Abatacept therapy and safety management

Management of patients on abatacept in daily practice S3

AbataceptTHERAPY AND SAFETY MANAGEMENT

Thao PHAM(1,*), Pascal CLAUDEPIERRE(2), Arnaud CONSTANTIN(3), Bruno FAUTREL(4), Laure

GOSSEC(5), Jacques-Éric GOTTENBERG(6), Philippe GOUPILLE(7), Éric HACHULLA(8), Charles MASSON(9),

Jacques MOREL(10), Alain SARAUX(11), Thierry SCHAEVERBEKE(12), Daniel WENDLING(13), Xavier

MARIETTE(14), Jean SIBILIA(15)

(1) Service de Rhumatologie, CHU Conception, Marseille. (2) Service de Rhumatologie, CHU Henri Mondor, Créteil. (3) Service de Rhumatologie,

Hôpital Larrey, Toulouse. (4) Service de Rhumatologie, CHU Pitié-Salpétrière, Paris. (5) Service de Rhumatologie,

CHU Cochin, Paris. (6) Service de Rhumatologie, CHU Hautepierre, Strasbourg. (7) Service de Rhumatologie, CHU Trousseau, Tours.

(8) Service Médecine Interne, Hôpital Roger Salengro, Lille. (9) Service de Rhumatologie, CHU Angers, Angers. (10) Service d’Immuno-

Rhumatologie, CHU Lapeyronie, Montpellier. (11) Service de Rhumatologie, CHU Cavale-Blanche, Brest. (12) Service de Rhumatologie, CHU

Pellegrin, Bordeaux. (13) Service de Rhumatologie, CHU Jean Minjoz, Besançon. (14) Service de Rhumatologie, CHU Bicêtre,

Le Kremlin-Bicêtre. (15) Service de Rhumatologie, CHU Hautepierre, Strasbourg ; all in France.

Evidence Based Medicine Official recommendations Expert opinion

Abstract

Objectives: To elaborate a how-to-use abatacept material intended to help

physicians in the management of patients with inflammatory diseases treated

with this drug in routine practice.

Methods: 1) Selection of the relevant domains by a rheumatologists’ panel;

2) Search for published evidence in each domain; 3) Elaboration of the clinical

tool guide with a 3 -level gradation of evidence (evidence-based medicine EBM,

official recommendations and expert’s opinion). The experts were 11 academic

rheumatologists with a large experience in prescribing abatacept and in

managing rheumatoid arthritis. They were all members of the CRI (Club

Rhumatismes et Inflammation), a section of the French Rheumatology Society

dedicated to the inflammatory rheumatic diseases. Each fact sheet was reviewed

by two other experts; 4) Regular updating based on medical literature and post-

marketing surveillance data.

*Corresponding author. Tel.: +33 4 91 38 34 62; fax: +33 4 91 38 38 87.

E-mail adress: [email protected] (T. Pham).

Joint Bone Spine 2009 ; 76 (Suppl1) : S1-S56

Management of patients on abatacept in daily practiceS4

Results: Four domains were considered relevant: abatacept contraindications,

management of side effects or associated diseases appearing during abatacept

treatment, management of "practical situations" such as surgery or pregnancy,

physician and patient information.

After the literature analysis and discussion during an experts' meeting, a

consensus was reached on:

– a pre-treatment checklist aimed at searching abatacept contraindications;

– a what-to-do document when facing side effects or associated diseases (auto-

immune pathology, bacterial or viral infections, cardiovascular diseases,

intolerance to abatacept, solid or haematological malignancy) or "practical

situations" (surgery, pregnancy, vaccination, travel, drug-drug interactions);

– an example of standard information letter to be addressed to the attending

physician (rheumatologist and general practitioner);

– an example of standard information letter to be addressed to the patient.

Conclusion: Based on both an EBM approach and an expert’s opinion approach,

this abatacept clinical tool guide should provide assistance to all physicians

attending patients treated with abatacept. For a better implementation in clinical

practice, this tool guide will be available online at www.cri-net.com and regularly

updated.

Keywords: Abatacept; Monitoring; Safety; Health services

© 2009 Société Française de Rhumatologie. Published by Elsevier Masson SAS. All rights reserved.


Management of patients on abatacept in daily practice

After TNF antagonists and rituximab…here comes abatacept!

Since 2005, the CRI (Club Rhumatismes et Inflammation) has been issuing fact

sheets designed to assist you in your everyday practice. These fact sheets reflect

a comprehensive view developed by experts who examined the literature,

unpublished data supplied by pharmaceutical companies, and numerous

personal communications. For all the situations that are not discussed in the EU

SPC (European Summary of Product Characteristics) and for which there is no

general agreement, we tried to give you our opinion (1,2).

As with previous fact sheets, a colour code is used to differentiate material that

is supported by evidence from the literature, official recommendations, and

expert opinion. Although the data on abatacept are not yet as substantial as

those available for TNF antagonists and rituximab, we believe the time has come

for a recapitulation of the main practical information.

A huge amount of energy has gone into developing these fact sheets, and we are

deeply grateful to the contributors for their effort and expertise. This interactive

document will be available on the CRI site (http://www.cri -net.com) and

published in print form in a special issue of Joint Bone Spine to whose editorial

board we are indebted for their invaluable cooperation.

Please feel free to provide feedback about these fact sheets. Your input will help

us improve them when we conduct the update scheduled for 2010.

Introduction

S5



This checklist is designed to help you conduct a systematic search for contraindications toabatacept therapy. It does not include the assessment of the level of activity and severity ofthe disease justifying this treatment.

When interviewing the patient, check the absence of the following:

❒ A history of tuberculosis in the patient or a family member, or a history of contact with apatient who had tuberculosis

❒ A history of severe, chronic, and/or recurrent infections (bacterial, viral)

❒ A history of solid cancer

❒ A history of chronic obstructive pulmonary disease

When conducting the physical examination of the patient, check the absence of:

❒ A fever

❒ Active infection

❒ Enlarged lymph nodes

❒ Signs suggesting a malignancy

❒ Hypertension

Vaccinations:❒ Before starting abatacept therapy, vaccinations should be updated

• Inactivated vaccines or component vaccines: if possible at least 2 weeks

• Lives attenuated vaccines (yellow fever...): at least 2 weeks and at best 4 weeks

❒ Administration of the pneumococcal vaccine is recommended

Investigations that should be obtained routinely at the first evaluation❒ Blood cell counts

❒ Serum protein electrophoresis

❒ Chest radiograph

❒ Intradermal test with 5 IU of tuberculin • In patients with a history of prophylactic antituberculous treatment given because a

previous intradermal test showed an induration larger than 5 mm in diameter, theintradermal test does not need to be repeated.

• In patients who had a negative intradermal test when screened at least 1 year earlier, thetest should be repeated.

• In patients who have never been screened, AFSSAPS recommendations for detectinglatent tuberculosis should be followed.

S6

Initial pre-treatment assessment


❒ Serological tests for hepatitis B and C and, with the consent of the patient, serologicaltest for HIV infection. If tests done within the last 5 years are available, re-testing isunnecessary unless the patient has risk factors or a history of a high-risk medicalprocedure in the interval.

❒ Standard practice should be followed regarding the detection of cancer according tolocal guidelines

• Screening for colorectal cancer• Individual screening for prostate cancer• Screening mammography for breast cancer

The following investigations are recommended:❒ In patients previously treated with rituximab: lymphocyte typing and immunoglobulin

assay by weight

Contraindications to abatacept therapy:❒ Hypersensitivity to abatacept or to any of its excipients

❒ Severe uncontrolled infection such as sepsis or opportunistic infections

❒ Cancer diagnosed within the last 5 years, except non-melanoma skin cancer that wasremoved completely with disease-free excision margins

Precautions when using abatacept:❒ Chronic obstructive pulmonary disease (COPD)

❒ Hypogammaglobulinemia

❒ Lymphopenia

❒ Monoclonal gammopathy of unknown significance (MGUS)

S7



● Treatment monitoring in patients receiving abatacept requires both clinical andlaboratory assessment to evaluate the effectiveness and safety of the drug.Since abatacept is given once a month after the first three infusions, regular clinicalfollow-up can be provided at each infusion (see the model letters for informing office-based rheumatologists and/or primary-care physicians).In the short-term, the risk of acute infusion reactions should be assessed (see the“Acute infusion reactions” fact sheet).

● Clinical monitoring aims at evaluating the treatment response, using the DAS 28.A treatment response is defined as follows:• improvement in the DAS 28 by at least 0.6 at week 16 (if this goal is not achieved,

abatacept therapy can be stopped)• and improvement in the DAS 28 by at least 1.2 (if possible with a DAS 28 no greater

than 3.2) at week 24

Subsequently, the patient should be evaluated at least once every 3 months to assessdisease activity (DAS 28 or SDAI), quality of life, and laboratory markers for inflammation(ESR and/or CRP every 3 months) (see the model letter for informing office-basedrheumatologists).

Structural disease progression should be evaluated (using radiographs of the hands andfeet) after 1 year of abatacept therapy.

Safety should be assessed at each abatacept infusion and whenever an unexpectedevent occurs. As with all biotherapies, careful attention should be given to bacterial orviral infections, most notably in patients with a history of recurrent infections or underlyingconditions (COPD); and to symptoms that may suggest a solid cancer or haematologicalmalignancy (see the “Bacterial and Viral Infections” and “Malignancies” fact sheets).

The response profile was evaluated over a 6-month period in the AIM, ATTEST, ATTAIN, andARRIVE trials. In patients who responded inadequately to TNF antagonist therapy, abataceptsignificantly decreased disease activity. A response defined as an at least 1.2-pointdecrease in the DAS 28 was significantly more common with abatacept, as early as the firstmonth, in the AIM and ATTEST studies. The mean 3-month response rate was 70% in theabatacept groups in the four studies overall. As the treatment response continues to developover the first 6 months, the best time for evaluating the patient is between the third and sixthmonth (3-5).

● Laboratory monitoringNo specific laboratory or immunological tests are needed to monitor abatacept therapy.Laboratory tests for inflammation are needed to compute the DAS, and the appropriatelaboratory tests should be obtained to monitor concomitant treatments (e.g., methotrexate),

Monitoring abatacept therapy

S8


according to standard practice. In the absence of specific problems, blood cell counts(leukopenia and thrombocytopenia are uncommon adverse events), transaminase assaysand renal function test (creatinine) should be performed every 3 months.

The tests required by concomitant treatments (e.g., methotrexate) should be performed.

Following EU SPC (European Summary of Product Characteristics), an effective birth controlmethod should be used throughout the treatment and for the first 14 weeks after treatmentdiscontinuation in women of reproductive potential.

However, given the elimination half-life of abatacept, 97% of the drug is eliminated within 18weeks of the last dose, assuming linear kinetics. Therefore, we considered thatattempts to conceive can be started 18 weeks after the last abatacept infusion (see the“Pregnancy” fact sheet).

Practical situations: pregnancy, vaccination, travel, surgery, and drug-drug interactions arediscussed in specific fact sheets (“Pregnancy”, “Vaccination”, “Travel”, “Surgery”, and “Drug-Drug Interactions”).

● Calendar: dates of the infusions, clinical evaluations, laboratory tests, and structural-damage assessments

14 days 14 days 1 month 1 monthAbatacepttreatment

1st inf.10 mg/kg

D0

2nd inf.10 mg/kg

D14

3rd inf.10 mg/kg

D30

4th inf.10 mg/kg

D60 M3

3 months 3 months 3 months 3 monthsDAS 28or SDAI

+ quality of life+ ESR and/or CRP

1st clinical evaluation

2nd clinical evaluation

3rd clinical evaluation

D0 M3 M6 M9 M12

M12

Blood cell counts + transaminases

+ creatinine

1st clinical evaluation

2nd clinical

evaluation3

rd clinical

evaluation

D0 M3 M6 M9

1 yearX-raysof handsand feet

D0 M12

1st structural evaluation

3 months 3 months 3 months 3 months

S9



● The mounting of an anti-infectious T-cell response is a complex process during whichcytokines and co-stimulation molecules generate signals that regulate adaptiveimmunity. By preventing T-cell activation via the B7/CD28 co-stimulation pathway,abatacept may inhibit the anti-infectious T-cell response (6).

● The crucial role for the B7/CD28 co-stimulation pathway in immunity against viruses hasbeen demonstrated in several models of infection, particularly with Herpes simplex virusand Influenza virus (7). The B7/CD28 pathway also makes an important contribution toimmunity against parasites, most notably Toxoplasma gondii and Leishmania major (8);fungi, such as Pneumocystis carinii (9); and bacteria, particularly some of the intracellularorganisms including Listeria monocytogenes, Salmonella enterica, and Chlamydiatrachomatis (10).

● In mouse models, however, treatment with abatacept or CTLA4-murine Ig did not affect theability of the animals to survive chronic infection with Mycobacterium tuberculosis (11), latentinfection with Mycobacterium tuberculosis, or acute infection with cytomegalovirus orPneumocystis carinii (12). However, the treatment was associated with decreased survival ofacute infection with Herpes simplex virus (12).

● Safety data were collected in 1955 patients exposed to abatacept during the five maincontrolled trials of the clinical development program for abatacept in rheumatoid arthritis(81.9% were also on methotrexate, 26.9% on another conventional DMARD, 9.4% on TNFantagonist therapy, and 1.1% on anakinra). Infectious adverse events were more common inthe abatacept groups than in the placebo groups (54.1% vs. 48.7%). The most common sitesof infection were the upper respiratory tract (nasopharyngitis, 11.6% vs. 9.1%; and rhinitis,2.7% vs. 1.7%) and the urinary tract (5.9% vs. 4.7%). There was an increase in Herpes simplexvirus infections (2% vs. 1%). Older patients had a higher risk of infection (13,14).

● These safety data show an increased risk of infectious serious adverse events in theabatacept groups than in the placebo groups (3% vs. 1.9%). The most common site ofserious infection was the respiratory tract (pneumonia, 0.5% in both groups; bronchitis,0.2% vs. 0%; bronchopneumonia, 0.1% vs. 0%; and sinusitis, 0.1% vs. 0%), thegenitourinary system (urinary tract infection, 0.2% vs. 0.1%, acute pyelonephritis, 0.2% vs.0%); the skin (infectious cellulitis, 0.3% vs. 0.2%; skin ulcer superinfection, 0.1% vs. 0%;and subcutaneous abscess, 0.1% vs. 0%), and the gastrointestinal tract (diverticulitis,0.2% vs. 0.1%) (13,14).

Current knowledge on the risk of bacterial and viral infections during abatacept therapy

Role for B7/CD28 co-stimulation pathway in immunity against infectious agents

Management of patients with past or present history ofbacterial or viral infections


● Of the 10 deaths (0.5%) that occurred in the abatacept groups during the double-blindphase, only 1 was caused by an infection (pulmonary aspergillosis in a patient withbronchiectasis and a history of miliary tuberculosis), compared to 2 of the 6 deaths (0.6%) inthe placebo groups (Pneumocystis carinii pneumonia and bloodstream infection) (13,15).

● A meta-analysis of the results of the five main controlled studies of the efficacy and safety ofabatacept in RA found no statistically significant increase in the risk of serious infections inthe abatacept groups compared to the placebo groups (odds ratio [OR], 1.35; 95%confidence interval [95%CI], 0.78-2.32; P=0.3). However, the statistical power of this meta-analysis is insufficient to warrant a conclusion that the risk of infection is not increasedduring abatacept therapy (16).

● Since the publication of this meta-analysis, the safety data from the clinical developmentprogram for abatacept in RA were updated to December 2007. Overall, 4150 patients withRA received abatacept during eight clinical studies (10,365 patient-years; median exposuretime, 26.2 months). The incidence of admission for infection was 3.05/100 patient-years inthe abatacept groups and 2.15/100 patient-years in the placebo groups during thecontrolled phase of these studies. The incidence of admissions remained stable over time,as shown by the 2.73/100 patient-years incidence during the cumulative follow-up ofpatients given abatacept in the controlled phase then in the open-label extension phase.Among the infections that led to admission, the most common were lower respiratory tractinfections, cellulitis, and urinary tract infections (17). Furthermore, in the abatacept clinicaltrial experience, a total of 6 cases of TB were reported with an incidence rate ofmycobacterium tuberculosis as of December 2007 of 0.06/100 patient-years (17). The4-year efficacy and safety data generated by the open-label extension phase of the AIM study(an evaluation of abatacept in RA patients having an inadequate response to methotrexate)indicate that 3 (0.7%) patients had tuberculosis.

● Overall evaluation of the infectious riskInfections contribute to the excess mortality seen in patients with RA. The increasedincidence and severity of infections in patients with RA is multifactorial. Factors thatincrease the risk of infection include the immune system dysfunction that underlies RA,the activity and severity of the disease, its functional impact, any co-morbidities (e.g.,diabetes mellitus, respiratory diseases, skin ulcers, and foreign material such as jointprostheses and catheters), and other immunosuppressive medications the patient maybe taking (most notably glucocorticoids and TNF antagonists) (18-20).

All these risk factors should be considered when evaluating the overall risk of infection inpatients with RA, particularly before starting an immunosuppressive medication such asabatacept.

● Minimizing the risk of bacterial infections• Abatacept is contraindicated in patients who have severe uncontrolled infections such

as bloodstream infections and opportunistic infections. Physicians should exercise

What should be done before the initiation of abatacept therapy to prevent bacterial and viral infections?


caution when considering the use of abatacept in patients with a history of recurrentinfections or underlying conditions which may predispose to infections.

• Situations associated with a high risk of bacterial infection (recent prosthesis infection,skin ulcers, indwelling catheter) also contraindicate the initiation of immunosuppressivetreatments such as abatacept.

• Therefore, before starting abatacept therapy, a medical history and physical examinationshould be performed to look for an overt or latent focus of infection (see the “Initial pre-treatment assessment” fact sheet).

● Minimizing the risk of tuberculosis• Six cases of TB were reported in the abatacept clinical trial program (17), in spite of the

fact that the risk of latent tuberculosis was evaluated routinely in patients consideredfor inclusion in studies of abatacept in RA and that patients were not included if they hada history of active tuberculosis within the 3 years preceding the selection visit or apositive screening test with no history of antituberculous treatment (13).

• Patients should be screened for latent tuberculosis prior to initiating abatacept Theavailable medical guidelines should be taken into account.

• In patients taking prophylactic antituberculous therapy, abatacept can be started after3 weeks according to local guidelines.

• If the 5 IU intradermal tuberculin test done before starting abatacept was positive andthe patient received prophylactic antituberculous therapy in compliance with Frenchrecommendations, repeating the intradermal tuberculin test seems unnecessary. Incontrast, if the 5 IU intradermal tuberculin test done before starting abatacept wasnegative and was performed more than 1 year earlier, another test should beperformed. If this second 5 IU intradermal tuberculin test is positive, prophylacticantituberculous therapy should be given as recommended by the AFSSAPS (21).

● Minimizing the risk of viral infection • The rate of Herpes simplex virus infections was increased in the five main controlled

studies of the clinical development program for abatacept in RA (2% in the abataceptgroups vs. 1% in the placebo groups). In contrast, there were no cases of hepatitis B or C,HIV infection, or JC virus infection during these studies (13).

• However, as the safety of abatacept has not been established in patients withviral infections (22), screening for viral hepatitis B, C and HIV should be performedin accordance with published guidelines before starting treatment with abatacept.If serological tests done within the last 5 years are available, re-testing is notnecessary, except in patients with risk factors or a high-risk medical procedure in theinterval. Serological testing for HIV infection is advisable (with the consent of thepatient).

• In patients with active HBV or HCV infection, advice from a hepatologist must beobtained before making treatment decisions.


• In patients who have HIV infection, advice from an infectiologist must be obtainedbefore making treatment decisions.

• In patients with recurrent oral or genital Herpes simplex virus infection, advice from aninfectiologist must be obtained before making treatment decisions, to determinewhether prophylactic acyclovir therapy is appropriate.

● Patients with evidence of severe infection requiring emergent probabilistic antimicrobialtherapy should be admitted to a specialized unit and taken off abatacept therapy.

● In all patients with infections, specimens for bacteriological studies must be obtainedbefore starting probabilistic antimicrobial therapy. Other tests (mycobacteriological,virological, mycological, or parasitic studies; and imaging studies) should be performed asindicated by the symptoms.

● The probabilistic antimicrobials should be selected based on the signs of infection,personal history, and co-morbidities.

• In patients with community-acquired respiratory tract infections, the first-line antimicrobialtreatment consists of amoxicillin–clavulanic acid or a third-generation cephalosporin(Cefotaxine®, Ceftriaxon®). If no improvement occurs within the first 48 hours, a macrolideshould be substituted for, or added to, the first antimicrobial. In specific settings, anantipneumococcal quinolone may be preferable.

• Evidence of interstitial pneumonia should routinely suggest the possibility of atypicalpneumonia (Chlamydia pneumoniae, Mycoplama pneumoniae) or of an opportunisticinfection (Legionella, Pneumocystis jiroveci). Serological tests should be obtained forChlamydia pneumoniae, C. psittaci, and Mycoplasma pneumoniae, as well as a Legionellapneumophila antigenuria assay, and the need for bronchoalveolar lavage should bediscussed. Chlamydiae, mycoplasms and Legionella are susceptible to macrolides.Identification of Legionella requires hospital admission. When P. jiroveci pneumonia issuspected, cotrimoxazol therapy should be started.

● The nature of the antimicrobials and their duration of use should be adjusted based onthe results of the microbiological studies, effects on signs of infection, and tolerance.

● All serious infections should be reported to the pharmacovigilance centre.

Course of action when evidence of infection develops during abatacept therapy

S13





● The risk of inducing malignant diseases is always a concern when a new T cellmodulating agent is registered, which plays a central role in fighting tumours. Closeattention was therefore given to this point in the development program for abatacept,particularly as preclinical carcinogenicity studies in a murine model showed an increasedincidence of lymphoma and mammary cancer related to loss of control of theproliferation of the viruses associated with the development of these malignancies.However, there are no human equivalents of these viruses, and the relevance of thesefindings to the clinical use of abatacept in humans, therefore, is unknown. Furthermore,during the double blind period of the Phase III clinical trials, 4 (0.2%) cases of lungcancer occurred in the abatacept arm, compared to none in the placebo arm.

● Safety data obtained during drug development programs are limited, however, because thesample sizes are too small to capture rare events. Pooling clinical trials is useful to obtain alarger sample size. This meta-analytic approach showed an increase in the risk of malignancyin patients treated with TNF antagonists. In the abatacept clinical development program with1688 patient-years, malignancies were reported in the abatacept and placebo groups (1.4%and 1.1%, respectively). However, 4 (0.2%) patients in the abatacept groups experienced lungcancer versus none in the placebo groups. No differences were noted between the twotreatment groups regarding the other incidence rates of cancer (skin, breast, urinary bladder,ovary, prostate, thyroid gland, and lymphomas (Table 1).

● An obvious advantage of clinical trials is that they include an ideal control group, that is,a group constituted by randomization. However, the double-blind phase is always fairlyshort, which does not allow the detection of events that may develop only after protracteduse of the drug. Open-label extension periods enable the detection of larger number ofevents over longer periods but do not include a control group. Two solutions areavailable.The incidence of malignant diseases recorded throughout the drug development programcould be compared to the expected incidence in the general population, but thisapproach does not factor in the risk increase related to the disease itself (for instancethe 2- to 5- fold increase in lymphoma risk in patients with RA compared to the generalpopulation).The incidence of malignancies could be compared in abatacept-treated patients and inseveral historical cohorts of RA patients established before the introduction ofbiotherapies.Both approaches have a major limitation related to the criteria for patient inclusion inrandomized trials. The practice of excluding patients with a history of cancer (withinthe last 5 years) undoubtedly diminishes the risk of cancer emerging subsequently.

Data from the litterature

Management of patients with past or present history ofsolid cancer or haematological malignancy


The selected populations included in randomized trials are not strictly comparable topatients in the general population (even when matching is used) or to cohorts of RApatients constituted without using exclusion criteria (Table 2 - Figures 1 and 2). Thismajor limitation should be borne in mind when considering the following findings:

1. Comparisons of the rates of solid cancers and lymphomas showed overall no increase inabatacept-treated patients compared to the expected rates in the general population(SIR = 0.75; 95%CI [0.5-1.09]). However, increases were found in the risk of lung cancer(SIR = 2.25; 95%CI [1.12-4.03]) and lymphoma (SIR = 3; 95%CI [0.81-7.67]). On theother hand, there was a trend toward a decrease in colorectal cancer (SIR = 0; 95%CI[0-1.04]). These findings are in line with those usually obtained in populations of RApatients, independently from the treatments used, and they probably reflect thecharacteristics of the disease rather than those of abatacept (13).

2. Comparisons to data from large cohorts are more informative. Six cohorts were used as thecomparison groups: the British Columbia Population-Based RA Cohort in Canada, NorfolkArthritis Registry in the UK, National Data Bank for Rheumatic Diseases in the US, GeneralPractice Research Database or GPRD in the UK, and Early RA Register in Sweden. Overall,these cohorts contain more than 94,000 RA patients treated without biologics. During theclinical development program,4134 patients with RA were exposed to abatacept, for a total of10,000 patient-years of exposure. Table 3 shows the incidence ratios for the mainmalignancies that were recorded. For none of these malignancies was the incidence outsidethe confidence interval of the incidence in the cohorts treated without biologics (Figures 1 and 2).

● These results do not suggest an increase in the risk of malignancies (particularlylymphoma and lung cancer) in abatacept-treated patients compared to RA patientstreated without biologics DMARDs. However, these data will have to be confirmed byobservational post-marketing studies.

● Additional studies were in order, particularly given the major role played by CTLA 4 inT-cell modulation. Therefore, monoclonal anti-CTLA 4 antibodies were evaluated invarious anti-tumor strategies. In murine models involving the implantation of humantumours, monoclonal anti-CTLA-4 antibodies induced the regression of solid tumoursand lymphomas. However, these antibodies used alone were not sufficient to induce theregression of tumours characterized by limited immunogenicity, such as melanoma andbreast cancer. In humans, this anti-tumour immunotherapy strategy was developedusing two monoclonal anti-CTLA-4 antibodies combined with a peptide vaccine. Anobjective response was obtained in 7% to 17% of patients with melanoma, renal cancer,prostate cancer, ovarian cancer, breast cancer, or colon cancer, most of whom hadmetastatic disease. Furthermore, these anti-CTLA-4 antibodies do not block theregulatory T cells (Treg), which infiltrate the tumour, where they decrease theeffectiveness of anti-tumour T cells (29-33).


1. History of solid cancer or haematological malignancyNo studies have been performed to evaluate the benefits or risks of abatacept therapyin patients with cancer, lymphoma, or a recent history of malignancy. Given the absenceof data, as with TNF antagonists, caution requires that physicians refrain from usingabatacept in patients who have a history of lymphoma or cancer within the last 5 years(except localized basal-cell and epidermoid skin cancer with disease-free excisionmargins).

2. Development of cancer or haematological malignancy during abatacept therapy Whether abatacept discontinuation is in order should be discussed on a case-by-casebasis, according to the nature of the cancer (e.g., a diagnosis of prostate cancer in a75-year-old man does not have the same significance as a diagnosis of lymphoma in ayoung individual). The event should be reported to the pharmacovigilance centre.

● Table 1 – Malignancy rates during abatacept therapy and during placebotherapy in the clinical trials (13)

Tumours n (%)

Abatacept (n=1955)

Placebo(n=989)

Benign 46 (2.4) 18 (1.8)

Malignant 27 (1.4) 11 (1.1)

• Non-melanoma skin cancer 16 (0.8) 6 (0.6)

• Lung 4 (0.2) 0

• Thyroid 2 (0.1) 0

• Lymphoma 1 (<0.1) 0

• Breast 1 (<0.1) 2 (0.2)

• Urinary bladder 1 (<0.1) 0

• Prostate 1 (<0.1) 0

• Kidney 1 (<0.1) 0

• Endometrium 0 2 (0.2)

• Melanoma 0 1 (0.1)

Tables

Course of action in clinical practice


● Table 2 – Malignancy rates during abatacept therapy in RCTs (randomizedclinical trials) compared to expected rates in the general population (13)

When interpreting this comparison of the number of cancer cases in randomized clinical trials (RCTs) and

in the general population, the fact that patients with a history of cancer are excluded from RCTs should be

borne in mind.

SIR: standardized incidence ratio

When SIR = 1, the observed number of events is equal to the expected number of events

● Table 3 - Malignancy rates during abatacept therapy during DB and cumulateperiods (28)

*events/100 patient-years; IR: incidence rate

IR (95%CI) of malignancies compared to RA cohorts*

MalignanciesDouble-blind

placeboN=989

Double-blindabataceptN=1955

5 pivotal abatacept trials

N=2689

CumulativeabataceptN=4150

Patient-years 794 1688 8837 10365

Overall (exceptnon-melanomaskin cancer)

0.63(0.26-1.50)

0.59(0.32-1.10)

0.74 (0.57-0.94)

0.71(0.55-0.89)

Lung 00.24

(0.09-0.64)0.18

(0.10-0.29)0.16

(0.10-0.26)

Lymphoma 00.06

(0.01-0.43)0.07

(0.02-0.15)0.07

(0.03-0.14)

Colon/Rectum 0 00.02

(0.00-0.08)0.02

(0.00-0.07)

Breast0.25

(0.06-1.01)0.06

(0.01-0.43)0.08

(0.03-0.16)0.09

(0.04-0.16)

Cancer or lymphoma observed expected SIR (95%CI)

Solid cancer 28 37.25 0.75 (0.5-1.09)

• Lung 11 4.88 2.25 (1.12-4.03)

• Breast 4 9.66 0.41 (0.11-1.10)

• Prostate 3 3.92 0.77 (0.15-2.24)

• Colon /rectum 0 3.54 0 (0-1.04)

Lymphoma 4 1.34 3 (0.81-7.67)


● Figure 1 - Incidence of lymphoma during abatacept therapy compared to theincidence in several RA cohorts (28)

● Figure 2 - Incidence of lung cancer during abatacept therapy compared to theincidence in several RA cohorts (28)

incidence in several RA cohorts (8)

SIR(SIR: standardized incidence ratios)

0.1 101

Observed: 17Expected confidence interval: 9-26

BC

NDB

GPRD

NOAR

Sweden ERA

The lung-cancer risk is not higher with abatacept than in cohorts of RA patients treated without biologics, keeping in mind that RCTs exclude patients with a history of cancer.

0.65

1.37

1.18

1.84

1.32

SIR(SIR: standardized incidence ratios)

0.1 101

0.60

0.85

1.17

0.95

1.23

Observed: 7Expected confidence interval: 6-12

BC

NDB

GPRD

NOAR

Sweden ERA

The lymphoma risk is not higher with abatacept than in cohorts of RA patients treated without biologics, keeping in mind that RCTs exclude patients with a history of cancer.



Cardiovascular events are uncommon during abatacept therapy.During the abatacept development program (controlled trials and open-label extensionperiods), cardiovascular adverse events were rare. They consisted of hypertension,palpitations, tachycardia or bradycardia, congestive heart failure, coronary artery disease ormyocardial infarction, and atrial fibrillation.The most commonly reported cardiovascular event was hypertension, which occurred in 6.6%of abatacept-treated patients and 4.6% of placebo-treated patients in the controlled trials.

During the controlled trials and the open-label extension phases, the overall rate ofcardiovascular events was not increased in the abatacept-treated patients.

Given the above-described findings, cardiovascular disease does not contraindicateabatacept therapy.In patients with inadequately controlled or unstable heart disease (heart failure, coronaryartery disease, or rhythm disorders) or vascular disease (hypertension), common sensemandates that the cardiovascular drug regimen be optimized and/or that the advice of acardiologist be obtained before starting abatacept therapy.

As with all patients who have RA, the presence of dyspnea, chest pain, or palpitationsshould be sought by specific questions. Blood pressure should be measured.

ManagementIf the blood pressure values are high,antihypertensive treatment should be adjusted or started.In patients with very high blood pressure levels (diastolic blood pressure greater than100 mmHg), postponing the abatacept infusion until the hypertension is controlled may beadvisable. When in doubt, or when blood pressure control proves difficult to achieve, adviceshould be sought from a cardiologist.

When can abatacept therapy be resumed?Abatacept therapy can be resumed a few days after achieving blood pressure control.

What alarm signals deserve special attention in patients receiving abatacept therapy?

What precautions should be taken before starting abatacept therapy in patients with a history of cardiovascular disease?

Is there a risk of cardiovascular events occurring during abatacept therapy?

Management of patients with past or present history ofcardiovascular disease


To date, there is no evidence that abatacept interacts with cardiovascular drugs.

To date, there is no evidence that abatacept interacts with oral or injectable anticoagulants.

Patients with RA are at increased risk of cardiovascular events, myocardial infarction andstroke (34,35). This excess cardiovascular risk is related to the systemic inflammation,which causes endothelial alterations and disturbances in lipid metabolism.Some disease-modifying drugs used to treat RA have been shown to decrease this excesscardiovascular risk, diminishing both the risk of cardiovascular events and the risk ofcardiovascular death.

To date, no information is available on whether abatacept may also decrease the excesscardiovascular morbidity and mortality associated with RA.

Current knowledge about the risk of cardiovascular events(other than heart failure) during abatacept therapy

Does abatacept interact with anticoagulant drugs?

Does abatacept interact with ongoing cardiovascular drugs?



Abatacept infusions may induce reactions, of usually mild to moderateintensity. Such reactions are uncommon. Therefore, no routine prophylacticmeasures are recommended.

Acute infusion reactions are defined as reactions that start within 1 hour after theinitiation of the infusion.Acute infusion reactions were recorded in 9.8% of abatacept-treated patients in phaseIII clinical trials (compared to 6.7% of placebo-treated patients) (5,13,24,36).The manifestations may include:

● headache● fatigue● dizziness● a fever, chills, and shivering● hypotension or hypertension● nausea, vomiting● erythema, urticaria, angio-oedema● rhinitis, cough, laryngeal irritation, bronchospasm

The most common clinical manifestations are dizziness, a headache, and hypertension.Severe hypersensitivity reactions requiring discontinuation of abatacept therapy arerare (4 of 2484 patients included in the published randomised trials) (24,36). Thesehypersensitivity reactions occurred at treatment initiation in the 2 patients for whom dataon timing are available (2nd and 4th infusion, respectively) (24).

Although acute infusion reactions are usually non-serious with abatacept, their possibleoccurrence require medical monitoring of patients during the infusions. However, nopremedication is needed.

● Heart rate and blood pressure measurements before starting the infusion● Abatacept infusion (100 ml in 30 minutes)● Heart rate and blood pressure measurements at the end of the infusion then 30

minutes later

Monitoring abatacept infusions

Description of acute infusion reactions

Management of patients with past or present history ofacute infusion reactions


The management depends on the type and severity of the reaction. Decreasing the infusionrate may suffice to ensure resolution of the reaction. Therefore, the following sequence canbe recommended.

Mild-to-moderate acute infusion reactions● 50% decrease in the infusion rate (e.g., decrease from 50 ml/h to 25 ml/h)● If needed, IV administration of an antipyretic agent (paracetamol) or antihistamine● Discontinuation of the infusion if the symptoms persist despite the slower infusion rate● Resumption of the infusion at a slower rate after complete resolution of the symptoms

Severe reactions (shock, anaphylactic reaction, bronchospasm)● Immediate permanent discontinuation of the infusion with disconnection of the tubing

from the pouch containing the abatacept● Appropriate resuscitation measures● Adrenalin, antihistamines, and glucocorticoids in patients with anaphylaxis;

advice from an intensivist● Symptomatic treatment (e.g., inhaled �2 adrenergic agonist and/or glucocorticoid

therapy, oxygen...)● Appropriate patient monitoring, in the ICU if needed● No subsequent use of abatacept

No delayed reactions resembling serum sickness have been reported to date, probablybecause abatacept is an entirely human fusion protein that exhibits little immunogenicpotential. In controlled trials, 2.8% of patients for whom sera obtained before and aftertreatment were available contained antibodies to the immunoglobulin component or CTLA-4component of abatacept (13). Overall, there was no apparent correlation of antibodydevelopment to clinical response or adverse events. However, the number of patients thatdeveloped antibodies was too limited to make a definitive assessment. This point requiresconfirmation by additional studies. The potential clinical relevance of neutralizing antibodyformation is not known. There is no need to assay these antibodies in everyday practice.

Delayed infusion reactions

Management of the patient with an acute infusion reaction during an abatacept infusion



● Many auto-immune diseases are related to activation of autoreactive T cells via theB7/CD28 pathway. Inhibition of this pathway by CTLA4-Ig (abatacept) might be beneficial,as shown in animal models of lupus nephritis (37) and in human patients with psoriasis(38), before the development of abatacept in RA.

● In the first randomized trial, which was presented at the 2008 ACR meeting, abataceptshowed no beneficial effects compared to the placebo in patients with systemic (non-renal) lupus erythematosus. Nevertheless, abatacept may have beneficial effects on anumber of secondary objectives. Therefore, in the future, studies using a more appropriatedesign regarding evaluation criteria and concomitant treatments (glucocorticoids) mightshow a beneficial effect (39).

● A phase I dose-escalation trial was recently conducted with abatacept in 16 patients withmultiple sclerosis. Treatment with one to four infusions was well tolerated and inducedpromising immunological effects (40). However, to date, no controlled trials have proventhat abatacept is effective in auto-immune diseases other than RA.

● The introduction of a new immunomodulating agent requires close monitoring for theoccurrence of induced auto-immune manifestations. During the abatacept developmentprogram, a few cases of cutaneous psoriasis were recorded. In contrast, no other auto-immune diseases developed, and no antinuclear nor anti-dsDNA antibodies wereinduced.

● The occurrence of autoimmune diseases was assessed in the abatacept developmentprogram consisting of cumulative (double-blind and open-label) data through December2007 integrated from eight abatacept RA trials (41). During the double-blind phases,auto-immune diseases were recorded in 28 (1.4%) of 1955 patients on abataceptversus 8 (0.8%) of 989 patients on the placebo. The most common auto-immunedisease were psoriasis, in 0.5% of abatacept-treated patients and in 0.0% of placebo-treated patients. Overall, data were obtained for 4150 abatacept-treated patients (10,365 patient-years) as of December 2007, and the cumulative rate of auto-immune disease was1.59/100 patient-years (41).

Data from the literature

Management of patients with past or present history ofauto-immune disease


● Table 4 - Development of auto-immune events in trials of abatacept

* Double-blind phases + long-term open-label extensions

This analysis found no evidence of an increased risk of auto-immune diseases duringabatacept therapy. The incidence of auto-immune manifestations did not increase with theduration of abatacept exposure.

Many manifestations may suggest a diagnosis of auto-immune disease (e.g., constitutionalsymptoms or organ involvement). In the current state of our knowledge, no specific diagnosisshould be considered preferentially, although cutaneous psoriasis seems slightly morecommon than other auto-immune diseases. It should be borne in mind that RA is associatedwith various systemic auto-immune disorders (Sjögren, lupus, scleroderma, …) and organ-specific auto-immune disorders (thyroiditis), independently from any inducing effect ofabatacept.

In patients with a history of auto-immune diseaseIn the current state of our knowledge, no specific auto-immune disease in the patient’s historycontraindicates the use of abatacept. On the contrary, experimental findings and preliminaryclinical data suggest that abatacept may have beneficial effects in some auto-immunediseases. To date, however, such beneficial effects remain unproven (see the “Data from theLiterature” paragraph).

Course of action in everyday practice

What are the alarm signals that should suggest an auto-immune disease in patients receiving abatacept?

Number of auto-immune events n (incidence/100 p/y)

Double-blind phases1688 patient-years

Cumulative data*10,365 patient-years

Total 28 (1.43) 161 (1.59)

Psoriasis 9 (0.53) 57 (0.56)

Sjögren syndrome 4 (0.24) 20 (0.19)

Systemic lupus erythematosus 1 (0.06) 5 (0.05)

Lupus like-syndrome 1 (0.06) 1 (0.01)

Multiple sclerosis 0 1 (0.01)


Development of an auto-immune diseaseeThe first step is to make sure that the manifestations reported by the patient are caused byan auto-immune disorder and not by some other process such as an infection. When anauto-immune disorder develops, several measures should be taken:

• report to the pharmacovigilance centre• evaluation of the risk/benefit ratio of abatacept therapy

– if the auto-immune manifestations are severe (vasculitis, systemic lupuserythematosus, demyelination), it is preferable to discontinue abatacept therapy andto initiate an immunosuppressive treatment known to be effective in these conditions

– if the auto-immune manifestations are not severe (psoriasis, thyroid dysfunction),abatacept can be continued if it is effective in controlling the RA. Symptomatictreatment for the auto-immune disease can be added if needed.



Given the absence of adequate data, abatacept (CTLA-4 Ig) is contraindicated inpregnant women, and effective contraceptive methods must be used, startingat treatment initiation. However, the product characteristics and the data fromanimal studies can be used to develop an expert opinion.

Several publications establish a beneficial effect of CTLA-4 on tolerance duringpregnancy (42-44). CTLA-4 is expressed on foetal cells, including the fibroblastic cells ofthe placental mesenchyme at the mother-foetus interface, and the level of expressionincreases from the first to the second trimester of pregnancy. In addition, in an abortion-prone mouse strain, monoclonal antibodies to CD80 and CD86 (specific ligands of theCD28/CTLA-4 co-stimulation pathway) induced CTLA-4 overexpression and maternaltolerance to the foetuses (45). Finally, a CTLA-4 gene polymorphism has been suspectedas a cause of recurrent abortion in a population of Chinese women (46).These preliminary data do not allow definitive conclusions but suggest a protective roleof CTLA-4 against spontaneous abortion.

● Animal studies (27,47-49)Abatacept is devoid of genotoxic or mutagenic effects and does not induce chromosomalabnormalities. In rats, abatacept had no adverse effect on fertility in males or females.Embryotoxicity studies in mice, rats, and rabbits with doses 20 to 30 times those usedin humans (10 mg/kg), found no evidence of foetotoxicity, teratogenicity, or negative effectson neonatal development. Mild disturbances in immune functions consisting of thyroid glandinflammation or exacerbation of the T-cell-dependent humoural response were noted in ratsbut only with a dose of 200 mg/kg (i.e., 11 times the dose used in humans). It should benoted that the animal toxicology studies of abatacept were conducted without concomitantmedications (i.e., without concomitant methotrexate).

● Pharmacological properties (27,47-49)Studies in rats indicate that abatacept can cross the placental barrier (producing dose-dependent foetal serum concentrations that are 1.7 to 2.4 times lower than maternalserum concentrations) and can be detected in milk (where concentrations are 10 timessmaller than in the mother). After a single administration of 10 mg/kg to healthyvolunteers, the mean half-life was 16.8 ± 4.5 days. After repeated intravenousadministration of 10 mg/kg to patients with RA, the mean half-life was 13.1 days (8 to25 days).

Available data on abatacept

CTLA-4 and risk of spontaneous abortion

Management of patients who are pregnant


● Exposure to abatacept during pregnancy in womenDuring the double-blind and open-label phases of the five pivotal studies of abataceptin RA, 8 patients became pregnant while taking abatacept. Among them, 7 were onconcomitant methotrexate and 1 was on concomitant leflunomide (27). Spontaneousabortion occurred during the first trimester of pregnancy in 3 of these patients (of whom2 had a history of spontaneous abortion and 1 was a primagravida). Elective abortionwas performed in 2 patients. The remaining 3 patients were still pregnant at the timethe study report was written. The spouse of a man treated with abatacept becamepregnant and delivered a healthy baby.During a phase II trial of abatacept in multiple sclerosis, 2 abatacept-treated womenbecame pregnant, as well as the spouse of an abatacept-treated man. Of the threewomen, one delivered a healthy baby, one underwent elective abortion, and oneexperienced a spontaneous abortion at 2 months’ gestational age (27).

Two registries of abatacept-exposed pregnancies have been set up:– in the US: Organization of Teratology Information Specialists (OTIS),

http://otispregnancy.org/otis_study_ra.asp – in Europe: European Network of Teratology Information Service (ENTIS),

http://www.entis-org.com

● Before starting abatacept therapyWomen of child-bearing potential who are being evaluated for abatacept therapy initiationshould be asked whether they want to have children. If a pregnancy is desired within thenext few months, initiation of abatacept therapy is not advisable. However, the severity ofthe disease should be assessed, and when abatacept therapy is crucial to preservefunction, the patient may be advised to postpone the pregnancy (in order to allowprevious stabilization of the disease followed by conception under more favourableclinical conditions). See “Available data on abatacept – Pharmacological properties”.

● Time from the last abatacept infusion to attempted conceptionConception should not be attempted immediately after the last abatacept infusion.Furthermore, methotrexate, if used concomitantly with abatacept, must be stopped atleast 3 months before attempting conception (recommendation in the current marketinglicense).The European Summary of Product Characteristics (EU SPC) contains the followingrecommendation about the time from the last abatacept infusion to attemptedconception (that is, the time during which effective contraceptive measures must beused: “Women of child-bearing potential should use effective contraceptive methodsduring treatment and for 14 weeks following the last infusion”.

Clinical Situations

Management of patients on abatacept in daily practiceManagement of patients on abatacept in daily practiceS28

● The following should be taken into consideration: • The wait before attempting conception recommended in the EU SPC (14 weeks) may

lead to challenging clinical situations (e.g., joint disease flare after the initial responseto abatacept), particularly as achieving a pregnancy may take time.

• The outcomes of the few pregnancies characterized by maternal exposure to abataceptwere similar to those of pregnancies without abatacept exposure.

• Methotrexate, which is known to induce birth defects and abortions, is usually given incombination with abatacept and must be stopped at least 3 months before attemptingconception.

● Two main clinical situations may arise:• The patient fails to respond to abatacept: failure to control the joint disease usually

requires a switch to another treatment option, and attempts to initiate a pregnancy musttherefore be postponed.

• Abatacept therapy ensures control of the disease: Methotrexate should be stopped andeffective contraceptive measures used for at least 3 months before attempting toinitiate a pregnancy. The elimination half-life of abatacept suggests that an 18-weekwait between the last abatacept infusion and the first attempts to conceive may beadequate (as the maximal half-life is 25 days, 18 weeks is about 5 times the half-life,which allows elimination of 97% of a compound exhibiting linear kinetics).

All these considerations suggest that waiting 18 weeks (4 months) or more betweenthe last abatacept infusion and attempts to initiate a pregnancy is reasonable inwomen.No specific data are available for chez l’homme. In particular, the potential effect ofabatacept on sperm cell production is unknown. Therefore, recommending an 18-weekwait, as with female patients, may be reasonable.

● Pregnancy initiation during abatacept therapyInitiation of a pregnancy during abatacept therapy requires the following measures:• immediate discontinuation of abatacept (and of concomitant methotrexate, if not

already done)• sonographic monitoring• a report to the pharmacovigilance centre

If a pregnancy is initiated in an abatacept-treated woman, the woman and her partnermust decide whether to continue the pregnancy. If the obstetrical investigations arenormal, continuing the pregnancy can be recommended.Detailed information given at the initiation of abatacept therapy should prevent theoccurrence of pregnancies during the treatment.

● Initiation of abatacept therapy during pregnancyThis situation is unlikely to occur in patients with RA, a disease that usuallyimproves during pregnancy. In the current state of our knowledge, abataceptinitiation during pregnancy is not advisable.

Management of patients on abatacept in daily practiceManagement of patients on abatacept in daily practice S29

● Breast-feedingAbatacept is detectable in milk in lactating animals (27). No data are available onabatacept excretion in human breast milk and, therefore, breast-feeding is not advisableduring abatacept therapy.In practice, breast-feeding is possible, since it is started at least 13 months after thelast abatacept infusion (4 months’ wait before attempting conception [see above] plus9 months’ gestation). After 13 months, the drug is completely eliminated from the body.In patients who want to breast-feed and who require abatacept re-treatment, this re-treatment must be postponed until the baby is fully weaned.If the joint disease flares after delivery (a fairly common event in RA), re-treatment withabatacept and, therefore, the need to refrain from breast-feeding should be discussed ona case-by-case basis.



RA does not contraindicate the administration of vaccines, and the response tovaccines is adequate in the absence of immunosuppressive treatment (50).However, in patients who use potentially immunosuppressive medications, whethervaccinations can be performed must be determined.

Abatacept shares with other biologics a potential for increasing the risk of infections.Although the antibody levels are slightly lower, vaccines are usually effective in inducing anantibody response (13,51-56).

The immunization history should be checked before starting abatacept therapy, whenswitching between biotherapies, once a year at the end of the summer, and whenever a tripabroad is planned.

Vaccinations in patients on biotherapies may raise two problems: decreased safety (withlive attenuated vaccines) and decreased effectiveness (with all vaccine types).

In abatacept-treated patients, live attenuated vaccines are contraindicated given the risk oftreatment-related loss of attenuation of the vaccine microorganism. Inactivated andcomponent vaccines can be used.

● Live attenuated vaccines• BCG• Yellow fever• Measles-Mumps-Rubella (MMR)• Oral polio (reserved for outbreaks)• Varicella

● Inactivated vaccines and component vaccines• Influenza• Pneumococcus• Meningococcus• Haemophilus influenza• Hepatitis A and B• Combined Diphtheria-Tetanus-Polio-Pertussis-Haemophilus influenza b• Typhoid fever• Injectable polio

When should attention be given to vaccinations?

Can vaccines be administered to patients on abatacept therapy?

Vaccinations in abatacept-treated patients


● The patient’s immunisation history should be checked to determine whethermandatory vaccines (most notably tetanus and polio) and vaccines recommendedunder specific circumstances were given appropriately and updated as needed.

● In the fall, the influenza vaccine is recommended in patients who are scheduled to startabatacept therapy.

● The pneumococcal vaccine is recommended, particularly in patients at high risk for lunginfections. At least 3 years must be allowed to elapse between administrations of thepneumococcus vaccine (which is usually given every 4 to 5 years). A history ofdocumented or suspected pneumococcal infection does not contra-indicateadministration of the pneumococcal vaccine. The pneumococcal vaccine can be given atthe same time as the influenza vaccine (if this situation arises), at a different injectionsite.

● We have not had to date enough data to advise Haemophilus vaccination.

● When a live attenuated vaccine is needed before starting abatacept therapy, it should begiven if possible at a time when there is no immunosuppression (that is, after the effectsof previous biotherapies have dissipated). At least 2 weeks and at best 4 weeks should beallowed to elapse between the vaccination and the first abatacept dose. In practice, yellowfever constitutes the most challenging vaccination problem. Patients must be asked abouttrips to countries where yellow fever is endemic, before starting abatacept then duringtreatment follow-up. If the patient may travel in the short or medium term to countrieswhere yellow fever immunisation is mandatory, the yellow fever vaccine (which is effectivefor 10 years) should be given after any immunosuppressive effects of the previoustreatment have worn off and at least 2 weeks but preferably 4 weeks before startingabatacept therapy.

The same vaccines are recommended for TNF antagonists and abatacept. Therefore, therecommendations are the same whether the patient is switched from one to the other or kepton the same treatment.

● The patient’s immunisation history should be checked to determine whether mandatoryvaccines (most notably tetanus and polio) and vaccines recommended under specificcircumstances were given appropriately and updated as needed.

● Administration of the influenza vaccine in the fall is recommended.

Vaccines that should be offered in the event of long-term abatacept therapy

Vaccines that should be offered when switching from a TNF antagonist to abatacept

Vaccines that should be given before starting abatacept therapy


● When a live vaccine (yellow fever, for instance) must be given to an abatacept-treatedpatient, abatacept must be discontinued at least 3 months before administering thevaccine. At least 2 weeks and at best 4 weeks should then be allowed to elapse beforere-starting abatacept therapy.

● When an inactivated vaccine or component vaccine must be given to an abatacept-treated patient, although abatacept discontinuation followed by a 3-month wait is optimal,the vaccine can be administered at any time.

Vaccination of contacts (children and grandchildren) can be considered, most notably to protectagainst influenza. This strategy may decrease the risk of disease communication to thebiotherapy-treated patient.

Should contacts be vaccinated?



Abatacept-treated patients can travel. The European Summary of Product Characteristics(EU SPC) contains no specific recommendations about travelling. Therefore, the advice givenhere is based on the opinions of experts. Precautions are in order, and travel to areas wheresanitary conditions are poor is not recommended.

Specific vaccinations are required when travelling to some countries. Therefore, careful planningis essential: ideally, inactivated vaccine or component vaccine should be completed at least2 weeks before the first abatacept infusion. However, administering the necessary vaccines isthe main priority.Live vaccines (BCG, yellow fever, measles-mumps-rubella (MMR), oral polio (for outbreaks only)and varicella) are contraindicated during abatacept therapy. If the patient plans to travel, thevaccines should be given at least 2 weeks and at best 4 weeks before the first abataceptinfusion. For yellow fever, at least 3 months should be allowed to elapse between the lastabatacept infusion and administration of the vaccine.

Antimalarial prophylaxis is not contraindicated. No major safety problems have been identified inpatients taking both abatacept and hydroxychloroquine. In the 1-year ASSURE study (36)comparing the safety of abatacept and of a placebo added to a conventional disease-modifyingdrug or to a biologic, hydroxychloroquine/chloroquine was used by 10.9% to 29.4% of patients,depending on the group. No significant differences were found between the abatacept andplacebo group regarding the rates of adverse events, serious adverse events, or treatmentdiscontinuation because of adverse events.

Patients should be advised to carry written information (in English if possible) about theirtreatment (dose and dates) for use in the event of health problems during their stay abroad.During their stay, they should follow the usual precautions regarding hygiene, food andbeverages, and insects. Medical advice should be obtained promptly in the event of a feveror symptoms of infection. Patients travelling to remote areas where medical help isunavailable should carry antibiotics for use in the event of infectious symptoms (e.g.,amoxicillin + clavulanic acid and a quinolone, a combination that is effective in commoninfections of the lower respiratory tract and urinary tract).

What other measures should be taken?

Can abatacept-treated patients take antimalarial prophylaxis?

Immunisations (see the “Immunisations” fact sheet)

Can abatacept-treated patients travel?

Management of patients who plan to travel



Surgery in a patient with rheumatoid arthritis (RA) treated with abatacept may, intheory, lead to infectious complications and/or delayed healing. Nevertheless,these risks have not been evaluated in detail in published studies, and no clearrecommendations are made in the European Summary of Product Characteristics(EU SPC) (27). Therefore, the advice given here is based on the opinion of experts,who considered, among other factors, the risk of infection associated with thesurgical procedure and the various biotherapy situations evaluated previously(1,2).

● Pharmacokinetic propertiesThe mean terminal half-life of abatacept in a dose of 10 mg/kg is 13.1 days, with a range of8 to 25 days.

● Published casesNo information is available about patients with RA who underwent surgery afterabatacept therapy.

● Management in the event of surgeryBased on the mechanisms of action of abatacept, the safety data reported in theliterature, and the specific characteristics of RA patients (who are usually taking othermedications), the two main concerns are:• intraoperative or postoperative infection• and delayed healingTo date, no information is available regarding potential delays in healing in abatacept-treated patients.

● Time from the last abatacept infusion to scheduled surgeryThis interval should be determined on a case-by-case basis based on the factors listedbelow.• Type of surgical procedure (because the risk of infection varies across procedures): “sterile

environment” (e.g., cataract surgery), “septic environment” (e.g., sigmoiditis), or“environment at risk for sepsis” (e.g., joint replacement surgery)

• Patient-related factors: history of infection, joint prostheses, diabetes mellitus,concomitant corticosteroid therapy…

• Severity of the joint disease and degree of control achieved by treatment

Clinical situations

Available data

Management of patients who require surgery


● Two main clinical situations may arise in abatacept-treated patients:• The treatment response is inadequate: when the joint disease remains uncontrolled,

switching to another treatment is usually required, and the surgical procedure mustusually be postponed.

• The joint disease is well controlled: the 5x half-life rule yields a wide range, of 40 to 200days. No routinely available method is available for determining the value in the individualpatient. Therefore, given the elimination half-life and the absence of available clinical(pharmacokinetic) data, caution suggests that a 2-month wait from the last abataceptinfusion to surgery may be adequate.

● Emergent surgery For patients who require immediate surgery, the experts suggest the followingrecommendations: – consider prophylactic antimicrobial therapy if the procedure carries a high risk of

infection (e.g., peritonitis)– monitor the patient closely during the postoperative period– do not re-treat with abatacept until complete healing is achieved and any antibiotics are

discontinued, in the absence of infection

● Dental careRegular oral hygiene and visits to the dentist are recommended. Patients with oral ordental health problems should receive appropriate treatment before starting abatacepttherapy:– routine dental care (cavities, scaling):

Prophylactic antibiotic therapy can be suggested.

– dental procedures associated with a risk of infection (extraction, apical granuloma,abscess…):The abatacept infusion should be postponed and prophylactic antibiotic therapy given(57).



The initiation of abatacept therapy in combination with conventional DMARDsor after the use of other biologics raises many questions that currently convergetoward three major issues regarding drug-drug interactions. However, datafrom the ASSURE trial also showed that abatacept in combination with anotherconventional DMARD seems effective and raises no major safety issues.Combined use of abatacept and another biologic, most notably a TNFantagonist, is associated with an increased risk of serious adverse events andtherefore is not recommended. Pharmacokinetic data have shown thatmethotrexate, NSAIDs, and glucocorticoids have no influence on the clearanceof abatacept.

Two studies, a phase IIb study of abatacept and etanercept (58) and the phase III ASSURE(36) (Abatacept Study of Safety in Use with Other RA Therapies), evaluated the safety ofabatacept used concomitantly with other biologics (TNF antagonist or anakinra). Theadverse event rate was increased nearly 2-fold with, in particular, the serious infections andmalignancies detailed in Table 5. In contrast, no opportunistic infections were reported.

● Table 5 – Serious adverse events in the groups treated with abatacept andbiologics in the ASSURE study (36)

*biologic = TNF antagonist or anakinra

placebo + biologic*n=64

abatacept + biologic*n=103

Serious adverse events 12.5% 22.3%

Serious infections 1.6% 5.8%

• Serious respiratory-tract infections 1.6% 2.9%

• Serious urinary-tract infections 0 1.9%

Solid cancer 1.6% 6.8%

• Basal cell carcinoma 0 1.9%

Abatacept combined with another biologic

Management of drug-drug interactions


The ARRIVE study provides the answer to this question, as it compared the efficacy andsafety of abatacept started immediately after TNF antagonist discontinuation or after awashout period (59). The adverse event rate was comparable in the groups with andwithout a washout period after TNF antagonist discontinuation.

● Abatacept/TNF antagonistIn placebo-controlled clinical trials, patients receiving concomitant treatment withabatacept and TNF blocking agents experienced more infections and serious infectionsthan patients treated with only TNF blocking agents. Therefore, concurrent therapy withabatacept and a TNF blocking agent is not recommended.After discontinuation of the TNF antagonist, abatacept can be started, except in highly selected situations, on the date of the next scheduled TNF antagonist dose. In patients at high risk for infections, a washout period equal to 5 times the half-life of the TNF antagonist before starting abatacept therapy may deserve consideration.

● Abatacept/anakinraThe data generated by the ASSURE study are not sufficient to evaluate the efficacy andsafety of the abatacept/anakinra combination. Therefore, use of this combination is notrecommended.

● Abatacept/rituximabNo data are available on this combination. Inhibiting both lymphocyte populations(T cells and B cells) raises theoretical concerns. In the current state of our knowledge,concomitant use of abatacept and rituximab is not recommended.

● After rituximab therapyWhen abatacept therapy is considered in a patient previously treated with rituximab, therisk/benefit ratio should be evaluated carefully. An immunoglobulin assay by weight andlymphocyte phenotype determination may help to assess the risk of infections. A newbiologic other than a TNF antagonist should not be introduced within the first 24 weeksafter the rituximab infusion.

● Rituximab after abatacept therapyRituximab initiation can be considered 8 weeks after the last abatacept infusion. Thereis no practical test (similar to Ig assay and lymphocyte phenotype determination forrituximab) for assessing immunological recovery after abatacept therapy.

Recommendations

In patients on TNF antagonist therapy, should there be a waiting period between discontinuing the TNF antagonists and starting abatacept?


● The AIM study (24) established the efficacy and safety of abatacept combined withmethotrexate in a mean dosage of 15 mg/week. When methotrexate is contraindicatedor poorly tolerated, the efficacy and safety of combining another conventional disease-modifying drug with abatacept must be considered.

● In the ASSURE study, patients received either abatacept or a placebo while continuingprevious conventional DMARDs or biologics. An analysis of subgroups defined based onthe concomitant DMARD (methotrexate, antimalarials, sulfasalazine, leflunomide, gold, orazathioprine) showed that these drugs had a good overall safety profile when used withabatacept. A higher rate of adverse events with the DMARD was seen only withleflunomide (23.6% in the abatacept group and 15.3% in the placebo group). The mostcommonly reported adverse events were severe infections and muscle and connectivetissue complaints.

● Table 6 – Serious adverse events reported in the groups given abatacept withoutbiologics in the ASSURE study (36)

Methotrexate is the recommended DMARD for combination with abatacept. However, whenmethotrexate is contraindicated or poorly tolerated, another DMARD can be used,preferably a drug with proven structural effects. In the current state of our knowledge, whena concomitant DMARD is used, there is no evidence to suggest a need for adjusting thedosage of the DMARD. The recommended methotrexate dosage is 15 mg/week; thisdosage may be decreased in the event of a prolonged remission without evidence ofstructural progression.

Recommendations about abatacept and conventional DMARDs

placebo + DMARDn=418

abatacept + DMARDn=856

Serious adverse events 12.2% 11.7%

Serious infections 1.7% 2.6%

• Serious respiratory-tract infections 1.0% 1.1%

• Serious urinary-tract infections 0.2% 0.5%

Solid cancers 3.8% 3.2%

• Basal-cell carcinoma 0.7% 0.4%

Combining abatacept with conventional disease-modifying antirheumatic drugs


In the event of intolerance to all available DMARDs, abatacept may be used alone. In a pilotstudy (60), abatacept was given 1 month after DMARD discontinuation, in a dosage of 0.5,2, or 10 mg/kg. The response rates on day 85 (3 months) were higher in the abataceptgroups than in the placebo group, and the highest response rate occurred with the dosageusually given in clinical practice (10 mg/kg) (Table 7).

● Table 7 – Percentages of patients meeting ACR20, 50, and 70 criteria on day 85 inthe groups given abatacept alone in a dosage of 0.5, 2, or 10 mg/kg and in theplacebo group (61)

There is no evidence suggesting that intolerance to abatacept may be increased byconcomitant use of a glucocorticoid, nonsteroidal antiinflammatory drug (NSAID), oranalgesic.

Pharmacokinetic data show that methotrexate, NSAIDs, or glucocorticoids have no effect onthe clearance of abatacept. Therefore, NSAIDs, glucocorticoids, and analgesics can be usedconcomitantly with abatacept.

Pharmacokinetic interactions

Combining abatacept with an antiinflammatory drug or analgesic

% ACR responders onD85

placebon=32

abatacept0.5 mg/kg

n=26

abatacept2 mg/kg

n=32

abatacept10 mg/kg

n=32

ACR20 (primary criterion) 31% 23% 44% 53%

ACR50 6% 0 19% 16%

ACR70 0 0 12% 6%

Use of abatacept alone



Expert-panel coordinatorsProf Xavier MARIETTE(14), Dr Thao PHAM(1), and Prof Jean SIBILIA(15)

Members of the CRI panelDr Thao PHAM(1), Prof Pascal CLAUDEPIERRE(2), Dr Arnaud CONSTANTIN(3), Prof Bruno FAU-TREL(4), Dr Laure GOSSEC(5), Dr Jacques-Éric GOTTENBERG(6), Prof Philippe GOUPILLE(7), Prof ÉricHACHULLA(8), Dr Charles MASSON (9), Prof Jacques MOREL(10), Prof Alain SARAUX (11),Prof Thierry SCHAEVERBEKE(12), Prof Daniel WENDLING(13), Prof Xavier MARIETTE(14), Prof JeanSIBILIA(15), received fees from the communications agency Katana Santé for developingthese fact sheets.

(1) Service de Rhumatologie, CHU Conception, Marseille. (2) Service de Rhumatologie, CHU Henri Mondor, Créteil. (3) Service deRhumatologie, Hôpital Larrey, Toulouse. (4) Service de Rhumatologie, CHU Pitié-Salpétrière, Paris. (5) Service de Rhumatologie,CHU Cochin, Paris. (6) Service de Rhumatologie, CHU Hautepierre, Strasbourg. (7) Service de Rhumatologie, CHU Trousseau, Tours. (8) Service Médecine Interne, Hôpital Roger Salengro, Lille. (9) Service de Rhumatologie, CHU Angers, Angers. (10) Service d’Immuno-Rhumatologie, CHU Lapeyronie, Montpellier. (11) Service de Rhumatologie, CHU Cavale-Blanche, Brest. (12) Service de Rhumatologie,CHU Pellegrin, Bordeaux. (13) Service de Rhumatologie, CHU Jean Minjoz, Besançon. (14) Service de Rhumatologie, CHU Bicêtre,Le Kremlin-Bicêtre. (15) Service de Rhumatologie, CHU Hautepierre, Strasbourg ; all in France.

These fact sheets were created with institutional support from Bristol-Myers Squibb Inc.

Acknowledgments / Conflicts of interest





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2) Pham T, Fautrel B, Gottenberg JE et al. Rituximab (Mabthera) therapy and safety management. Clinical tool guide elaborated by theRheumatic Diseases and inflammation Group (Club Rhumatismes et Inflammation, CRI), of the French Society of Rheumatology(Société Française de Rhumatologie, SFR). Joint Bone Spine 2008;75(Suppl 1):S1-100.

3) Kremer JM, Westhovens R, Le Bars M et al. Time to treatment response with abatacept in patients with rheumatoid arhritis and aninadequate response to methotrexate. Arthritis Rheum 2008;58(Suppl 9):378.

4) Schiff M, Dougados M, Le Bars M et al. Time to treatment response with abatacept in patients with RA and an inadequate responseto anti-TNF therapy. Arthritis Rheum 2008;58(Suppl 9):377.

5) Genovese M, Becker JC, Schiff M et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor inhibition. N Engl J Med2005;353:1114-23.

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7) Bertram EM, Dawicki W, Watts TH. Role of T cell costimulation in antiviral immunity. Semin Immunol 2004;16:185-96.

8) Hunter CA, Lieberman LA, Mason N et al. Costimulation in resistance to infection and development of immune pathology: lessonsfrom toxoplasma. Immunol Res 2003;27:331-40.

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11) Bigbee CL, Gonchoroff DG, Vratsanos G et al. Abatacept treatment does not exacerbate chronic mycobacterium tuberculosis infec-tion in mice. Arthritis Rheum 2007;56:2557-65.

12) Haggerty HG, Nadler SG, Simon TA et al. Utilization of host resistance models (HRMs) in the prediction of human safety of abata-cept (ABA): a translational approach. Arthritis Rheum 2007;56(Suppl):S701.

13) Sibilia J, Westhovens R. Safety of T-cell co-stimulation modulation with abatacept in patients with rheumatoid arthritis. Clin ExpRheumatol 2007;25(Suppl 46):S46-56.

14) CHMP review of data on quality, safety and efficacy of abatacept. EMEA 2007. www.emea.europa.eu/humandocs/PDFs/EPAR/oren-cia/H-701-en6.pdf

15) Briefing document for abatacept (BMS – 188667). FDA Arthritis Advisory Committee. 6 September 2005.www.fda.gov/ohrms/dockets/AC/05/briefing/2005-4170B1_01_01-BMS-abatacept.pdf

16) Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra therapies for rheumatoidarthritis: meta-analyses of randomized placebo-controlled trials. Ann Rheum Dis 2008 Jan 18; [Epub ahead of print].

17) Smitten A, Simon T, Qi K et al. Hospitalized infections in the abatacept RA clinical development program: an updated epidemiolo-gical assessment with >10,000 person-years of exposure. Arthritis Rheum 2008;58(Suppl 9):S786-7.

18) Naz SM, Symmons DP. Mortality in established rheumatoid arthritis. Best Pract Res Clin Rheumatol 2007;21:871-83.

19) Strangfeld A, Listing J. Infection and musculoskeletal conditions: bacterial and opportunistic infections during anti-TNF therapy. BestPract Res Clin Rheumatol 2006;20:1181-95.

20) Michaud K, Wolfe F. Comorbidities in rheumatoid arthritis. Best Pract Res Clin Rheumatol 2007;21:885-906.

21) Prévention et prise en charge des tuberculoses survenant sous anti-TNF·. AFSSAPS Juillet 2005.www.agmed.sante.gouv.fr/htm/10/tnf/reco.pdf

22) Furst DE, Breedveld FC, Kalden JR et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases,2007. Ann Rheum Dis 2007;66(Suppl 3):iii2-22.

23) Kremer JM, Dougados M, Emery P et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept:twelve-month results of a phase IIb, double-blind, randomized, placebo-controlledtrial. Arthritis and rheumatism 2005;52:2263-71.

24) Kremer JM, Genant HK, Moreland LW et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis:a randomized trial. Annals of internal medicine 2006;144:865-76.

25) Schiff M, Keiserman M, Codding C et al. Efficacy and safety of abatacept or infliximab versus placebo in ATTEST: a phase III, mul-ticenter, randomized, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response tomethotrexate. Ann Rheum Dis 2007.

26) Bruce SP, Boyce EG. Update on abatacept: a selective costimulation modulator for rheumatoid arthritis. The Annals of pharmaco-therapy 2007;41:1153-62.

27) Bristol-Myers Squibb: Summary of product characteristics 2007. www.emea.europa.eu/humandocs/PDFs/EPAR/orencia/H-701-PI-en.pdf

28) Smitten A, Simon T, Qi K et al. Malignancies in the abatacept RA clinical development program: an updated epidemiological assess-ment with >10,000 person-years of exposure. Arthritis Rheum 2008;58(Suppl 9):S787.

29) Quezada SA, Peggs KS, Curran MA et al. CTLA-4 blockade and GM-CSF combination immunotherapy alters the intratumor balanceof effector and regulatory T cells. J Clin Invest 2006;116:1935-45.

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32) Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treatedwith CTLA-4 blockade. J Immunol 2005;175:7746-54.

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34) Solomon DH, Karlson EW, Rimm EB et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis.Circulation 2003;107:1303-7.

35) Maradit-Kremers H, Nicola PJ, Crowson CS et al. Cardiovascular death in rheumatoid arthritis: a population-based study. ArthritisRheum 2005;52:722-32.

36) Weinblatt M, Combe B, Covucci A et al. Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patientsreceiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlledstudy. Arthritis Rheum 2006;54:2807-16.

37) Cunnane G, Chan OT, Cassafer G et al. Prevention of renal damage in murine lupus nephritis by CTLA-4Ig and cyclophosphamide.Arthritis Rheum 2004;50:1539-48.

38) Abrams JR, Lebwohl MG, Guzzo CA et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. JClin Invest 1999;103:1243-52.

39) Viglietta V, Bourcier K, Buckle GJ et al. CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial.Neurology 2008;71:917-24.

40) Merrill JT, Burgos-Vargas R, Westhovens R et al. The efficacy and safety of abatacept in SLE: results of a 12-month exploratorystudy. Late-Breaking ACR 2008, Abst L15.

41) Smitten A, Qi K, Simon T et al. Autoimmune adverse events in the abatacept RA clinical development program: a safety analysiswith >10,000 person-years of exposure. Arthritis Rheum 2008;58(Suppl 9):S786.

42) Tsai AF, Kaufman KA, Walker MA et al. Transmission disequilibrium of maternally-inherited CTLA-4 microsatellite alleles in idiopa-thic recurrent miscarriage. J Reprod Immunol 1998;40:147-57.

43) Kaufman KA, Bowen JA, Tsai AF et al. The CTLA-4 gene is expressed in placental fibroblasts. Mol Hum Reprod 1999;5:84-7.

44) Von Rango U. Fetal tolerance in human pregnancy – A crucial balance between acceptance and limitation of trophoblast invasion.Immunol Lett 2008;115:21-32.

45) Jin LP, Zhou YH,Wang MY et al. Blockade of CD80 and CD86 at the time of implantation inhibits maternal rejection to the alloge-neic fetus in abortion-prone matings. J Reprod Immunol 2005;65:133-46.

46) Wang X, Lin Q, Ma Z et al. Association of the A/G polymorphism at position 49 in exon 1 of CTLA-4 with the susceptibility to unex-plained recurrent spontaneous abortion in the Chinese population. Am J Reprod Immunol 2005;53:100-5.

47) FDA Pharmacological review. www.fda.gov/cder/foi/nda/2005/125118_S0000_PharmR.pdf

48) Health Canada, Summary basis of decision, Orencia®– abatacept. www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfbdgpsa/pdf/prod-pharma/sbd_smd_2007_orencia_098531_e.pdf

49) Centre de Référence sur les Agents Tératogènes (CRAT) www.lecrat.org

50) Ravikumar R, Anolik J, Looney RJ. Vaccine responses in patients with rheumatoid arthritis. Curr Rheumatol Rep 2007;9:407-15.

51) Tay L, Leon F, Vratsanos G et al. Vaccination response to tetanus toxoid and 23-valent pneumococcal vaccines following adminis-tration of a single dose of abatacept: a randomized, open-label, parallel group study in healthy subjects. Arthritis Res Ther2007;9:R38.

52) Wu ZQ, Shen Y, Khan AQ et al. The mechanism underlying T cell help for induction of an antigen-specific in vivo humoral immuneresponse to intact Streptococcus pneumoniae is dependent on the type of antigen. J Immunol 2002;168:5551-7.

53) Jeurissen A, Wuyts G, Kasran A et al. The human antibody reponse to pneumococcal capsular polysaccharides is dependent on theCD40-CD40 ligand interaction. Eur J Immunol 2004;34:850-8.

54) Ndejembi M, Patke D, Bingaman A. CTLA-4Ig inhibits IL-2 production and in vivo expansion of antigenstimulated memory CD4 Tcells. Clin Immunol 2005;115:S219-20.

55) Schaeverbeke T, Vittecoq O, Dougados M et al. Étude de la réponse immunitaire au vaccin antigrippal chez les patients ayant unepolyarthrite rhumatoïde et traités par abatacept. Rev Rheum 2007;74:1066-7.

56) Schiff M, Kaell L, Tay L et al. Response to pneumococcal vaccine in rheumatoid arthritis patients with an inadequate response toanti-tnf therapy treated with abatacept in the arrive trial Ann Rheum Dis 2007;66 (S11) 437.

57) Tong DC, Rothwell BR. Antibiotic prophylaxis in dentistry: a review and practice recommendations. J Am Dent Assoc 2000;131:366-74.

58) Weinblatt M, Schiff M, Goldman A et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthri-tis while receiving etanercept: a randomised clinical trial. Ann Rheum Dis 2007;66:228-34.

59) Schiff M, Pritchard C, Zhou X et al. The efficacy of abatacept in patients with active rheumatoid arthritis and an inadequate res-ponse to anti-TNF-therapy: the ARRIVE trial. Arthritis Rheum 2007;56:S391.

60) Moreland LW, Alten R, Van den Bosch F 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 Rheum2002;46:1470-9.

61) Labelling Orencia®(abatacept) Highlights of prescribing information, US April 2008;www.fda.gov/medwAtch/SAFETY/2008/Apr_PI/Orencia_PI.pdfhttp://packageinserts.bms.com/pi/pi_orencia.pdf



Annexe 1: Model information letterfor an office-based rheumatologist


…………….., ……………

Dear Colleague,

Thank you for referring your patient, Mr/Ms …………………… born on …………………..for treatment with abatacept.

You are following this patient for rheumatoid arthritis, with unresponsiveness or intole-rance to TNF�-antagonist therapy.

The practical points below were evaluated before starting abatacept therapy.

● The patient stopped TNF�-antagonist therapy (with or without a washout period), for thefollowing reason: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

● The following were assessed before the first abatacept injection:– DAS 28 (Disease Activity Score): ❒ date . . . . . . . . . . . . . . . . . . . .– CRP: ❒ date . . . . . . . . . . . . ❒ not done– RF: ❒ date . . . . . . . . . . . . ❒ not done– anti-CCP: ❒ date . . . . . . . . . . . . ❒ not done– X-rays of the hands and feet: ❒ date . . . . . . . . . . . . ❒ not done

- Erosions: ❒ yes ❒ no- Chondrolysis: ❒ yes ❒ no

– HAQ (Health Assessment Questionnary): ❒ date . . . . . . . . . . . . ❒ not done

● The patient has no contraindications to abatacept therapy (allergy, active infection,or premalignant or malignant lesions within the last 5 years).

● We have checked the immunisation status of the patient (including tetanus, polio,influenza, and pneumococcal vaccines). Non-live vaccines, particularly those administe-red seasonally, can be given safely after the abatacept infusion, although their effective-ness may be decreased in this situation, and administration of the influenza vaccineonce a year is recommended. Live viral vaccines (yellow fever, varicella, oral polio, andMMR) are contraindicated. When administration of a live vaccine is required, abatacepttherapy must be stopped at least 3 months before the vaccination and, if possible, aba-tacept therapy should not be re-started until at least 2 weeks and at best 4 weeks afterthe vaccination.

● We performed❒ No vaccinations❒ One or more vaccinations: . . . . . . . . . . . . . . . . . . . ❒ date . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . ❒ date . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . ❒ date . . . . . . . . . . . . . . . .

● We checked that the patient was evaluated for latent tuberculosis (medical history,chest radiograph, intradermal tuberculin test).


● The pre-treatment status of your patient is as follows:

– Contact with a TB patient ❒ yes date …/…/… ❒ no ❒ UK

– Chest X-ray abnormality ❒ yes date …/…/… ❒ no ❒ UK

– ID test ❒ yes date …/…/… ❒ no ❒ UK

– History of prophylactic antituberculous treatment ❒ yes date …/…/… ❒ no ❒ UK

Date D1: …/…/…

1) If the tuberculosis screen was positive before TNF antagonist therapy, the patient recei-ved prophylactic antituberculous therapy. Provided adherence to the prophylactic treat-ment was good and the patient had no subsequent contact with tuberculosis patients,abatacept therapy can be started without further precautions.

2) If the tuberculosis screen was negative before TNF antagonist therapy and was perfor-med more than 1 year ago, it should be repeated. This precaution is recommendeddespite the absence of data on the risk of tuberculosis during abatacept therapy. Thisrisk cannot be evaluated accurately, as the patients included in the initial studies werescreened, and those with positive screening tests were either excluded or given prophy-lactic antibiotic therapy. In the event of a positive screen, the recommended antibiotic the-rapy regimen is the same as for TNF antagonist therapy (AFSSAPS 2005). The firstabatacept infusion can be given 3 weeks after starting the antituberculous drugs, whichshould be continued for a total of 3 months (when the isoniazid (Rimifon®) + rifampicincombination is used).

● We evaluated the following:

1) Risk of infection, based on conventional risk factors (age, diabetes, glucocorticoid therapy,and co-morbidities) and iatrogenic factors related to previous biological therapy. Inpatients previously treated with rituximab, the immunoglobulin levels and circulatingB-cell counts should be taken into consideration when evaluating the risk of infection.

2) The risk of malignant disease, based on the presence of a known malignant or prema-lignant lesion and on the presence of risk factors in the patient or in family members.

The main findings in your patient are as follows:

❒ Risk factors for infection ❒ yes ❒ no

If yes, specify

❒ Risk factors for malignancy ❒ yes ❒ no

If yes, specify

❒ None

Conduct of abatacept therapy?

● Abatacept was started in a dose of ……………. mg without premedication. Abataceptwas given in combination with methotrexate or, in the event methotrexate was contrain-dicated, with ……………………………………………


● The administration of abatacept

❒ Was uneventful. There was no acute infusion reaction

❒ The patient experienced the following event . . . . . . . . . . . . . . . . . . . . . . . . . .

Intolerance (reaction to the molecule) can develop during or after the abatacept infusion.Such acute infusion reactions are rare (about 5% to 10% of patients) and, moreimportantly, they are very rarely severe (fewer than 1% of infusions). Symptomatictreatment is sufficient in patients with mild reactions. Patients with constitutional symp-toms, respiratory or cardiovascular manifestations, or diffuse skin lesions must beadmitted on an emergency basis.

● The second injection is scheduled 14 days after the first, in the same dosage. The thirdinjection will be given 14 days after the second injection. Thereafter, the patient will receiveone injection per month, in the same dosage.

Evaluating the clinical and biological response to abatacept

The monthly infusions provide the opportunity for regular monitoring, with the patientbeing evaluated before each infusion. However, you will continue to provide rheumato-logical follow-up.

Your objective is to evaluate the treatment response and to provide follow-up in collabo-ration with the patient’s primary-care physician.

The treatment objective is to obtain a response

– at week 16, with an at least 0.6-point decrease in the DAS 28

– at week 24, with an at least 1.2-point decrease in the DAS 28 and, if possible, aDAS 28 no greater than 3.2

To monitor the response to abatacept, the following should be determined at least onceevery 3 months: clinical disease activity (DAS 28 or SDAI), quality of life, and laboratorymarkers for inflammation (erythrocyte sedimentation rate [ESR] or C-reactive protein[CRP]). Structural effects should be assessed by obtaining radiographs of the hands andfeet about 1 year after the first abatacept infusion.

Evaluating the safety of abatacept therapyLaboratory tests required to monitor are blood cell count (risk of leukopenia and thrombo-cytopenia, which are rare), liver function tests (transaminases) and renal function test(creatinine), which should be obtained at 3-month intervals. When selecting follow-uptests, concomitant drugs (most notably methotrexate) should be considered. No widelyused immunological tests are available for monitoring and measuring the response to aba-tacept.

Risks associated with abatacept therapy• Infections may occur during abatacept therapy. The most common infections are

pneumonia and bronchitis, although cellulitis, pyelonephritis, and diverticulitis may


develop. Prompt treatment with appropriate antimicrobial agents is required.• Other adverse events have been reported, such as blood pressure changes (hypertension,

hypotension), hepatic cytolysis (without severe hepatitis), and headaches.• There is no risk of induced systemic or localized autoimmune diseases, except

perhaps an increased rate of cutaneous psoriasis.

To date, there is no evidence indicating that abatacept therapy increases the risk ofmalignant disease. However, close monitoring is required.

Subsequent abatacept therapy• If the patient has no response at week 16 (DAS 28 decrease by less than 0.6 point),

the treatment can be stopped.• If there is a partial response at week 16 (DAS 28 decrease by more than 0.6 but less

than 1.2 points), the treatment can be continued until week 24.• If there is no response at week 24 (DAS 28 decrease by less than 1.2 points), the

treatment strategy should be re-considered.

In patients who respond to abatacept (DAS 28 decrease greater than 1.2 at week 24) but whoexhibit residual disease activity (DAS 28 greater than 3.2), the treatment strategy should bereappraised in the light of other treatment options.

Modalities of follow-up in dayly practiceRecommendations regarding vaccinations, surgery, travelling, pregnancy, and breast-feeding are available as information sheets that you can obtain from us or from the CRI(Club Rhumatismes et Inflammation) website (www.cri.net.com). We have given thepatient a written document that describes abatacept and the treatment modalities.

Improving the follow-up of abatacept-treated patients and obtaining usefulinformationThe SFR (Société Française de Rhumatologie) and CRI (Club Rhumatismes et Inflammation)have established a prospective registry called ORA, of which objective is to collect data onpatients with RA who are treated with abatacept.

We will be happy to provide you with any additional information you may need.

Sincerely.

Physician in charge: Dr ............................................

Téléphone : ............................................................

physician’s stamp



Annexe 2: Model information letterfor the primary-care physician


…………….., ……………

Dear colleague,

You will soon receive a visit from Mr/Ms ………………………………..…..………….,born on ………………………………… to whom we recently started providing follow-upfor the initiation of abatacept therapy for rheumatoid arthritis.

What is abatacept?

Abatacept is a fusion protein analogous to CTLA-4 and therefore inhibits the activation ofT cells. Abatacept has been proven effective in decreasing the symptoms and destructivelesions associated with RA. These results prompted the healthcare authorities to grantabatacept a marketing authorization for RA, in 2007. Abatacept must be given incombination with methotrexate.

Your patient received abatacept as an intravenous infusion, in a dose of …………,in the department of ………..…..………. (Dr …………..……………………….),on …………………………………………………………

The next infusion is scheduled to take place 14 days after the first infusion, in thesame dose, and the third infusion 14 days after the second infusion, in the samedose. Thereafter, your patient will receive one infusion per month, in the same dose.

Abatacept was given in addition to your patient’s usual treatment for RA, i.e.,

What is known about the effectiveness of abatacept?

The effect of abatacept on the signs and symptoms of RA usually becomes apparentgradually over the first few months of the treatment. The final effectiveness evaluationis usually performed at the end of the sixth month.

What is known about the risks associated with abatacept therapy?● A reaction to the molecule during the infusion or within the next few hours is a very

rare event. Simple symptomatic treatment is usually sufficient. However, thedevelopment of constitutional symptoms, respiratory or cardiovascularmanifestations, or diffuse skin lesions should lead to hospital admission on anemergency basis.

● Infections may occur in abatacept-treated patients. The most common infections arepneumonia and bronchitis, although cellulitis, acute pyelonephritis or other urinarytract infections, diverticulitis, and other infections may develop. When there is noevidence of severe disease, appropriate antibiotic therapy should be given promptly.Patients with systemic manifestations or complications must be admittedimmediately.

…………………………………………….…………………………………………….…………………………………………….…………………………………………….

…………………………………………….…………………………………………….…………………………………………….…………………………………………….


● Other adverse events are uncommon. The following have been reported: transaminaseelevation, hypertension or hypotension, weight gain, tachycardia or bradycardia,thrombocytopenia, leukopenia, and headaches. This non-exhaustive list should notdistract from the very good overall safety profile of abatacept to date.

Practical considerations

● After the first three infusions, which occur over 1 month, an infusion is given once amonth during a brief hospital stay (one to a few hours). The effectiveness and safetyof the treatment should be assessed during a visit to the patient’s usualrheumatologist, at least once every 3 months. However, your patient may ask yourreferral in the event of unusual symptoms, to evaluate the causality of abatacept. Ifyou are in any doubt, please contact a member of our team.

• A rheumatologist visit is needed at least once every 3 months to assesseffectiveness based on clinical data (Disease Activity Score, DAS) and laboratorytests (ESR-CRP).

• We provide most of the monitoring required to assess safety. Laboratory testsrequired are blood cell count, transaminase assays and creatinine at 3-monthintervals. Additional tests should be performed as indicated by the concomitantmedications (e.g., methotrexate and glucocorticoids).

● Before the first infusion, we checked the immunization status of your patient.

❒ The following vaccine ………………………… was given on ……………………..

❒ No vaccinations were considered necessary.

Vaccination or re-vaccination with a non-live vaccine (e.g., influenza) can beperformed during abatacept therapy. Annual administration of the influenza vaccineis recommended. Live viral vaccines (oral polio, MMR, varicella, yellow fever) arecontraindicated throughout abatacept therapy and for the first 3 months afterabatacept discontinuation.

● In the current state of our knowledge, pregnancy is contraindicated until 18 weeksafter the end of abatacept therapy. No data are available about the potential effects ofabatacept on the fœtus.

● When a surgical procedure is scheduled, the time needed from the last abataceptinfusion to surgery is 2 months. This interval may be adjusted based on the type ofsurgical procedure (because the risk of infection varies across procedures), patient-related factors (particularly the risk of infection in the individual patient), the severityof the rheumatic disease, and the degree of control achieved by the treatment.Abatacept can be re-started without any loading dose afterwards (clinical trialexperience).

● When emergent surgery is needed, the need for prophylactic antimicrobial therapyshould be discussed on a case-by-case basis.


● For routine dental care (cavities, scaling), prophylactic antimicrobial therapy can begiven, without changing the antirheumatic regimen. For dental proceduresassociated with a risk of infection (extraction, apical granuloma, abscess…), thenext abatacept infusion should be postponed, as with surgical procedures, andprophylactic antimicrobial therapy offered.

● The patient may travel provided no live vaccines (yellow fever) are required. As withall travellers, measures aimed at preventing infections should be followedscrupulously. Antimalarial prophylaxis can be used.

An information sheet was given to the patient before the abatacept infusion.

Please let us know about any events that you feel are unusual. We will be happy toprovide any additional information you may need.

Sincerely.

Physician in charge: Dr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Téléphone : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

physician’s stamp





To give you a good understanding of the benefits and specificities of abatacepttreatment, we have written detailed answers to ten important questions.

Abatacept is a medication that treats rheumatoid arthritis (RA) by regulating yourimmune system, in order to decrease your joint pain, joint swelling, and fatigue. Theobjective of abatacept treatment is to halt the progression of your disease bydiminishing your risk of experiencing further joint damage (joint space narrowing andbone erosions).

Your rheumatologist suggested abatacept because this medication has been provedeffective in patients with rheumatoid arthritis, in particular when TNF� antagonists arenot effective or not well tolerated.For this reason, several healthcare authorities granted abatacept a MarketingAuthorization, in 2007. You and your rheumatologist have decided together to useabatacept based on the features of your disease and on your own characteristics (pastmedical history, infections, allergies…).

Abatacept is one of the “biotherapies” or “biologics”. These names mean that abataceptspecifically targets a biological component of your immune system. This component is acell (white blood cell, also called leukocyte). The white blood cells targeted by abataceptare T lymphocytes. By preventing the stimulation of T lymphocytes, abatacept blocks oneof the steps of the inflammatory response that causes joint swelling.Abatacept is an antibody that resembles the antibodies produced normally by yourimmune system. However, it was obtained synthetically to ensure that it would bind to,and prevent the activation of, these T lymphocytes, which are partly responsible for yourdisease.

Abatacept has been used in Europe since 2002. The experience acquired over theyears has provided valuable knowledge on abatacept. At present, several thousands ofpatients with rheumatoid arthritis are receiving abatacept, which has produced furtherinformation. The main risk is the development of infections, since abatacept blunts theimmune responses related to T lymphocytes. The most common infections involve thelungs, the lower airways, and the urinary tract. Most of them are non-serious infectionsthat can be treated easily.

4) What are the risks of abatacept therapy?

3) How does abatacept work?

2) Why did your rheumatologist suggest abatacept treatment?

1) What is abatacept?

S52

Annexe 3: Information patientUse of abatacept in rheumatoid arthritis


Other abatacept-related complications may occur. For this reason, your doctor willmonitor you closely during and after the treatment. You must inform your doctor of anysymptoms you may experience.

Abatacept can only be given in hospitals. Your doctor will refer you to a hospitaldepartment where the specialists have acquired experience with abatacept and areaccredited to use it. Abatacept must be given as intravenous infusions once a month(with an additional infusion 15 days after the first infusion). The infusion, whichcontains only abatacept, is given over 30 minutes, on a day-hospitalization basis.You will continue your other treatments for rheumatoid arthritis. In particular,methotrexate is useful, as it increases the effectiveness of abatacept. Do not changeyour treatment without first talking to your doctor.

Your doctor will ask questions about several important points.

● Your doctor will need detailed information on the medications you are taking.

● Your doctor will need to obtain details on your medical history. In particular, yourdoctor will need to know whether you have had any of the following:• infections• viral hepatitis (B or C)• heart disease or hypertension• lung disease or another chronic disease• allergies to medications or foods

● You must check that you are properly immunised against tetanus and polio, and yourdoctor may recommend that you receive vaccines against influenza andpneumococcal disease. If your immunisations are not up to date, you will have toreceive new shots.

● If you are a woman, you must make sure that you are not pregnant, and if you havejust had a baby you will not be able to breast-feed, since the effects of abataceptduring pregnancy and breast-feeding are unknown.

If you have any questions before the first abatacept infusion, feel free to discuss themwith your doctor.

6) What will happen before the first abatacept infusion?

14 days 14 days 1 month 1 monthAbatacepttreatment

1st inf.

D0

2nd inf.

D14

3rd inf.

D30

4th inf.

D60 M3

5) How is abatacept used?


You will be expected at the hospital early in the morning. The infusion will last about 30minutes. You may eat breakfast before leaving home. Remember to bring the thingsyou might need (such as books, drinks, your phone…).

You will be comfortable during the infusion. You will be able to read, listen to music, orwatch television.

During the infusion, pay attention to any abnormal symptoms that might indicate areaction to the medication. Reactions to abatacept are rare. The symptoms mayconsist of trouble breathing, swelling of your tongue and lips, a headache, a feeling ofwarmth and/or shivering, redness or itching of the skin, nausea and/or vomiting,itchiness inside your nose and/or sneezing, itchiness in your throat, pain in your chest,and/or an abnormally fast heartbeat.

You must report all your symptoms to the nurse in charge of monitoring you. If youexperience symptoms of any kind, the nurse will stop or slow the infusion and call thedoctor working in the hospital department. If your symptoms resolve rapidly, the doctormay decide to continue the infusion. Severe reactions that require permanentdiscontinuation of the infusion are extremely rare. If you experience any symptomsduring the infusion, you will be monitored at the hospital for at least 2 hours beforereturning home.

When the infusion is over, you will return home. You may leave with a family member orfriend and ask us to help you find an appropriate means of transportation.

Pay attention to any possible symptoms during the first few hours and days following theinfusion.

• During the first few hours: delayed allergic reactions are exceedingly rare.

• During the first days: pay attention to any symptoms you may experience and that mayindicate an infection. These symptoms may consist of a fever, chills, a sore throat or badcold, an unusual cough and/or trouble breathing, a burning sensation during urination, orback pain.

Feel free to contact your rheumatologist if you notice anything that is unusual, or talk to yourprimary-care doctor if needed. It is better to ask questions right away than to wait. Do nottake any medications without first talking to your doctor.

8) What will happen after the infusion?

7) What will happen during the abatacept infusion?



Abatacept has been proven effective in rheumatoid arthritis. Abatacept alleviates thepain and fatigue and also decreases the joint swelling. However, the treatment effectoften requires several weeks to develop (often 2 to 4 months after treatment initiation).You will objectively document your improvements with your doctor, who will perform aphysical examination and order blood tests to evaluate the degree of inflammation(based on the erythrocyte sedimentation rate or C-reactive protein level). The longerterm effectiveness of the treatment will be assessed by obtaining radiographs of yourhands and feet about 1 year after the first abatacept infusion.

Although abatacept therapy may induce a remission, your disease will return ifabatacept is stopped. Therefore, if the drug is well tolerated and effective, it should becontinued. The maximal treatment duration is not known, but some patients have beentaking abatacept for several years. Your rheumatologist will see you regularly, at leastonce every 6 months, to ask questions, perform a physical examination, and orderblood tests to measure the level of inflammation. You will discuss the appropriatenessof continued therapy with your rheumatologist. In the intervals between rheumatologistvisits, you will see your primary doctor if needed, according to the course of your jointdisease and to whether you have other health problems that require attention,particularly infections, which may be promoted by abatacept therapy.

We hope this information has been helpful.

If you have questions, do not hesitate to discuss them with your doctor.

10) How long should you stay on abatacept therapy?

9) How and when will you notice the effects of the treatment?

Documents

Abatacept therapy and safety management