacy should lead to consideration of the role of ADAs. In a patient who is losing response to a first anti-TNF agent: optimise dose, consider optimising the drug dose and when possible, the interval between doses. For infliximab, consider reducing dosing interval. For adalimumab, consider switching to weekly therapy and optimise dose of companion DMARD.
For patients who lose efficacy of multiple biologic agents, consider switching to combination DMARD therapy to avoid the issue of ADAs. In these patients, the JAK kinase inhibitor tofacitinib may be considered. Serial measurements of ANA and anti-DNA positivity may identify patients at-risk for ADAs and allow for interventions to preserve response to therapy. The occurrence of infusion reactions or persistent injection site reactions should encourage consideration of the role of ADAs.
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32 CPD 9: Rheumatoid Arthritis SUMMARY Biologics have revolutionised the treatment of RA, and have raised expectations for treatment outcomes. The prognosis for patients with RA is much better than it was 20-30 years ago, and patients today have improved quality of life48. Biologics have been proven to slow disease progression in RA, leading to better quality of life and less work-related disability for patients49,50. All biologics are immunogenic - i.e. they have the ability to induce an immune response in the treated patient, which can lead to loss of efficacy. Loss of efficacy should lead to consideration of the role of ADAs when choosing a treatment. Immunogenicity occurs when biologic anti-TNFs trigger the body’s immune system into forming antibodies that can impact treatment progress51,52. These anti-drug antibodies are either neutralising or non-neutralising. The production of neutralising antibodies can lead to nonresponse to therapy in RA and result in the treatment ceasing to work effectively53,54. Patients may initially show a good response to the treatment in question followed by a loss of clinical response as the level of active medicine in the body decreases after the first few months of treatment55,56. Etanercept, research has shown, differs from the other antiTNF agents — its immunogenic effects on the patient appear to be less than those seen with the other agents. This is likely because etanercept mimics the naturally occurring TNF receptors57. When making prescribing decisions for RA patients to achieve long-term disease remission, all factors influencing long-term outcomes, including the immunogenic profile of the drug and potential for dose escalation, should be considered. Patients should be closely monitored for loss of efficacy after they have achieved target treatment goals. REFERENCES 1. Weaver AL. The impact of new biologicals in the treatment of rheumatoid arthritis. Rheumatology 2004: 43(Suppl.3):iii17-iii23. 2. Pollard L, Choy EH, Scott DL. The consequences of rheumatoid arthritis: quality of life measures in the individual patient. Clin Exper Rheumatol 2005; 23(Suppl.39):S43-S52.
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3. Department of Social Protection – Rheumatoid Arthritis, 2008. Accessed on July 02 2014. 4. Department of Social Protection – Rheumatoid Arthritis, 2008. Accessed on July 02 2014. 5. Curr Opin Rheumatol. 2009;21(3):211215. 6. National Rheumatoid Arthritis Society. Biologics the story so far. April 2012. Available at http://www.nras.org.uk/ includes/documents/cm_docs/2013/j/ j5866biologics_lowres_sep_13.pdf 7. Anderson P. Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin ArthritisRheum. 2005; 34(suppl 1):19-22. 8. Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of biologicals: assessment and clinical relevance. Curr Opin Rheumatol. 2009;21:211-215. 9. Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne T. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor αinhibitor infliximab. Arthritis Rheum. 2006;54:37823789. 10. Finckh A, Dudler J, Wermelinger F, et al, on behalf of the physicians of the SCQM. Influence of anti-infliximab antibodies and residual infliximab concentrations on the occurrence of acquired drug resistance to infliximab in rheumatoid arthritis patients. Joint Bone Spine. 2010;77:313-318. 11. Radstake TRDJ, Svenson M, Eijsbouts AM, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009;68:1739-1745. 12. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: relationship to antiadalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66:921-926. 13. Schellekens H, et al. Immunogenicity of therapeutic proteins: Clinical implications and future prospects. Clin Ther 2002;24:1720–1740. 14. Actas Dermosifiliogr. 2013;104:4719. - Vol. 104 Num.06 DOI: 10.1016/j. adengl.2013.02.003 15. Actas Dermosifiliogr. 2013;104:4719. - Vol. 104 Num.06 DOI: 10.1016/j. adengl.2013.02.003 16. Actas Dermosifiliogr. 2013;104:4719. - Vol. 104 Num.06 DOI: 10.1016/j. adengl.2013.02.003 17. Maneiro JR, Salgado E, GomexReino JJ. Immunogenicity of monoclonal antibodies against tumour necrosis factor used in chronic immune mediated inflammatory conditions: systemic review and meta-analysis. JAMA Intern Med. 2013 Jun 24:1-13. doi: 10.1001/ jamainternmed.2013.7430. [Epub ahead of print] 18. Krieckaert Cl, Numohamet MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 2012 Nov;71(11):1914-5 19. Krieckaert C et al. The effect of immunomodulators on the immunogenicity of TNF- blocking monoclonal antibodies: a review. Arthritis Res Ther 2010; 12(5):217. 20. Jani M, Barton A, Warren RB et al. The role of DMARDS in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford). 2013 Aug 14. 21. Curr Med Res Opin. 2012 Apr;28(4):569-80. doi: 10.1185/03007995.2012.656844. Epub 2012 Mar 6. 22. Humira Summary of Product Characteristics, Abbott Laboratories.
23. Remicade Summary of Product Characteristics, Centocor, Inc. 24. Bendtzen K, Geborek P, Svenson M, et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor α inhibitor infliximab. Arthritis Rheum. 2006; 54:37823789. 25. Finckh A, Dudler J, Wermelinger F, et al, on behalf of the physicians of the SCQM. Influence of anti-infliximab antibodies and residual infliximab concentrations on the occurrence of acquired drug resistance to infliximab in rheumatoid arthritis patients. Joint Bone Spine. 2010; 77:313-318. 26. Alonso-Ruiz A, Pijoan JI, Ansuategui E, et al. Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and meta analysis of efficacy and safety. BMC Musculoskeletal Disorders 2008, 9:52-78 27. Perdriger A. Infliximab in the treatment of rheumatoid arthritis. Biologics: Targets & Therapy 2009:3 183–191 28. Joyce AT, Gandra SR, Fox KM, et al. National and regional dose escalation and cost of tumor necrosis factor blocker therapy in biologic-naive rheumatoid arthritis patients in US health plans. J Med Econ. 2013; 1–10. 29. Alonso-Ruiz A, Pijoan JI, Ansuategui E, et al. Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and meta analysis of efficacy and safety. BMC Musculoskel Dis 2008, 9:52-78 30. van der Laken CJ, Voskuyl AE, Roos JC, et al. Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti infliximab in responders and nonresponders to therapy for rheumatoid arthritis. Ann Rheum Dis 2007; 66:253-256. 31. Wouters D, Stapel S, Vis, et al. Human anti chimeric antibodies and infusion related allergic reactions in patients with rheumatoid arthritis. Allergy Clin Immunol Int: J World Allergy Org, Supplement 2 (2007). 32. Bartelds GM, Wolbink GJ, Stapel S, et al. High levels of human antihuman antibodies to adalimumab in a patient not responding to adalimumab treatment. Ann Rheum Dis 2006; 65:1249-1250. 33. Enbrel Summary of Product Characteristics, Pfizer Inc. 34. Enbrel Summary of Product Characteristics, Pfizer Inc. 35. Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of biologicals: assessment and clinical relevance. Curr Opin Rheumatol. 2009; 21:211-215. 36. Therapeutic efficacy of multiple intravenous infusions of antitumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41:1552-1563. 37. Maini RN, Breedveld FC, Kalden, et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004; 50:1051-1065. 38. Maini RN, Breedveld FC, Kalden, et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004; 50:1051-1065. 39. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human antitumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003; 48:35-45. 40. van de Putte LB, Atkins C, Malaise M, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid
arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis 2004; 63:508516. 41. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: relationship to anti adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis 2007; 66:921-926. 42. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease -modifying antirheumatic drugs. Ann Rheum Dis. 2010; 69:964-975. 43. Joyce AT, Gandra SR, Fox K, et al. National and regional dose escalation and cost of tumor necrosis factor blocker therapy in biologic-naïve rheumatoid arthritis patients in US health plans. J Med Econ 2013; 1-10. 44. Arthritis Rheum. 2006 Dec;54(12):37829. http://www.ncbi.nlm.nih.gov/ pubmed/17133559 45. Actas Dermosifiliogr. 2013;104:4719. - Vol. 104 Num.06 DOI: 10.1016/j. adengl.2013.02.003 46. Garcês S, Antunes M, Benito-Garcia E, et al. A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies. Ann Rheum Dis. 2013 May 11. 47. Jamnitski A et al. The presence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis. 2011 Feb;70(2): 284-8. 48. Smolen JS et al. EULAR recommendations for the management of RA with synthetic and biological diseasemodifying antirheumatic drugs. Ann Rheum Dis. 2010; 69:964-975. 49. Weaver AL. The impact of new biologicals in the treatment of rheumatoid arthritis. Rheumatology 2004: 43(Suppl.3):iii17-iii23. 50. Pollard L, Choy EH, Scott DL. The consequences of rheumatoid arthritis: quality of life measures in the individual patient. Clin Exper Rheumatol 2005; 23(Suppl.39):S43-S52. 51. Anderson P. Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin ArthritisRheum. 2005; 34(suppl 1):19-22. 52. Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of biologicals: assessment and clinical relevance. Curr Opin Rheumatol. 2009;21:211-215. 53. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: relationship to antiadalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66:921-926. 54. Lecluse LLA, Driessen RJB, Spuls PI, et al. Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. Arch Dermatol. 2010;146:127-132 55. de Vries MK, Wolbink GJ, Stapel SO, et al. Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formulation. Ann Rheum Dis. 2007;66:1252-1254. 56. Bartelds GM, Krieckaert CLM, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term followup. JAMA. 2011;305:1460-1468. 57. Anderson P. Tumour necrosis factor inhibitors: clinical implications of their different immunogenicity profiles.Semin Arthritis Rheum. 2005; 34 (suppl 1):19-22.