Abatacept THERAPY AND SAFETY MANAGEMENT

Transcription

1 S3 Abatacept THERAPY 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. Abstract Evidence Based Medicine Official recommendations Expert opinion 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 postmarketing surveillance data. * Corresponding author. Tel.: ; fax: adress: thao.pham@mail.ap-hm.fr (T. Pham). Joint Bone Spine 2009 ; 76 (Suppl1) : S1-S56

2 S4 Management of patients on abatacept in daily practice 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 (autoimmune 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 and regularly updated. Keywords: Abatacept; Monitoring; Safety; Health services 2009 Société Française de Rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

3 S5 Introduction Evidence Based Medicine Official recommendations Expert opinion 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 ( 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.

4 S6 Management of patients on abatacept in daily practice Initial pre-treatment assessment Evidence Based Medicine Official recommendations Expert opinion This checklist is designed to help you conduct a systematic search for contraindications to abatacept therapy. It does not include the assessment of the level of activity and severity of the 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 a patient 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, the intradermal test does not need to be repeated. In patients who had a negative intradermal test when screened at least 1 year earlier, the test should be repeated. In patients who have never been screened, AFSSAPS recommendations for detecting latent tuberculosis should be followed.

5 S7 Serological tests for hepatitis B and C and, with the consent of the patient, serological test for HIV infection. If tests done within the last 5 years are available, re-testing is unnecessary unless the patient has risk factors or a history of a high-risk medical procedure in the interval. Standard practice should be followed regarding the detection of cancer according to local 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 was removed completely with disease-free excision margins Precautions when using abatacept: Chronic obstructive pulmonary disease (COPD) Hypogammaglobulinemia Lymphopenia Monoclonal gammopathy of unknown significance (MGUS)

6 S8 Management of patients on abatacept in daily practice Monitoring abatacept therapy Evidence Based Medicine Official recommendations Expert opinion Treatment monitoring in patients receiving abatacept requires both clinical and laboratory assessment to evaluate the effectiveness and safety of the drug. Since abatacept is given once a month after the first three infusions, regular clinical follow-up can be provided at each infusion (see the model letters for informing officebased 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 assess disease 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-based rheumatologists). Structural disease progression should be evaluated (using radiographs of the hands and feet) after 1 year of abatacept therapy. Safety should be assessed at each abatacept infusion and whenever an unexpected event occurs. As with all biotherapies, careful attention should be given to bacterial or viral infections, most notably in patients with a history of recurrent infections or underlying conditions (COPD); and to symptoms that may suggest a solid cancer or haematological malignancy (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, and ARRIVE trials. In patients who responded inadequately to TNF antagonist therapy, abatacept significantly decreased disease activity. A response defined as an at least 1.2-point decrease in the DAS 28 was significantly more common with abatacept, as early as the first month, in the AIM and ATTEST studies. The mean 3-month response rate was 70% in the abatacept groups in the four studies overall. As the treatment response continues to develop over the first 6 months, the best time for evaluating the patient is between the third and sixth month (3-5). Laboratory monitoring No specific laboratory or immunological tests are needed to monitor abatacept therapy. Laboratory tests for inflammation are needed to compute the DAS, and the appropriate laboratory tests should be obtained to monitor concomitant treatments (e.g., methotrexate),

7 S9 according to standard practice. In the absence of specific problems, blood cell counts (leukopenia and thrombocytopenia are uncommon adverse events), transaminase assays and 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 control method should be used throughout the treatment and for the first 14 weeks after treatment discontinuation in women of reproductive potential. However, given the elimination half-life of abatacept, 97% of the drug is eliminated within 18 weeks of the last dose, assuming linear kinetics. Therefore, we considered that attempts 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 are discussed in specific fact sheets ( Pregnancy, Vaccination, Travel, Surgery, and Drug- Drug Interactions ). Calendar: dates of the infusions, clinical evaluations, laboratory tests, and structuraldamage assessments Abatacept treatment 1 st inf. 10 mg/kg D0 2 nd inf. 10 mg/kg 14 days 14 days 1 month 1 month D14 3 rd inf. 10 mg/kg D30 4 th inf. 10 mg/kg D60 M3 DAS 28 or SDAI + quality of life + ESR and/or CRP 1 st clinical evaluation 2 nd clinical evaluation 3 rd clinical evaluation 3 months 3 months 3 months 3 months D0 M3 M6 M9 M12 Blood cell counts + transaminases + creatinine X-rays of hands and feet 1 st clinical evaluation 2 nd clinical evaluation 3 rd clinical evaluation D0 M3 M6 M9 D0 3 months 3 months 3 months 3 months 1 year M12 1 st structural evaluation M12

8 S10 Management of patients on abatacept in daily practice Management of patients with past or present history of bacterial or viral infections Evidence Based Medicine Official recommendations Expert opinion Role for B7/CD28 co-stimulation pathway in immunity against infectious agents The mounting of an anti-infectious T-cell response is a complex process during which cytokines and co-stimulation molecules generate signals that regulate adaptive immunity. 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 has been demonstrated in several models of infection, particularly with Herpes simplex virus and Influenza virus (7). The B7/CD28 pathway also makes an important contribution to immunity against parasites, most notably Toxoplasma gondii and Leishmania major (8); fungi, such as Pneumocystis carinii (9); and bacteria, particularly some of the intracellular organisms including Listeria monocytogenes, Salmonella enterica, and Chlamydia trachomatis (10). In mouse models, however, treatment with abatacept or CTLA4-murine Ig did not affect the ability of the animals to survive chronic infection with Mycobacterium tuberculosis (11), latent infection with Mycobacterium tuberculosis, or acute infection with cytomegalovirus or Pneumocystis carinii (12). However, the treatment was associated with decreased survival of acute infection with Herpes simplex virus (12). Current knowledge on the risk of bacterial and viral infections during abatacept therapy Safety data were collected in 1955 patients exposed to abatacept during the five main controlled 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 TNF antagonist therapy, and 1.1% on anakinra). Infectious adverse events were more common in the abatacept groups than in the placebo groups (54.1% vs. 48.7%). The most common sites of 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 simplex virus 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 the abatacept groups than in the placebo groups (3% vs. 1.9%). The most common site of serious 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%), the genitourinary 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).

9 S11 Of the 10 deaths (0.5%) that occurred in the abatacept groups during the double-blind phase, only 1 was caused by an infection (pulmonary aspergillosis in a patient with bronchiectasis and a history of miliary tuberculosis), compared to 2 of the 6 deaths (0.6%) in the 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 of abatacept in RA found no statistically significant increase in the risk of serious infections in the abatacept groups compared to the placebo groups (odds ratio [OR], 1.35; 95% confidence interval [95%CI], ; P=0.3). However, the statistical power of this metaanalysis is insufficient to warrant a conclusion that the risk of infection is not increased during abatacept therapy (16). Since the publication of this meta-analysis, the safety data from the clinical development program for abatacept in RA were updated to December Overall, 4150 patients with RA received abatacept during eight clinical studies (10,365 patient-years; median exposure time, 26.2 months). The incidence of admission for infection was 3.05/100 patient-years in the abatacept groups and 2.15/100 patient-years in the placebo groups during the controlled 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 of patients 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 tract infections, cellulitis, and urinary tract infections (17). Furthermore, in the abatacept clinical trial experience, a total of 6 cases of TB were reported with an incidence rate of mycobacterium tuberculosis as of December 2007 of 0.06/100 patient-years (17). The 4-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. What should be done before the initiation of abatacept therapy to prevent bacterial and viral infections? Overall evaluation of the infectious risk Infections contribute to the excess mortality seen in patients with RA. The increased incidence and severity of infections in patients with RA is multifactorial. Factors that increase 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 joint prostheses and catheters), and other immunosuppressive medications the patient may be taking (most notably glucocorticoids and TNF antagonists) (18-20). All these risk factors should be considered when evaluating the overall risk of infection in patients with RA, particularly before starting an immunosuppressive medication such as abatacept. 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

10 S12 Management of patients on abatacept in daily practice caution when considering the use of abatacept in patients with a history of recurrent infections 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 immunosuppressive treatments such as abatacept. Therefore, before starting abatacept therapy, a medical history and physical examination should be performed to look for an overt or latent focus of infection (see the Initial pretreatment 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 considered for inclusion in studies of abatacept in RA and that patients were not included if they had a history of active tuberculosis within the 3 years preceding the selection visit or a positive screening test with no history of antituberculous treatment (13). Patients should be screened for latent tuberculosis prior to initiating abatacept The available medical guidelines should be taken into account. In patients taking prophylactic antituberculous therapy, abatacept can be started after 3 weeks according to local guidelines. If the 5 IU intradermal tuberculin test done before starting abatacept was positive and the patient received prophylactic antituberculous therapy in compliance with French recommendations, repeating the intradermal tuberculin test seems unnecessary. In contrast, if the 5 IU intradermal tuberculin test done before starting abatacept was negative and was performed more than 1 year earlier, another test should be performed. If this second 5 IU intradermal tuberculin test is positive, prophylactic antituberculous 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 abatacept groups 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 with viral infections (22), screening for viral hepatitis B, C and HIV should be performed in accordance with published guidelines before starting treatment with abatacept. If serological tests done within the last 5 years are available, re-testing is not necessary, except in patients with risk factors or a high-risk medical procedure in the interval. Serological testing for HIV infection is advisable (with the consent of the patient). In patients with active HBV or HCV infection, advice from a hepatologist must be obtained before making treatment decisions.

11 S13 In patients who have HIV infection, advice from an infectiologist must be obtained before making treatment decisions. In patients with recurrent oral or genital Herpes simplex virus infection, advice from an infectiologist must be obtained before making treatment decisions, to determine whether prophylactic acyclovir therapy is appropriate. Course of action when evidence of infection develops during abatacept therapy Patients with evidence of severe infection requiring emergent probabilistic antimicrobial therapy should be admitted to a specialized unit and taken off abatacept therapy. In all patients with infections, specimens for bacteriological studies must be obtained before starting probabilistic antimicrobial therapy. Other tests (mycobacteriological, virological, mycological, or parasitic studies; and imaging studies) should be performed as indicated 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 antimicrobial treatment consists of amoxicillin clavulanic acid or a third-generation cephalosporin (Cefotaxine, Ceftriaxon ). If no improvement occurs within the first 48 hours, a macrolide should be substituted for, or added to, the first antimicrobial. In specific settings, an antipneumococcal quinolone may be preferable. Evidence of interstitial pneumonia should routinely suggest the possibility of atypical pneumonia (Chlamydia pneumoniae, Mycoplama pneumoniae) or of an opportunistic infection (Legionella, Pneumocystis jiroveci). Serological tests should be obtained for Chlamydia pneumoniae, C. psittaci, and Mycoplasma pneumoniae, as well as a Legionella pneumophila antigenuria assay, and the need for bronchoalveolar lavage should be discussed. Chlamydiae, mycoplasms and Legionella are susceptible to macrolides. Identification of Legionella requires hospital admission. When P. jiroveci pneumonia is suspected, cotrimoxazol therapy should be started. The nature of the antimicrobials and their duration of use should be adjusted based on the results of the microbiological studies, effects on signs of infection, and tolerance. All serious infections should be reported to the pharmacovigilance centre.

12 S14 Management of patients on abatacept in daily practice Management of patients with past or present history of solid cancer or haematological malignancy Evidence Based Medicine Official recommendations Expert opinion Data from the litterature The risk of inducing malignant diseases is always a concern when a new T cell modulating agent is registered, which plays a central role in fighting tumours. Close attention was therefore given to this point in the development program for abatacept, particularly as preclinical carcinogenicity studies in a murine model showed an increased incidence of lymphoma and mammary cancer related to loss of control of the proliferation of the viruses associated with the development of these malignancies. However, there are no human equivalents of these viruses, and the relevance of these findings 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 lung cancer occurred in the abatacept arm, compared to none in the placebo arm. Safety data obtained during drug development programs are limited, however, because the sample sizes are too small to capture rare events. Pooling clinical trials is useful to obtain a larger sample size. This meta-analytic approach showed an increase in the risk of malignancy in patients treated with TNF antagonists. In the abatacept clinical development program with 1688 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 lung cancer versus none in the placebo groups. No differences were noted between the two treatment 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 fairly short, which does not allow the detection of events that may develop only after protracted use of the drug. Open-label extension periods enable the detection of larger number of events over longer periods but do not include a control group. Two solutions are available. The incidence of malignant diseases recorded throughout the drug development program could be compared to the expected incidence in the general population, but this approach does not factor in the risk increase related to the disease itself (for instance the 2- to 5- fold increase in lymphoma risk in patients with RA compared to the general population). The incidence of malignancies could be compared in abatacept-treated patients and in several historical cohorts of RA patients established before the introduction of biotherapies. Both approaches have a major limitation related to the criteria for patient inclusion in randomized trials. The practice of excluding patients with a history of cancer (within the last 5 years) undoubtedly diminishes the risk of cancer emerging subsequently.

13 S15 The selected populations included in randomized trials are not strictly comparable to patients in the general population (even when matching is used) or to cohorts of RA patients constituted without using exclusion criteria (Table 2 - Figures 1 and 2). This major 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 in abatacept-treated patients compared to the expected rates in the general population (SIR = 0.75; 95%CI [ ]). However, increases were found in the risk of lung cancer (SIR = 2.25; 95%CI [ ]) and lymphoma (SIR = 3; 95%CI [ ]). On the other 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 RA patients, independently from the treatments used, and they probably reflect the characteristics of the disease rather than those of abatacept (13). 2. Comparisons to data from large cohorts are more informative. Six cohorts were used as the comparison groups: the British Columbia Population-Based RA Cohort in Canada, Norfolk Arthritis Registry in the UK, National Data Bank for Rheumatic Diseases in the US, General Practice 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 the clinical development program, 4134 patients with RA were exposed to abatacept, for a total of 10,000 patient-years of exposure. Table 3 shows the incidence ratios for the main malignancies that were recorded. For none of these malignancies was the incidence outside the 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 (particularly lymphoma and lung cancer) in abatacept-treated patients compared to RA patients treated without biologics DMARDs. However, these data will have to be confirmed by observational post-marketing studies. Additional studies were in order, particularly given the major role played by CTLA 4 in T-cell modulation. Therefore, monoclonal anti-ctla 4 antibodies were evaluated in various anti-tumor strategies. In murine models involving the implantation of human tumours, monoclonal anti-ctla-4 antibodies induced the regression of solid tumours and lymphomas. However, these antibodies used alone were not sufficient to induce the regression of tumours characterized by limited immunogenicity, such as melanoma and breast cancer. In humans, this anti-tumour immunotherapy strategy was developed using two monoclonal anti-ctla-4 antibodies combined with a peptide vaccine. An objective 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 had metastatic disease. Furthermore, these anti-ctla-4 antibodies do not block the regulatory T cells (Treg), which infiltrate the tumour, where they decrease the effectiveness of anti-tumour T cells (29-33).

14 S16 Management of patients on abatacept in daily practice Course of action in clinical practice 1. History of solid cancer or haematological malignancy No studies have been performed to evaluate the benefits or risks of abatacept therapy in patients with cancer, lymphoma, or a recent history of malignancy. Given the absence of data, as with TNF antagonists, caution requires that physicians refrain from using abatacept 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 excision margins). 2. Development of cancer or haematological malignancy during abatacept therapy Whether abatacept discontinuation is in order should be discussed on a case-by-case basis, according to the nature of the cancer (e.g., a diagnosis of prostate cancer in a 75-year-old man does not have the same significance as a diagnosis of lymphoma in a young individual). The event should be reported to the pharmacovigilance centre. Tables Table 1 Malignancy rates during abatacept therapy and during placebo therapy 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)

15 S17 Table 2 Malignancy rates during abatacept therapy in RCTs (randomized clinical trials) compared to expected rates in the general population (13) Cancer or lymphoma observed expected SIR (95%CI) Solid cancer ( ) Lung ( ) Breast ( ) Prostate ( ) Colon /rectum (0-1.04) Lymphoma ( ) 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 cumulate periods (28) IR (95%CI) of malignancies compared to RA cohorts* Malignancies Double-blind placebo N=989 Double-blind abatacept N= pivotal abatacept trials N=2689 Cumulative abatacept N=4150 Patient-years Overall (except non-melanoma skin cancer) 0.63 ( ) 0.59 ( ) 0.74 ( ) 0.71 ( ) Lung ( ) 0.18 ( ) 0.16 ( ) Lymphoma ( ) 0.07 ( ) 0.07 ( ) Colon/Rectum ( ) 0.02 ( ) Breast 0.25 ( ) 0.06 ( ) 0.08 ( ) 0.09 ( ) *events/100 patient-years; IR: incidence rate

16 S18 Management of patients on abatacept in daily practice Figure 1 - Incidence of lymphoma during abatacept therapy compared to the incidence in several RA cohorts (28) BC NDB GPRD NOAR Sweden ERA Observed: 7 Expected confidence interval: SIR (SIR: standardized incidence ratios) 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. Figure 2 - Incidence of lung cancer during abatacept therapy compared to the incidence in several RA cohorts (28) incidence in several RA cohorts (8) BC NDB GPRD NOAR Sweden ERA Observed: 17 Expected confidence interval: SIR (SIR: standardized incidence ratios) 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.

17 S19 Management of patients with past or present history of cardiovascular disease Evidence Based Medicine Official recommendations Expert opinion Is there a risk of cardiovascular events occurring during abatacept therapy? Cardiovascular events are uncommon during abatacept therapy. During the abatacept development program (controlled trials and open-label extension periods), cardiovascular adverse events were rare. They consisted of hypertension, palpitations, tachycardia or bradycardia, congestive heart failure, coronary artery disease or myocardial 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 of cardiovascular events was not increased in the abatacept-treated patients. What precautions should be taken before starting abatacept therapy in patients with a history of cardiovascular disease? Given the above-described findings, cardiovascular disease does not contraindicate abatacept therapy. In patients with inadequately controlled or unstable heart disease (heart failure, coronary artery disease, or rhythm disorders) or vascular disease (hypertension), common sense mandates that the cardiovascular drug regimen be optimized and/or that the advice of a cardiologist be obtained before starting abatacept therapy. What alarm signals deserve special attention in patients receiving abatacept therapy? As with all patients who have RA, the presence of dyspnea, chest pain, or palpitations should be sought by specific questions. Blood pressure should be measured. Management If 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 than 100 mmhg), postponing the abatacept infusion until the hypertension is controlled may be advisable. When in doubt, or when blood pressure control proves difficult to achieve, advice should be sought from a cardiologist. When can abatacept therapy be resumed? Abatacept therapy can be resumed a few days after achieving blood pressure control.

18 S20 Management of patients on abatacept in daily practice Does abatacept interact with ongoing cardiovascular drugs? To date, there is no evidence that abatacept interacts with cardiovascular drugs. Does abatacept interact with anticoagulant drugs? To date, there is no evidence that abatacept interacts with oral or injectable anticoagulants. Current knowledge about the risk of cardiovascular events (other than heart failure) during abatacept therapy Patients with RA are at increased risk of cardiovascular events, myocardial infarction and stroke (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 excess cardiovascular risk, diminishing both the risk of cardiovascular events and the risk of cardiovascular death. To date, no information is available on whether abatacept may also decrease the excess cardiovascular morbidity and mortality associated with RA.

19 S21 Management of patients with past or present history of acute infusion reactions Evidence Based Medicine Official recommendations Expert opinion Abatacept infusions may induce reactions, of usually mild to moderate intensity. Such reactions are uncommon. Therefore, no routine prophylactic measures are recommended. Description of acute infusion reactions Acute infusion reactions are defined as reactions that start within 1 hour after the initiation of the infusion. Acute infusion reactions were recorded in 9.8% of abatacept-treated patients in phase III 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 are rare (4 of 2484 patients included in the published randomised trials) (24,36). These hypersensitivity reactions occurred at treatment initiation in the 2 patients for whom data on timing are available (2 nd and 4 th infusion, respectively) (24). Monitoring abatacept infusions Although acute infusion reactions are usually non-serious with abatacept, their possible occurrence require medical monitoring of patients during the infusions. However, no premedication 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

20 S22 Management of patients on abatacept in daily practice Management of the patient with an acute infusion reaction during an abatacept infusion The management depends on the type and severity of the reaction. Decreasing the infusion rate may suffice to ensure resolution of the reaction. Therefore, the following sequence can be 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 Delayed infusion reactions No delayed reactions resembling serum sickness have been reported to date, probably because abatacept is an entirely human fusion protein that exhibits little immunogenic potential. In controlled trials, 2.8% of patients for whom sera obtained before and after treatment were available contained antibodies to the immunoglobulin component or CTLA-4 component of abatacept (13). Overall, there was no apparent correlation of antibody development to clinical response or adverse events. However, the number of patients that developed antibodies was too limited to make a definitive assessment. This point requires confirmation by additional studies. The potential clinical relevance of neutralizing antibody formation is not known. There is no need to assay these antibodies in everyday practice.

21 S23 Management of patients with past or present history of auto-immune disease Evidence Based Medicine Official recommendations Expert opinion Data from the literature Many auto-immune diseases are related to activation of autoreactive T cells via the B7/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, abatacept showed no beneficial effects compared to the placebo in patients with systemic (nonrenal) lupus erythematosus. Nevertheless, abatacept may have beneficial effects on a number of secondary objectives. Therefore, in the future, studies using a more appropriate design regarding evaluation criteria and concomitant treatments (glucocorticoids) might show a beneficial effect (39). A phase I dose-escalation trial was recently conducted with abatacept in 16 patients with multiple sclerosis. Treatment with one to four infusions was well tolerated and induced promising immunological effects (40). However, to date, no controlled trials have proven that abatacept is effective in auto-immune diseases other than RA. The introduction of a new immunomodulating agent requires close monitoring for the occurrence of induced auto-immune manifestations. During the abatacept development program, a few cases of cutaneous psoriasis were recorded. In contrast, no other autoimmune diseases developed, and no antinuclear nor anti-dsdna antibodies were induced. The occurrence of autoimmune diseases was assessed in the abatacept development program consisting of cumulative (double-blind and open-label) data through December 2007 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 abatacept versus 8 (0.8%) of 989 patients on the placebo. The most common auto-immune disease were psoriasis, in 0.5% of abatacept-treated patients and in 0.0% of placebotreated patients. Overall, data were obtained for 4150 abatacept-treated patients (10,365 patientyears) as of December 2007, and the cumulative rate of auto-immune disease was 1.59/100 patient-years (41).

22 S24 Management of patients on abatacept in daily practice Table 4 - Development of auto-immune events in trials of abatacept * Double-blind phases + long-term open-label extensions Number of auto-immune events n (incidence/100 p/y) Double-blind phases 1688 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) This analysis found no evidence of an increased risk of auto-immune diseases during abatacept therapy. The incidence of auto-immune manifestations did not increase with the duration of abatacept exposure. What are the alarm signals that should suggest an auto-immune disease in patients receiving abatacept? Many manifestations may suggest a diagnosis of auto-immune disease (e.g., constitutional symptoms or organ involvement). In the current state of our knowledge, no specific diagnosis should be considered preferentially, although cutaneous psoriasis seems slightly more common than other auto-immune diseases. It should be borne in mind that RA is associated with various systemic auto-immune disorders (Sjögren, lupus, scleroderma, ) and organspecific auto-immune disorders (thyroiditis), independently from any inducing effect of abatacept. Course of action in everyday practice In patients with a history of auto-immune disease In the current state of our knowledge, no specific auto-immune disease in the patient s history contraindicates the use of abatacept. On the contrary, experimental findings and preliminary clinical data suggest that abatacept may have beneficial effects in some auto-immune diseases. To date, however, such beneficial effects remain unproven (see the Data from the Literature paragraph).

23 S25 Development of an auto-immune diseasee The first step is to make sure that the manifestations reported by the patient are caused by an auto-immune disorder and not by some other process such as an infection. When an auto-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 lupus erythematosus, demyelination), it is preferable to discontinue abatacept therapy and to 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. Symptomatic treatment for the auto-immune disease can be added if needed.

24 S26 Management of patients on abatacept in daily practice Management of patients who are pregnant Evidence Based Medicine Official recommendations Expert opinion Given the absence of adequate data, abatacept (CTLA-4 Ig) is contraindicated in pregnant women, and effective contraceptive methods must be used, starting at treatment initiation. However, the product characteristics and the data from animal studies can be used to develop an expert opinion. CTLA-4 and risk of spontaneous abortion Several publications establish a beneficial effect of CTLA-4 on tolerance during pregnancy (42-44). CTLA-4 is expressed on foetal cells, including the fibroblastic cells of the placental mesenchyme at the mother-foetus interface, and the level of expression increases from the first to the second trimester of pregnancy. In addition, in an abortionprone mouse strain, monoclonal antibodies to CD80 and CD86 (specific ligands of the CD28/CTLA-4 co-stimulation pathway) induced CTLA-4 overexpression and maternal tolerance to the foetuses (45). Finally, a CTLA-4 gene polymorphism has been suspected as a cause of recurrent abortion in a population of Chinese women (46). These preliminary data do not allow definitive conclusions but suggest a protective role of CTLA-4 against spontaneous abortion. Available data on abatacept Animal studies (27,47-49) Abatacept is devoid of genotoxic or mutagenic effects and does not induce chromosomal abnormalities. 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 used in humans (10 mg/kg), found no evidence of foetotoxicity, teratogenicity, or negative effects on neonatal development. Mild disturbances in immune functions consisting of thyroid gland inflammation or exacerbation of the T-cell-dependent humoural response were noted in rats but only with a dose of 200 mg/kg (i.e., 11 times the dose used in humans). It should be noted that the animal toxicology studies of abatacept were conducted without concomitant medications (i.e., without concomitant methotrexate). Pharmacological properties (27,47-49) Studies in rats indicate that abatacept can cross the placental barrier (producing dosedependent foetal serum concentrations that are 1.7 to 2.4 times lower than maternal serum concentrations) and can be detected in milk (where concentrations are 10 times smaller than in the mother). After a single administration of 10 mg/kg to healthy volunteers, the mean half-life was 16.8 ± 4.5 days. After repeated intravenous administration of 10 mg/kg to patients with RA, the mean half-life was 13.1 days (8 to 25 days).

25 S27 Exposure to abatacept during pregnancy in women During the double-blind and open-label phases of the five pivotal studies of abatacept in RA, 8 patients became pregnant while taking abatacept. Among them, 7 were on concomitant methotrexate and 1 was on concomitant leflunomide (27). Spontaneous abortion occurred during the first trimester of pregnancy in 3 of these patients (of whom 2 had a history of spontaneous abortion and 1 was a primagravida). Elective abortion was performed in 2 patients. The remaining 3 patients were still pregnant at the time the study report was written. The spouse of a man treated with abatacept became pregnant and delivered a healthy baby. During a phase II trial of abatacept in multiple sclerosis, 2 abatacept-treated women became pregnant, as well as the spouse of an abatacept-treated man. Of the three women, one delivered a healthy baby, one underwent elective abortion, and one experienced 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), in Europe: European Network of Teratology Information Service (ENTIS), Clinical Situations Before starting abatacept therapy Women of child-bearing potential who are being evaluated for abatacept therapy initiation should be asked whether they want to have children. If a pregnancy is desired within the next few months, initiation of abatacept therapy is not advisable. However, the severity of the disease should be assessed, and when abatacept therapy is crucial to preserve function, the patient may be advised to postpone the pregnancy (in order to allow previous stabilization of the disease followed by conception under more favourable clinical conditions). See Available data on abatacept Pharmacological properties. Time from the last abatacept infusion to attempted conception Conception should not be attempted immediately after the last abatacept infusion. Furthermore, methotrexate, if used concomitantly with abatacept, must be stopped at least 3 months before attempting conception (recommendation in the current marketing license). The European Summary of Product Characteristics (EU SPC) contains the following recommendation about the time from the last abatacept infusion to attempted conception (that is, the time during which effective contraceptive measures must be used: Women of child-bearing potential should use effective contraceptive methods during treatment and for 14 weeks following the last infusion.

26 S28 Management of patients on abatacept in daily practice 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 response to abatacept), particularly as achieving a pregnancy may take time. The outcomes of the few pregnancies characterized by maternal exposure to abatacept were similar to those of pregnancies without abatacept exposure. Methotrexate, which is known to induce birth defects and abortions, is usually given in combination with abatacept and must be stopped at least 3 months before attempting conception. 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 must therefore be postponed. Abatacept therapy ensures control of the disease: Methotrexate should be stopped and effective contraceptive measures used for at least 3 months before attempting to initiate a pregnancy. The elimination half-life of abatacept suggests that an 18-week wait between the last abatacept infusion and the first attempts to conceive may be adequate (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 between the last abatacept infusion and attempts to initiate a pregnancy is reasonable in women. No specific data are available for chez l homme. In particular, the potential effect of abatacept on sperm cell production is unknown. Therefore, recommending an 18-week wait, as with female patients, may be reasonable. Pregnancy initiation during abatacept therapy Initiation 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 partner must decide whether to continue the pregnancy. If the obstetrical investigations are normal, continuing the pregnancy can be recommended. Detailed information given at the initiation of abatacept therapy should prevent the occurrence of pregnancies during the treatment. Initiation of abatacept therapy during pregnancy This situation is unlikely to occur in patients with RA, a disease that usually improves during pregnancy. In the current state of our knowledge, abatacept initiation during pregnancy is not advisable.

27 S29 Breast-feeding Abatacept is detectable in milk in lactating animals (27). No data are available on abatacept excretion in human breast milk and, therefore, breast-feeding is not advisable during abatacept therapy. In practice, breast-feeding is possible, since it is started at least 13 months after the last abatacept infusion (4 months wait before attempting conception [see above] plus 9 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 retreatment must be postponed until the baby is fully weaned. If the joint disease flares after delivery (a fairly common event in RA), re-treatment with abatacept and, therefore, the need to refrain from breast-feeding should be discussed on a case-by-case basis.

28 S30 Management of patients on abatacept in daily practice Vaccinations in abatacept-treated patients Evidence Based Medicine Official recommendations Expert opinion RA does not contraindicate the administration of vaccines, and the response to vaccines is adequate in the absence of immunosuppressive treatment (50). However, in patients who use potentially immunosuppressive medications, whether vaccinations can be performed must be determined. Can vaccines be administered to patients on abatacept therapy? 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 an antibody response (13,51-56). When should attention be given to vaccinations? The immunization history should be checked before starting abatacept therapy, when switching between biotherapies, once a year at the end of the summer, and whenever a trip abroad is planned. Vaccinations in patients on biotherapies may raise two problems: decreased safety (with live attenuated vaccines) and decreased effectiveness (with all vaccine types). In abatacept-treated patients, live attenuated vaccines are contraindicated given the risk of treatment-related loss of attenuation of the vaccine microorganism. Inactivated and component 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

29 S31 Vaccines that should be given before starting abatacept therapy The patient s immunisation history should be checked to determine whether mandatory vaccines (most notably tetanus and polio) and vaccines recommended under specific circumstances were given appropriately and updated as needed. In the fall, the influenza vaccine is recommended in patients who are scheduled to start abatacept therapy. The pneumococcal vaccine is recommended, particularly in patients at high risk for lung infections. At least 3 years must be allowed to elapse between administrations of the pneumococcus vaccine (which is usually given every 4 to 5 years). A history of documented or suspected pneumococcal infection does not contra-indicate administration of the pneumococcal vaccine. The pneumococcal vaccine can be given at the same time as the influenza vaccine (if this situation arises), at a different injection site. 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 be given if possible at a time when there is no immunosuppression (that is, after the effects of previous biotherapies have dissipated). At least 2 weeks and at best 4 weeks should be allowed to elapse between the vaccination and the first abatacept dose. In practice, yellow fever constitutes the most challenging vaccination problem. Patients must be asked about trips to countries where yellow fever is endemic, before starting abatacept then during treatment follow-up. If the patient may travel in the short or medium term to countries where yellow fever immunisation is mandatory, the yellow fever vaccine (which is effective for 10 years) should be given after any immunosuppressive effects of the previous treatment have worn off and at least 2 weeks but preferably 4 weeks before starting abatacept therapy. Vaccines that should be offered when switching from a TNF antagonist to abatacept The same vaccines are recommended for TNF antagonists and abatacept. Therefore, the recommendations are the same whether the patient is switched from one to the other or kept on the same treatment. Vaccines that should be offered in the event of long-term abatacept therapy The patient s immunisation history should be checked to determine whether mandatory vaccines (most notably tetanus and polio) and vaccines recommended under specific circumstances were given appropriately and updated as needed. Administration of the influenza vaccine in the fall is recommended.

30 S32 Management of patients on abatacept in daily practice When a live vaccine (yellow fever, for instance) must be given to an abatacept-treated patient, abatacept must be discontinued at least 3 months before administering the vaccine. At least 2 weeks and at best 4 weeks should then be allowed to elapse before re-starting abatacept therapy. When an inactivated vaccine or component vaccine must be given to an abatacepttreated patient, although abatacept discontinuation followed by a 3-month wait is optimal, the vaccine can be administered at any time. Should contacts be vaccinated? Vaccination of contacts (children and grandchildren) can be considered, most notably to protect against influenza. This strategy may decrease the risk of disease communication to the biotherapy-treated patient.

31 S33 Management of patients who plan to travel Evidence Based Medicine Official recommendations Expert opinion Can abatacept-treated patients travel? Abatacept-treated patients can travel. The European Summary of Product Characteristics (EU SPC) contains no specific recommendations about travelling. Therefore, the advice given here is based on the opinions of experts. Precautions are in order, and travel to areas where sanitary conditions are poor is not recommended. Immunisations (see the Immunisations fact sheet) Specific vaccinations are required when travelling to some countries. Therefore, careful planning is essential: ideally, inactivated vaccine or component vaccine should be completed at least 2 weeks before the first abatacept infusion. However, administering the necessary vaccines is the 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, the vaccines should be given at least 2 weeks and at best 4 weeks before the first abatacept infusion. For yellow fever, at least 3 months should be allowed to elapse between the last abatacept infusion and administration of the vaccine. Can abatacept-treated patients take antimalarial prophylaxis? Antimalarial prophylaxis is not contraindicated. No major safety problems have been identified in patients 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-modifying drug 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 and placebo group regarding the rates of adverse events, serious adverse events, or treatment discontinuation because of adverse events. What other measures should be taken? Patients should be advised to carry written information (in English if possible) about their treatment (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 and beverages, and insects. Medical advice should be obtained promptly in the event of a fever or symptoms of infection. Patients travelling to remote areas where medical help is unavailable 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 common infections of the lower respiratory tract and urinary tract).

32 S34 Management of patients on abatacept in daily practice Management of patients who require surgery Evidence Based Medicine Official recommendations Expert opinion Surgery in a patient with rheumatoid arthritis (RA) treated with abatacept may, in theory, lead to infectious complications and/or delayed healing. Nevertheless, these risks have not been evaluated in detail in published studies, and no clear recommendations 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 the surgical procedure and the various biotherapy situations evaluated previously (1,2). Available data Pharmacokinetic properties The mean terminal half-life of abatacept in a dose of 10 mg/kg is 13.1 days, with a range of 8 to 25 days. Published cases No information is available about patients with RA who underwent surgery after abatacept therapy. Management in the event of surgery Based on the mechanisms of action of abatacept, the safety data reported in the literature, and the specific characteristics of RA patients (who are usually taking other medications), the two main concerns are: intraoperative or postoperative infection and delayed healing To date, no information is available regarding potential delays in healing in abatacepttreated patients. Clinical situations Time from the last abatacept infusion to scheduled surgery This interval should be determined on a case-by-case basis based on the factors listed below. 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

33 S35 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 must usually be postponed. The joint disease is well controlled: the 5x half-life rule yields a wide range, of 40 to 200 days. No routinely available method is available for determining the value in the individual patient. Therefore, given the elimination half-life and the absence of available clinical (pharmacokinetic) data, caution suggests that a 2-month wait from the last abatacept infusion to surgery may be adequate. Emergent surgery For patients who require immediate surgery, the experts suggest the following recommendations: 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 care Regular oral hygiene and visits to the dentist are recommended. Patients with oral or dental health problems should receive appropriate treatment before starting abatacept therapy: 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).

34 S36 Management of patients on abatacept in daily practice Management of drug-drug interactions Evidence Based Medicine Official recommendations Expert opinion The initiation of abatacept therapy in combination with conventional DMARDs or after the use of other biologics raises many questions that currently converge toward three major issues regarding drug-drug interactions. However, data from the ASSURE trial also showed that abatacept in combination with another conventional DMARD seems effective and raises no major safety issues. Combined use of abatacept and another biologic, most notably a TNF antagonist, is associated with an increased risk of serious adverse events and therefore is not recommended. Pharmacokinetic data have shown that methotrexate, NSAIDs, and glucocorticoids have no influence on the clearance of abatacept. Abatacept combined with another biologic 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 of abatacept used concomitantly with other biologics (TNF antagonist or anakinra). The adverse event rate was increased nearly 2-fold with, in particular, the serious infections and malignancies detailed in Table 5. In contrast, no opportunistic infections were reported. Table 5 Serious adverse events in the groups treated with abatacept and biologics in the ASSURE study (36) 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% *biologic = TNF antagonist or anakinra

35 S37 In patients on TNF antagonist therapy, should there be a waiting period between discontinuing the TNF antagonists and starting abatacept? The ARRIVE study provides the answer to this question, as it compared the efficacy and safety of abatacept started immediately after TNF antagonist discontinuation or after a washout period (59). The adverse event rate was comparable in the groups with and without a washout period after TNF antagonist discontinuation. Recommendations Abatacept/TNF antagonist In placebo-controlled clinical trials, patients receiving concomitant treatment with abatacept and TNF blocking agents experienced more infections and serious infections than patients treated with only TNF blocking agents. Therefore, concurrent therapy with abatacept 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/anakinra The data generated by the ASSURE study are not sufficient to evaluate the efficacy and safety of the abatacept/anakinra combination. Therefore, use of this combination is not recommended. Abatacept/rituximab No 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 therapy When abatacept therapy is considered in a patient previously treated with rituximab, the risk/benefit ratio should be evaluated carefully. An immunoglobulin assay by weight and lymphocyte phenotype determination may help to assess the risk of infections. A new biologic other than a TNF antagonist should not be introduced within the first 24 weeks after the rituximab infusion. Rituximab after abatacept therapy Rituximab initiation can be considered 8 weeks after the last abatacept infusion. There is no practical test (similar to Ig assay and lymphocyte phenotype determination for rituximab) for assessing immunological recovery after abatacept therapy.

36 S38 Management of patients on abatacept in daily practice Combining abatacept with conventional disease-modifying antirheumatic drugs The AIM study (24) established the efficacy and safety of abatacept combined with methotrexate in a mean dosage of 15 mg/week. When methotrexate is contraindicated or poorly tolerated, the efficacy and safety of combining another conventional diseasemodifying drug with abatacept must be considered. In the ASSURE study, patients received either abatacept or a placebo while continuing previous conventional DMARDs or biologics. An analysis of subgroups defined based on the concomitant DMARD (methotrexate, antimalarials, sulfasalazine, leflunomide, gold, or azathioprine) showed that these drugs had a good overall safety profile when used with abatacept. A higher rate of adverse events with the DMARD was seen only with leflunomide (23.6% in the abatacept group and 15.3% in the placebo group). The most commonly reported adverse events were severe infections and muscle and connective tissue complaints. Table 6 Serious adverse events reported in the groups given abatacept without biologics in the ASSURE study (36) placebo + DMARD n=418 abatacept + DMARD n=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% Recommendations about abatacept and conventional DMARDs Methotrexate is the recommended DMARD for combination with abatacept. However, when methotrexate is contraindicated or poorly tolerated, another DMARD can be used, preferably a drug with proven structural effects. In the current state of our knowledge, when a concomitant DMARD is used, there is no evidence to suggest a need for adjusting the dosage of the DMARD. The recommended methotrexate dosage is 15 mg/week; this dosage may be decreased in the event of a prolonged remission without evidence of structural progression.

37 S39 Use of abatacept alone In the event of intolerance to all available DMARDs, abatacept may be used alone. In a pilot study (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 abatacept groups than in the placebo group, and the highest response rate occurred with the dosage usually given in clinical practice (10 mg/kg) (Table 7). Table 7 Percentages of patients meeting ACR20, 50, and 70 criteria on day 85 in the groups given abatacept alone in a dosage of 0.5, 2, or 10 mg/kg and in the placebo group (61) % ACR responders on D85 placebo n=32 abatacept 0.5 mg/kg n=26 abatacept 2 mg/kg n=32 abatacept 10 mg/kg n=32 ACR20 (primary criterion) 31% 23% 44% 53% ACR50 6% 0 19% 16% ACR % 6% Combining abatacept with an antiinflammatory drug or analgesic There is no evidence suggesting that intolerance to abatacept may be increased by concomitant use of a glucocorticoid, nonsteroidal antiinflammatory drug (NSAID), or analgesic. Pharmacokinetic interactions Pharmacokinetic data show that methotrexate, NSAIDs, or glucocorticoids have no effect on the clearance of abatacept. Therefore, NSAIDs, glucocorticoids, and analgesics can be used concomitantly with abatacept.

38 S40 Management of patients on abatacept in daily practice Acknowledgments / Conflicts of interest Evidence Based Medicine Official recommendations Expert opinion Expert-panel coordinators Prof Xavier MARIETTE (14), Dr Thao PHAM (1), and Prof Jean SIBILIA (15) Members of the CRI panel Dr 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 Éric HACHULLA (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 Jean SIBILIA (15), received fees from the communications agency Katana Santé for developing these fact sheets. (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. These fact sheets were created with institutional support from Bristol-Myers Squibb Inc.

39 S41 References Evidence Based Medicine Official recommendations Expert opinion 1) Pham T, Claudepierre P, Deprez X et al. Anti-TNF alpha therapy and safety monitoring. Clinical tool guide elaborated by the Club Rhumatismes et Inflammation (CRI), section of the French Society of Rheumatology (Société Française de Rhumatologie, SFR). Joint Bone Spine 2005;72(Suppl 1):S ) Pham T, Fautrel B, Gottenberg JE et al. Rituximab (Mabthera) therapy and safety management. Clinical tool guide elaborated by the Rheumatic 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):S ) Kremer JM, Westhovens R, Le Bars M et al. Time to treatment response with abatacept in patients with rheumatoid arhritis and an inadequate 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 response to 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 Med 2005;353: ) Hunter CA, Reiner SL. Cytokines and T cells in host defense. Curr Opin Immunol 2000;12: ) Bertram EM, Dawicki W, Watts TH. Role of T cell costimulation in antiviral immunity. Semin Immunol 2004;16: ) Hunter CA, Lieberman LA, Mason N et al. Costimulation in resistance to infection and development of immune pathology: lessons from toxoplasma. Immunol Res 2003;27: ) Rose CM, Kimzey SL, Green JM. The host response of CD28-deficient mice to pneumocystis infection. Microb Pathog 2006;40: ) Marks E, Verolin M, Stensson A et al. Differential CD28 and inducible costimulatory molecule signalling requirements for protective CD4+ T-cell-mediated immunity against genital tract Chlamydia trachomatis infection. Infect Immun 2007;75: ) Bigbee CL, Gonchoroff DG, Vratsanos G et al. Abatacept treatment does not exacerbate chronic mycobacterium tuberculosis infection in mice. Arthritis Rheum 2007;56: ) Haggerty HG, Nadler SG, Simon TA et al. Utilization of host resistance models (HRMs) in the prediction of human safety of abatacept (ABA): a translational approach. Arthritis Rheum 2007;56(Suppl):S ) Sibilia J, Westhovens R. Safety of T-cell co-stimulation modulation with abatacept in patients with rheumatoid arthritis. Clin Exp Rheumatol 2007;25(Suppl 46):S ) CHMP review of data on quality, safety and efficacy of abatacept. EMEA ) Briefing document for abatacept (BMS ). FDA Arthritis Advisory Committee. 6 September ) Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra therapies for rheumatoid arthritis: 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 epidemiological assessment with >10,000 person-years of exposure. Arthritis Rheum 2008;58(Suppl 9):S ) Naz SM, Symmons DP. Mortality in established rheumatoid arthritis. Best Pract Res Clin Rheumatol 2007;21: ) Strangfeld A, Listing J. Infection and musculoskeletal conditions: bacterial and opportunistic infections during anti-tnf therapy. Best Pract Res Clin Rheumatol 2006;20: ) Michaud K, Wolfe F. Comorbidities in rheumatoid arthritis. Best Pract Res Clin Rheumatol 2007;21: ) Prévention et prise en charge des tuberculoses survenant sous anti-tnf. AFSSAPS Juillet ) Furst DE, Breedveld FC, Kalden JR et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, Ann Rheum Dis 2007;66(Suppl 3):iii ) 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: ) 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: ) Schiff M, Keiserman M, Codding C et al. Efficacy and safety of abatacept or infliximab versus placebo in ATTEST: a phase III, multicenter, randomized, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis ) Bruce SP, Boyce EG. Update on abatacept: a selective costimulation modulator for rheumatoid arthritis. The Annals of pharmacotherapy 2007;41: ) Bristol-Myers Squibb: Summary of product characteristics ) Smitten A, Simon T, Qi K et al. Malignancies in the abatacept RA clinical development program: an updated epidemiological assessment with >10,000 person-years of exposure. Arthritis Rheum 2008;58(Suppl 9):S ) Quezada SA, Peggs KS, Curran MA et al. CTLA-4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 2006;116:

40 S42 Management of patients on abatacept in daily practice 30) Lute KD, May KF Jr, Lu P et al. Human CTLA-4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-ctla-4 antibodies. Blood 2005;106: ) Hodi FS, Mihm MC, Soiffer RJ et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 2003;100: ) Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 2005;175: ) Phan GQ, Yang JC, Sherry RM et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003;100: ) Solomon DH, Karlson EW, Rimm EB et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003;107: ) Maradit-Kremers H, Nicola PJ, Crowson CS et al. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 2005;52: ) Weinblatt M, Combe B, Covucci A et al. Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. Arthritis Rheum 2006;54: ) 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: ) Abrams JR, Lebwohl MG, Guzzo CA et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest 1999;103: ) 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: ) Merrill JT, Burgos-Vargas R, Westhovens R et al. The efficacy and safety of abatacept in SLE: results of a 12-month exploratory study. 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 analysis with >10,000 person-years of exposure. Arthritis Rheum 2008;58(Suppl 9):S ) Tsai AF, Kaufman KA, Walker MA et al. Transmission disequilibrium of maternally-inherited CTLA-4 microsatellite alleles in idiopathic recurrent miscarriage. J Reprod Immunol 1998;40: ) Kaufman KA, Bowen JA, Tsai AF et al. The CTLA-4 gene is expressed in placental fibroblasts. Mol Hum Reprod 1999;5: ) Von Rango U. Fetal tolerance in human pregnancy A crucial balance between acceptance and limitation of trophoblast invasion. Immunol Lett 2008;115: ) Jin LP, Zhou YH,Wang MY et al. Blockade of CD80 and CD86 at the time of implantation inhibits maternal rejection to the allogeneic fetus in abortion-prone matings. J Reprod Immunol 2005;65: ) 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 unexplained recurrent spontaneous abortion in the Chinese population. Am J Reprod Immunol 2005;53: ) FDA Pharmacological review. 48) Health Canada, Summary basis of decision, Orencia abatacept. 49) Centre de Référence sur les Agents Tératogènes (CRAT) 50) Ravikumar R, Anolik J, Looney RJ. Vaccine responses in patients with rheumatoid arthritis. Curr Rheumatol Rep 2007;9: ) Tay L, Leon F, Vratsanos G et al. Vaccination response to tetanus toxoid and 23-valent pneumococcal vaccines following administration of a single dose of abatacept: a randomized, open-label, parallel group study in healthy subjects. Arthritis Res Ther 2007;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 immune response to intact Streptococcus pneumoniae is dependent on the type of antigen. J Immunol 2002;168: ) Jeurissen A, Wuyts G, Kasran A et al. The human antibody reponse to pneumococcal capsular polysaccharides is dependent on the CD40-CD40 ligand interaction. Eur J Immunol 2004;34: ) Ndejembi M, Patke D, Bingaman A. CTLA-4Ig inhibits IL-2 production and in vivo expansion of antigenstimulated memory CD4 T cells. Clin Immunol 2005;115:S ) Schaeverbeke T, Vittecoq O, Dougados M et al. Étude de la réponse immunitaire au vaccin antigrippal chez les patients ayant une polyarthrite rhumatoïde et traités par abatacept. Rev Rheum 2007;74: ) Schiff M, Kaell L, Tay L et al. Response to pneumococcal vaccine in rheumatoid arthritis patients with an inadequate response to anti-tnf therapy treated with abatacept in the arrive trial Ann Rheum Dis 2007;66 (S11) ) Tong DC, Rothwell BR. Antibiotic prophylaxis in dentistry: a review and practice recommendations. J Am Dent Assoc 2000;131: ) Weinblatt M, Schiff M, Goldman A et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann Rheum Dis 2007;66: ) Schiff M, Pritchard C, Zhou X et al. The efficacy of abatacept in patients with active rheumatoid arthritis and an inadequate response to anti-tnf-therapy: the ARRIVE trial. Arthritis Rheum 2007;56:S ) 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 Rheum 2002;46: ) Labelling Orencia (abatacept) Highlights of prescribing information, US April 2008;

41 S43 Annexe 1: Model information letter for an office-based rheumatologist Evidence Based Medicine Official recommendations Expert opinion

42 S44 Management of patients on abatacept in daily practice.., 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 intolerance 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 the following 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 administered seasonally, can be given safely after the abatacept infusion, although their effectiveness may be decreased in this situation, and administration of the influenza vaccine once a year is recommended. Live viral vaccines (yellow fever, varicella, oral polio, and MMR) are contraindicated. When administration of a live vaccine is required, abatacept therapy must be stopped at least 3 months before the vaccination and, if possible, abatacept therapy should not be re-started until at least 2 weeks and at best 4 weeks after the 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).

43 S45 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 received prophylactic antituberculous therapy. Provided adherence to the prophylactic treatment 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 performed more than 1 year ago, it should be repeated. This precaution is recommended despite the absence of data on the risk of tuberculosis during abatacept therapy. This risk cannot be evaluated accurately, as the patients included in the initial studies were screened, and those with positive screening tests were either excluded or given prophylactic antibiotic therapy. In the event of a positive screen, the recommended antibiotic therapy regimen is the same as for TNF antagonist therapy (AFSSAPS 2005). The first abatacept infusion can be given 3 weeks after starting the antituberculous drugs, which should be continued for a total of 3 months (when the isoniazid (Rimifon ) + rifampicin combination 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. In patients previously treated with rituximab, the immunoglobulin levels and circulating B-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 premalignant 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. Abatacept was given in combination with methotrexate or, in the event methotrexate was contraindicated, with

44 S46 Management of patients on abatacept in daily practice 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, more importantly, they are very rarely severe (fewer than 1% of infusions). Symptomatic treatment is sufficient in patients with mild reactions. Patients with constitutional symptoms, respiratory or cardiovascular manifestations, or diffuse skin lesions must be admitted on an emergency basis. The second injection is scheduled 14 days after the first, in the same dosage. The third injection will be given 14 days after the second injection. Thereafter, the patient will receive one 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 patient being evaluated before each infusion. However, you will continue to provide rheumatological follow-up. Your objective is to evaluate the treatment response and to provide follow-up in collaboration 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, a DAS 28 no greater than 3.2 To monitor the response to abatacept, the following should be determined at least once every 3 months: clinical disease activity (DAS 28 or SDAI), quality of life, and laboratory markers for inflammation (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]). Structural effects should be assessed by obtaining radiographs of the hands and feet about 1 year after the first abatacept infusion. Evaluating the safety of abatacept therapy Laboratory tests required to monitor are blood cell count (risk of leukopenia and thrombocytopenia, which are rare), liver function tests (transaminases) and renal function test (creatinine), which should be obtained at 3-month intervals. When selecting follow-up tests, concomitant drugs (most notably methotrexate) should be considered. No widely used immunological tests are available for monitoring and measuring the response to abatacept. 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

45 S47 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 of malignant 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 who exhibit residual disease activity (DAS 28 greater than 3.2), the treatment strategy should be reappraised in the light of other treatment options. Modalities of follow-up in dayly practice Recommendations regarding vaccinations, surgery, travelling, pregnancy, and breastfeeding are available as information sheets that you can obtain from us or from the CRI (Club Rhumatismes et Inflammation) website ( We have given the patient a written document that describes abatacept and the treatment modalities. Improving the follow-up of abatacept-treated patients and obtaining useful information The 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 on patients 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... physician s stamp Téléphone :...

46 S48 Management of patients on abatacept in daily practice Annexe 2: Model information letter for the primary-care physician Evidence Based Medicine Official recommendations Expert opinion