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Antiinfliximab antibody status and its relation to clinical response in psoriatic patients: a pilot studyJournal of Dermatology 2010; 37: 708–713 Anti-infliximab antibody status and its relation toclinical response in psoriatic patients: A pilot study Esra ADIS¸EN,1 Arzu ARAL,2 Cemalettin AYBAY,2 Mehmet Ali GU Departments of 1Dermatology and 2Immunology, Gazi University, Faculty of Medicine, Ankara, Turkey Although the mechanisms underlying the loss of response to infliximab are not completely understood, the forma-tion of antibodies to infliximab (ATI) are thought to play a role. The aim of this study was to investigate the presenceof ATI in psoriatic patients and to evaluate its relationship to the clinical response. Fifteen patients with psoriasiswere treated with infliximab (5 mg ⁄ kg) every 8 weeks after an initial three-dose induction treatment. An enzymelinked immunosorbent assay kit was used for analyzing the presence of ATI in sera. Effectiveness assessmentsincluded the change in Psoriasis Area and Severity Index (PASI) compared with study entry. Five (33.3%) patientsdeveloped ATI. While 5.9 ± 3.2 infliximab infusions achieved a fall in the PASI score from a mean of 20.4 ± 8.3to 5.3 ± 2.4 in ATI-negative patients, these values changed from 23.3 ± 11 to 10 ± 4.9 after 9 ± 5.2 infusions inATI-positive patients. Our results suggested that ATI measured in psoriatic patients are of clinical importance.
Therefore, monitoring for the induction of ATI and rescue strategies should be developed to avoid or to maintain adelay in ATI development.
antibodies to infliximab, clinical response, infliximab, loss of efficacy.
Severity Index (PASI 75) and PASI 90 was achievedby 54.5% and 34.3%, respectively, of patients receiv- Infliximab is a recombinant immunoglobulin G1-j, ing 5 mg ⁄ kg on an every 8-week regimen, compared human-murine chimeric monoclonal antibody that with 38.1% and 10.4%, respectively, by patients specifically binds to both soluble and membrane- receiving 5 mg ⁄ kg on an as-needed regimen.2 There- bound tumor necrosis factor (TNF)-a and neutralizes fore, currently, continuous infliximab therapy is its biological activity. It has been shown to be highly recommended in psoriatic patients. However, many effective for the treatment of psoriasis in several pre- clinical studies have reported that some patients trea- vious clinical studies. The recommended dose for ted with infliximab experienced a loss of efficacy over psoriasis is 5 mg ⁄ kg given as an i.v. infusion lasting time. Although the mechanisms underlying the loss of 2 h followed by similar doses at weeks 2 and 6, then response to infliximab are not completely under- stood, antibody formation against infliximab may play Several studies investigated the effects of varying a role. In addition to loss of efficacy, the development dosing regimens on the clinical responses and of antibodies to infliximab (ATI) are thought to be showed that responses in every 8-week maintenance related to the occurrence of acute and delayed dosing regimens were significantly better when com- type reactions. These reactions and loss of efficacy pared to on-demand therapy groups. In one study, at are the current problems encountered during the week 50, a 75% reduction in Psoriasis Area and Correspondence: Esra Adis¸en, M.D., Department of Dermatology, Gazi University Faculty of Medicine, 11.kat, 06500 Besevler, Ankara, Turkey.
Email: [email protected] authors have contributed significantly, and all authors are in agreement with the content of the manuscript.
Received 27 August 2009; accepted 24 November 2009.
Ó 2010 Japanese Dermatological Association Anti-infliximab antibodies in psoriasis patients Monoclonal antibodies, like any other immunoglob- If patients had chest radiographs indicative of prior ulin, may elicit side-effects. For infliximab, it is the TB infection or a positive purified protein derivative murine binding portion which comprises 25% of (PPD) tuberculin skin test, appropriate prophylactic the antibody that is antigenic and is responsible for anti-TB therapy was to be initiated before entering the study. A total of six (40%) patients received isoni- Infliximab has been approved for treatment of azid prophylaxis for TB based on baseline chest psoriasis after approval of the agent in rheumatoid radiograph indicative of latent TB, positive PPD skin arthritis (RA), ankylosing spondylitis (AS) and Crohn’s disease (CD); therefore, much of the data on the safety Demographic data of our patients are presented in and efficacy of infliximab has been conducted with Table 1. Patients were assessed at screening, and these patients.10–19 In RA, CD and AS, the presence then at baseline, weeks 2, 8 and 16, and every of ATI and their relationship to clinical response and 8 weeks thereafter through the treatment period.
allergic reactions have been previously shown.10–19 At each visit, the presence of infections, side-effects This issue and the clear-cut demonstration of the or infusion reactions were recorded. Effectiveness presence of ATI in psoriasis have been examined in assessments included the change in PASI compared few studies to date. In this pilot study, we investigated the presence of ATI in psoriatic patients and evaluatedits relationship to the clinical response to infliximab In the study, peripheral blood samples of 5–10 mLwere collected from patients at the beginning of thestudy and thereafter just before infliximab infusions.
Venous blood samples were collected and centri- fuged at 3000 g for 10 min, aspirated and stored Fifteen patients (seven female and eight male) with at )80°C until analysis. A commercially available moderately severe to severe plaque-type psoriasis enzyme linked immunosorbent assay (ELISA) kit vulgaris, generalized pustular psoriasis or erythroder- (Matriks Biotek Laboratories, Ankara, Turkey) was mic psoriasis were consecutively recruited into the used for analyzing the presence of ATI in sera. The study. Inclusion criteria were patients who had a PASI assay was based on a highly specific double antigen score of more than 10 with at least 10% total body binding assay principle. In this procedure, the specific surface area (BSA) involvement, and had not antibody in serum, namely ATI, binds to the inflix- responded to other systemic therapies including imab-coated well with one of its Fab arms and also methotrexate, oral retinoids, cyclosporine or psoralen binds to the biotinylated infliximab with the aid of its plus ultraviolet A therapy (PUVA), or had not tolerated other Fab arm. The ELISA kit demonstrates the pres- these agents, and had no history of serious infection, ence of antibodies to infliximab, and the intensity of lymphoproliferative disease or active tuberculosis the color developed is proportional to the amount of (TB). Following the introduction of infliximab for clini- specific antibodies. Results were expressed as posi- cal use at our department, blood samples were routinely collected just before every infliximab admin-istration. The age and sex of the patients, duration of psoriasis, previous treatments, concomitant thera- Data analysis was carried out using the SPSS pies, baseline PASI and PASI follow-up values and ver. 11.00 statistical package software. Data were summarized descriptively. Comparisons between The dose of infliximab was adjusted for body- ATI-positive and ATI-negative groups were per- weight. A single dose of 5 mg ⁄ kg was administrated formed using a Mann–Whitney U-test for continuous at weeks 0, 2 and 6 and thereafter regularly every data and v2-test for categorical data. Statistical signif- 8 weeks. Generally, in erythrodermic patients, inflix- icance was defined as P < 0.05. A Wilcoxon signed imab was started in combination with systemic corti- rank test was used to assess changes in PASI costeroids that were gradually tapered over 2 weeks.
Ó 2010 Japanese Dermatological Association Table 1. Features of antibodies to infliximab (ATI)-positive and -negative patients Duration of psoriasis, years, mean ± SD (min–max) Mean of baseline PASI, mean ± SD (min–max) Infliximab infusion number, mean ± SD (min–max) Concomitant immunosuppressive therapy, n (%) *Mann–Whitney U-test, **v2-test, ***P = 0.01; comparison of the mean of baseline Psoriasis Area and Severity Index (PASI) with last PASI score,Wilcoxon signed rank, ****P = 0.1; comparison of the mean of baseline PASI with last PASI score, Wilcoxon signed rank. SD, standard deviation.
(P = 0.01), in the current study. In addition, thoughthe mean of baseline PASI scores were not showing Table 1 shows the characteristics of the study difference between the groups (P = 0.63), the mean population. All patients received 3–16 infliximab of last PASI scores were higher in ATI-positive infusions during the study. Five (5 ⁄ 15, 33.3%) patients when compared to ATI-negative patients patients developed ATI at the time of the 5th, 6th, 7th, 10th and 13th infusion of infliximab ther- All five patients with ATI presented with either new lesion development or a loss of efficacy which was reaction requiring infliximab discontinuation after reflected by an increase in PASI in these patients the third infusion. All other patients were contin- uing infliximab therapy without any problem at the Because the numbers of the patients receiving time of the study. Four patients received concom- concomitant corticosteroid treatment were low, the itant corticosteroid treatment. Three patients had effect of corticosteroids on ATI positivity could not be subjected to any statistical analysis.
Clinical characteristics of patients who developed When all the ATI-positive patients receiving inflix- ATI (n = 5) and those who did not (n = 10) were imab were treated with additional methotrexate with shown in Table 1. Statistical analysis revealed no dif- doses ranging 5–15 mg ⁄ week, the disappearance of ference according to age (P = 0.58) and sex (P = ATI was observed only after 8 weeks of methotrexate 0.95) characteristics, the duration of the disease (P = 0.79) or types (plaque-type psoriasis vulgaris,generalized pustular psoriasis or erythrodermic pso- riasis) of psoriasis (P = 0.38, P = 0.13, P = 0.67,respectively) between the ATI-positive and -negative Our study, which aimed to document the frequency patients. In ATI-negative patients, 5.9 ± 3.2 (3–14) of of ATI formation in psoriatic patients receiving inflix- infliximab infusions achieved a fall in the PASI score imab monotherapy on a regularly scheduled basis, from a mean of 20.4 ± 8.3 (11–34) to 5.3 ± 2.4 (1–9) showed that one-third of patients receiving infliximab (P = 0.01). However, in ATI-positive patients, inflix- for psoriasis developed ATI during their therapy. More imab treatment achieved a fall in the PASI score from importantly, we were able to show that the forma- a mean of 23.3 ± 11 (16–36) to 10 ± 4.9 (5–16) after tion of ATI reflected the loss of efficacy of inflixi- 9 ± 5.2 (3–16) infusions (P = 0.01). This finding mab in these patients. Interestingly, our results were showed that the similar numbers of infusions of inflix- in agreement with a previous study that reported imab (P = 0.16) failed to satisfactorily reduce the that 35.8% of the psoriatic patients developed ATI mean PASI scores of ATI-positive patients (P = 0.1) after 60 weeks of 5 mg ⁄ kg infliximab applied every when compared to that of ATI-negative patients Ó 2010 Japanese Dermatological Association Anti-infliximab antibodies in psoriasis patients Table 2. Antibodies to infliximab (ATI)-positive patients and their characteristics infusion number(no. at the time of ATIpositivity)Last PASI before MTX, methotrexate; PASI, Psoriasis Area and Severity Index.
reported in other psoriasis clinical trials4,20 and in However, these findings need to be clarified by long- other indications of the drug.9–11,13,19,21 The develop- ment of ATI up to 61%, 43% and 64% have been Hypersensitivity reactions are among other prob- reported in patients with CD,22,23 RA,11 and AS,12 lems encountered during infliximab use. One impor- respectively. In RA, AS and CD, it has been shown tant consequence of the formation of ATI is the that ATI was among the determinants of the thera- increased risk for hypersensitivity reactions.6,19 A cor- peutic response11,19,22 on the other hand, in contrast relation between antibody level and increased likeli- to our observations, some authors have proposed hood of reaction was not observed in some studies.14 that this does not hold true for psoriasis.2 In our study, We observed only one infusion reaction in one patient five out of 15 patients (33.3%) developed ATI at 5th that occurred in the third infusion. However, this to 13th infusions. These patients experienced new patient was observed to be ATI negative.
lesion development or an increase in erythema and Most of the hummanized monoclonal antibodies an increase in induration in the previous lesions are immunogenic to a greater or lesser extent. The reflecting an increase in PASI suggesting that ATI incidence of immunogenicity of therapeutic proteins measured in our patients are of clinical importance.
is variable; though not totally understood, patient- Moreover, the similar numbers of infusions of inflix- related and treatment-related factors may have an imab failed to satisfactorily reduce the mean PASI affect.6–8,24,25 The half-life elimination of infliximab is scores in ATI-positive patients when compared to also related to other substantial inter-subject variabili- that of ATI-negative patients, in the current study.
ties.9 Possibly because of this, the frequency and the Ó 2010 Japanese Dermatological Association timing of the development of ATI varied among stud- approaches will have obvious financial implications.
In RA, AS and CD patients, the loss of response could Several strategies such as continuous therapy on a be prevented by the increase in infliximab dosage.7,18 regularly scheduled basis, concomitant use of metho- In the case of psoriasis, however, current knowledge trexate, slowing infusion rate, shortening the infusion does not support that this approach may work in pso- interval, switching to another anti-TNF agent such as riasis treatment. In contrast to other indications of the adalimumab, and premedication with systemic ste- infliximab, the response of psoriasis to infliximab roids have been developed to prevent ATI forma- does not appear to be dose dependent. Two studies tion.5,6,26 However, these strategies fail especially in investigated the efficacy of infliximab, 3, 5 or 10 patients who are intolerant to methotrexate or who mg ⁄ kg, in psoriasis. A dose of 3 or 5 mg ⁄ kg provided have developed severe infusion reactions. Also, in a PASI 75 in 72% and 88% of the patients, respec- psoriatic patients, administration of prophylactic sys- tively, and a PASI 90 in 45.5% or 57.6% of the temic steroids before every infliximab infusion does patients, respectively, whereas infliximab in doses of 10 mg ⁄ kg did not produce an increase in efficacy.3,20 An induction regimen followed by regularly sched- A further increase in the efficacy was not observed uled maintenance infusions decreases the likelihood with 10 mg ⁄ kg when compared to the lesser doses of of antibody formation possibly by generating immuno- the drug. Therefore, the recommended dose of inflix- logical tolerance.10,15,16 It has been suggested that imab is 5 mg ⁄ kg for psoriasis.3 This is the optimum with the extended intervals between the infusions, the dose of the drug to achieve a sustained response, probability of the formation of infliximab antibodies and it is not known how much increase in infliximab increases.5 In accordance with that suggestion, doses in ATI-positive patients will provide a simi- Menter et al.2 have shown that the probability of lar response that was previously achieved in a ATI- development of ATI was higher in as-needed regimens (41.5%) when compared to every 8-week At the moment, infliximab in psoriasis appears to infliximab regimens (35.8%), and favored use of every offer the advantage of rapid healing, reduced mor- 8-week therapy. Moreover, induction regimen and bidity and hospital stay, and freedom from the maintenance therapy with 8-week intervals have common side-effects of other immunosuppressives.
been found better than the addition of an immuno- However, prolonged use of infliximab is generally modulator for preventing antibody formation.7 recommended to achieve a sustained response. On It has been shown that the use of concomitant the other hand, prolonged use of infliximab has immunomodulators prior to starting infliximab is been associated with loss of efficacy which is gen- effective in reducing antibody production in indica- erally but not totally2 believed to be related to the tions other than psoriasis.7,10,26 When it comes to formation of anti-neutralizing antibodies. Therefore, psoriasis, there is no study that investigated the effect monitoring for the induction of ATI and rescue strat- of concomitant use of immunosuppressants on the egies should be developed to avoid or to maintain formation of antibodies. Even with a limited number a delay in ATI development. Although our patient of subjects, the present study demonstrated that in number is low, our results showed that the forma- psoriasis adding methotrexate (5–15 mg ⁄ week) to inf- tion of ATI development may be responsible for the liximab provided a negative ATI status and achieved loss of efficacy of infliximab in long-term use, espe- a sustained clinical efficacy in previously ATI-positive cially in patients whose clinical benefit wanes over patients. At present, it is not known for how long immunosuppressive therapy with methotrexate incombination with infliximab should be continued inany of the indications of the drug.6,26 In ATI-positive patients, the infliximab levels will 1 Gottlieb AB, Chaudhari U, Mulcahy LD, Li S, Dooley LT, be decreased. Therefore, patients with ATI may Baker DG. Infliximab monotherapy provides rapid and require higher infliximab doses or more frequent sustained benefit for plaque-type psoriasis. J Am Acad administration to maintain response, however, these Ó 2010 Japanese Dermatological Association Anti-infliximab antibodies in psoriasis patients 2 Menter A, Feldman SR, Weinstein GD et al. A random- 15 Sandborn W. Preventing antibodies to infliximab in ized comparison of continuous vs. intermittent infliximab patients with Crohn’s disease: optimize not immunize.
maintenance regimens over 1 year in the treatment of Gastroenterology 2003; 124: 1140–1145.
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17 Martı´nez-Borra J, Lo´pez-Larrea C, Gonza´lez S et al.
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High serum tumor necrosis factor-alpha levels are asso- 4 Reich K, Nestle FO, Papp K et al. Infliximab induction ciated with lack of response to infliximab in fistulizing and maintenance therapy for moderate-to severe psori- Crohn’s disease. Am J Gastroenterol 2002; 97: 2350– asis: a phase III, multicentre, double blind trial. Lancet 18 Haraoui B, Cameron L, Ouellet M, White B. Anti-inflix- 5 Nast A, Kopp IB, Augustin M et al. Deutsche Dermato- imab antibodies in patients with rheumatoid arthritis logische Gesellschaft (DDG); Berufsverband Deutscher who require higher doses of infliximab to achieve Dermatologen (BVDD). Evidence-based (S3) guidelines or maintain a clinical response. J Rheumatol 2006; 33: for the treatment of psoriasis vulgaris. J Dtsch Dermatol 19 van der Laken CJ, Voskuyl AE, Roos JC et al. Imaging 6 Baert F, De Vos M, Louis E, Vermeire S; Belgian IBD and serum analysis of immune complex formation of Research Group. Immunogenicity of infliximab: how to radiolabelled infliximab and anti-infliximab in responders handle the problem? Acta Gastroenterol Belg 2007; 70: and non-responders to therapy for rheumatoid arthritis.
7 Cheifetz A, Mayer L. Monoclonal antibodies, immuno- 20 Gottlieb AB, Evans R, Li S et al. Infliximab induction genicity, and associated infusion reactions. Mt Sinai J therapy for patients with severe plaque type psoriasis: a randomized, double-blind, placebo-controlled trial.
8 Pendley C, Schantz A, Wagner C. Immunogenicity of J Am Acad Dermatol 2004; 51: 534–542.
therapeutic monoclonal antibodies. Curr Opin Mol Ther 21 van der Bijl AE, Breedveld FC, Antoni CE et al. An open- label pilot study of the effectiveness of adalimumab in 9 Aybay C, Ozel S, Aybay C. Demonstration of specific patients with rheumatoid arthritis and previous infliximab antibodies against infliximab induced during treatment treatment: relationship to reasons for failure and anti- of a patient with ankylosing spondylitis. Rheumatol Int infliximab antibody status. Clin Rheumatol 2008; 27: 10 Maini RN, Breedveld FC, Kalden JR et al. Therapeutic 22 Ainsworth MA, Bendtzen K, Brynskov J. Tumor necrosis efficacy of multiple intravenous infusions of anti-tumor factor-alpha binding capacity and anti-infliximab anti- necrosis factor alpha monoclonal antibody combined bodies measured by fluid-phase radioimmunoassays as with low-dose weekly methotrexate in rheumatoid predictors of clinical efficacy of infliximab in Crohn’s arthritis. Arthritis Rheum 1998; 41: 1552–1563.
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11 Wolbink GJ, Vis M, Lems W et al. Development of 23 Baert F, Noman M, Vermeire S et al. Influence of antiinfliximab antibodies and relationship to clinical immunogenicity on the longterm efficacy of infliximab response in patients with rheumatoid arthritis. Arthritis in Crohn’s disease. N Engl J Med 2003; 348: 601–608.
24 Forero A, Meredith RF, Khazaeli MB et al. A novel mono- 12 de Vries MK, Wolbink GJ, Stapel SO et al. Decreased clonal antibody design for radioimmunotherapy. Cancer clinical response to infliximab in ankylosing spondylitis is Biother Radiopharm 2003; 18: 751–759.
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Human antichimeric antibody in children and young 13 Hanauer SB, Wagner CL, Bala M et al. Incidence and adults with inflammatory bowel disease receiving importance of antibody responses to infliximab after infliximab. J Pediatr Gastroenterol Nutr 2004; 38: maintenance or episodic treatment in Crohn’s disease.
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26 Vermeire S, Noman M, Van Assche G et al. Effective- 14 Hanauer SB, Feagan BG, Lichtenstein GR et al. Mainte- ness of concomitant immunosuppressive therapy in nance infliximab for Crohn’s disease: the ACCENT I suppressing the formation of antibodies to infliximab in randomized trial. Lancet 2002; 359: 1541–1549.
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Ó 2010 Japanese Dermatological Association
Átdolgozott finanszírozási eljárásrend tervezet Differenciál diagnózis: Régen a differenciál diagnózis kritériuma a 6 hónapos tünetcsoport fennállása volt. Az 1 hónap utáni diagnosztika szakmailag nevetséges, világosan magában hordozza a diagnosztikai hibák nagyon komoly előfordulásának növekedését, egy ilyen diagnózis kiosztása pedig növeli a stigmát, prede