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Available online at www.sciencedirect.com

Recommendations

Recommendations for using TNF␣ antagonists and French Clinical Practice Guidelines endorsed by the French National Authority for Health夽 Vincent Goëb a,∗ , Marc Ardizzone b , Laurent Arnaud c , Jérôme Avouac d , Athan Baillet e , Alexandre Belot f , Béatrice Bouvard g , Pascal Coquerelle h , Sabrina Dadoun i , Alain Diguet j , David Launay k , Danielle Lebouc l,1 , Pierre Loulergue m , Sophie Mahy n , Pascal Mestat o , Gaël Mouterde p , Benjamin Terrier q , Coralie Varoquier r , Mathieu Verdet s , Xavier Puéchal t , Jean Sibilia u , on behalf of the Club Rhumatismes et Inflammations (CRI) a

Service de Rhumatologie, CHU d’Amiens et EA 4666, Faculté de Médecine, Université Picardie-Jules-Verne, Amiens, France Service de Rhumatologie, CH de Mulhouse, 68100 Mulhouse, France Service de Médecine Interne, La Pitié Salpêtrière, AP–HP, 75013 Paris, France d Service de Rhumatologie A, Hôpital Cochin, Inserm U1016, Institut Cochin, 75014 Paris, France e Service de Rhumatologie, Hôpital Sud, GREPI, AGIM, UJF-CNRS FRE3405, 38434 Echirolles, France f Service de Néphrologie et Rhumatologie pédiatriques, Hôpital Femme-Mère–Enfant, Hospices Civils de Lyon, Bron, Unité Inserm U851, 69677 Lyon, France g Service de Rhumatologie, CHU d’Angers, 49100 Angers, France h Service de Néphrologie-Rhumatologie, Centre Hospitalier de Béthune, 62660 Beuvry, France i Service de Rhumatologie, La Pitié Salpêtrière, AP–HP, 75013 Paris, France j Service de Gynécologie–Obstétrique, CHU, Hôpitaux de Rouen, 76034 Rouen, France k Service de Médecine Interne, Hôpital Claude-Huriez, CHRU de Lille, EA 2686, Faculté de Médecine, Pôle Recherche, Laboratoire d’Immunologie, 59000 Lille, France l 49000 Angers, France m Service de Maladies Infectieuses, Hôpital Cochin, AP–HP, 75014 Paris, France n Service de Maladies Infectieuses, CHU de Dijon, 21079 Dijon, France o Maison médicale, médecine générale, 78800 Houilles, France p Département de Rhumatologie, Hôpital Lapeyronie, CHU de Montpellier, 34295 Montpellier, France q Médecine Interne, Hôpital Cochin, AP–HP, 75014 Paris, France r Rhumatologie, Polyclinique Saint-André, 51100 Reims, France s Service de Rhumatologie, CH d’Elbeuf, 76503 Elbeuf, France t Service de Médecine Interne, Hôpital Cochin, AP–HP, Paris, France u Service de Rhumatologie, CHRU de Strasbourg, 67000 Strasbourg, France b c

a r t i c l e

i n f o

Article history: Accepted 6 August 2013 Available online 29 October 2013 Keywords: TNF␣ antagonist Etanercept Adalimumab Infliximab Golimumab Certolizumab Cancer Infection Vaccination Pregnancy

a b s t r a c t The use of TNF␣ antagonists must follow specific guidelines to ensure optimal effectiveness and safety. The French Society for Rheumatology (SFR) and Task Force on Inflammatory Joint Diseases (CRI), in partnership with several French learned societies, asked the French National Authority for Health (HAS) to develop and endorse good practice guidelines for the prescription and monitoring of TNF␣ antagonist therapy by physicians belonging to various specialties. These guidelines were developed, then, validated by two multidisciplinary panels of experts based on an exhaustive review of the recent literature and in compliance with the methodological rules set forth by the HAS. They pertain to the initial prescription of TNF␣ antagonists and to a variety of clinical situations that can arise during the followup of patients receiving TNF␣ antagonists (infections, malignancies, pregnancy, vaccination, paradoxical adverse events, surgery, use in older patients, and vasculitides). © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

夽 The Good Practice Guidelines reported herein have been endorsed by the French National Authority for Health (Haute autorité de santé franc¸aise, HAS). This endorsement means that the Good Practice Guidelines were developed in compliance with the procedures and methodological rules recommended by the HAS. Any challenges to the contents of the guidelines should be directed to the promoter of this work, that is, the French Society for Rheumatology (Société franc¸aise de rhumatologie, SFR). ∗ Corresponding author. E-mail address: [email protected] (V. Goëb). 1 Patient. 1297-319X/$ – see front matter © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2013.09.001

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Older patients Surgery Vasculitis Paradoxical adverse events Recommendations French National Authority for Health (HAS)

1. Objectives of these recommendations TNF␣ antagonists were among the first targeted immunotherapies introduced on the market. These drugs have radically changed the management of patients with autoimmune and inflammatory diseases, such as rheumatoid arthritis (RA), spondyloarthritis, Crohn’s disease, and psoriasis. The objectives of this work were to provide advice for using TNF␣ antagonists and to develop good practice guidelines based on the most recent data available. We will not discuss the indications of TNF␣ antagonists, their risk/benefit ratio, or the appropriateness in some situations of dosage adjustments. TNF␣ antagonists are used in several specialties (rheumatology, hepatogastroenterology, dermatology, and internal medicine). When using TNF␣ antagonists, ensuring optimal patient safety is a foremost concern that requires careful attention to various clinical and laboratory parameters. For instance, patients may need to receive primary or booster vaccine injections before starting TNF␣ antagonist therapy. The patient’s medical history, particularly, regarding infections or malignancies, may affect the prescription of TNF␣ antagonists. Patients receiving TNF␣ antagonist therapy may experience events requiring the expertise of physicians in other specialties (e.g. infectiologists). Surgeons may need to perform emergent or scheduled procedures in patients on TNF␣ antagonist therapy, and primary care physicians must often deal with the adverse events related to these drugs (infections and paradoxical clinical manifestations), as well as with unrelated events (e.g. pregnancy). These events require a discerning response in order to optimize patient safety while maximizing the chances of continuing a treatment regimen that is effective in controlling the underlying disease. These recommendations about the use of TNF␣ antagonists were developed by multidisciplinary panels of experts under the aegis of the French Society for Rheumatology (Société Franc¸aise de Rhumatologie, SFR) and Task Force on Inflammatory Joint Diseases (Club Rhumatismes et Inflammation, CRI), in partnership with various learned societies, such as the French-Language Society for Infectious Diseases and the French Society for Internal Medicine. The development of the recommendations provided the opportunity to collect various complementary viewpoints and to scrutinize them in the light of the most recent data, thus, ensuring that all relevant considerations receive the attention they deserve in the everyday practice of physicians in all specialties called upon to use TNF␣ antagonists.

literature and to analyze the data thus retrieved. The group included rheumatologists, infectiologists, internists, a pediatrician, a gynecologist–obstetrician, a primary care physician, and a patient (Vincent Goëb, Marc Ardizzone, Laurent Arnaud, Jérôme Avouac, Athan Baillet, Alexandre Belot, Béatrice Bouvard, Pascal Coquerelle, Sabrina Dadoun, Alain Diguet, David Launay, Danielle Lebouc, Pierre Loulergue, Sophie Mahy, Pascal Mestat, Gaël Mouterde, Benjamin Terrier, Coralie Varoquier, and Mathieu Verdet) (Supplementary data Online appendix in French). The analysis of the data focused on a number of specific topics (TNF␣ antagonists and malignancies, infections, vaccinations, pregnancy, surgery, advanced age, paradoxical events, and vasculitides). The data were taken from a selection of numerous publications, including high-powered randomized controlled trials and meta-analyses of randomized controlled trials or of decision analyses based on well conducted studies (established scientific evidence allowing grade A recommendations); low-powered randomized controlled trials, well conducted non-randomized controlled trials, and well conducted prospective uncontrolled studies, such as observational longitudinal cohort studies (presumptive scientific evidence allowing grade B recommendations); and case–control studies, controlled studies with biases, retrospective studies, case–series studies, and crosssectional or longitudinal descriptive epidemiological studies (weak scientific evidence allowing grade C recommendations). When no data were available (no scientific evidence), the recommendations were based on expert opinion. The study group experts drafted the recommendations, which were then communicated to a second group of experts (the revision task force), who anonymously suggested the modifications. The drafting task force amended the recommendations based on these suggestions then communicated them to the HAS to be validated and endorsed. Here, we present several practical recommendations that take into account the constraints unique to each of the specialties involved with managing candidates to TNF␣ antagonist therapy. These recommendations were crafted with the aim of assisting primary care physicians and specialists with their treatment decisions, both at treatment initiation (Table 1) and during the various events frequently encountered during the management of patients taking TNF␣ antagonists. However, presenting exhaustive recommendations would not be feasible and some clinical situations are therefore not discussed (such as heart failure, tuberculosis, lung diseases, and a number of commonplace or opportunistic infections). These situations may be discussed in additional recommendations developed to complement the present work.

2. Methodology The review of previously published data performed to develop the recommendations was conducted according to the methodological rules established by the French National Authority for Health (Haute autorité de santé franc¸aise, HAS). We searched several electronic databases (including PubMed, Medline, and Embase) using the specific indexing terms and retrieval matrices developed by the HAS and the various experts. This search focused on the period from January 2000 to September 2012. A multidisciplinary group of experts (the drafting task force) met several times to perform an exhaustive review of the relevant

3. Malignancies and TNF␣ antagonist therapy 3.1.1. Solid cancer 3.1.1.1. Course of action before initiating TNF˛ antagonist therapy 3.1.1.1.1. Patients with no known history of solid cancer. Before starting TNF␣ antagonist therapy, check that the patient has had the cancer screening tests recommended for his or her gender and age group (e.g. Pap smear and mammogram) (EO).

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Table 1 Recommended evaluation before in-hospital initiation of TNF␣ antagonist therapy. Perform a thorough physical evaluation Obtain advice from the relevant specialist in patients with doubtful skin lesions, gastrointestinal symptoms suggesting chronic inflammatory bowel disease, or joint symptoms suggesting rheumatoid arthritis or spondyloarthritis Check that standard cancer screening tests recommended for the patient’s gender and age group have been performed (e.g. mammograms and Pap smears). Perform any tests that have not been done Obtain lifestyle information from the patient (e.g. about travel and contact with young children at work or in the family) Check the patient’s immunization records (ideally before starting any immunosuppressant agent). Evaluate the potential benefits from any live vaccines relative to the adverse consequences of a longer time to disease control due to the delay in TNF␣ antagonist initiation (bone and joint destruction in rheumatoid arthritis, intestinal tract lesions in chronic inflammatory bowel disease, extension of psoriasis. . .) Routinely obtain serological tests for the HIV and hepatitis B and C viruses (and in some cases, the hepatitis A virus) Discuss the appropriateness of serological tests for varicella, measles, mumps, rubella, yellow fever (in previously vaccinated patients), the CMV, and Parvovirus Arrange for appropriate oral and dental care Obtain the following laboratory tests before treatment initiation: blood cell and platelet counts, renal function tests (serum creatinine and urea), urine dipstick test for protein and infection, transaminases, gamma-glutamyl transpeptidase, Quantiferon, serum protein electrophoresis, immunoglobulin assays by weight, total cholesterol, HDL cholesterol, and triglycerides Obtain an anteroposterior chest radiograph before treatment initiation: (tuberculosis. . .) and discuss the need for computed tomography of the lungs in some patients (rheumatoid lung disease. . .) Prescribe an effective contraceptive method to women of childbearing potential Teach the patient to self-administer the TNF␣ antagonist (if given subcutaneously) and to respond appropriately to specific events, such as infections (stop the TNF␣ antagonist), development of a skin lesion (seek medical advice and stop the TNF␣ antagonist), and scheduled surgery During TNF␣ antagonist therapy Perform a thorough physical examination at regular intervals (including an examination for peripheral lymphadenopathy) Obtain blood cell counts and transaminase levels every 3 months Obtain renewal of the TNF␣ antagonist prescription at the hospital once a year

Depending on the patient’s risk-factor profile, conduct investigations to look for cancer (EO). Conduct a thorough examination of the skin for pre-malignant or malignant lesions and obtain the advice of a dermatologist in the event of suspicious lesions or multiple naevi (EO). Inform the patient of the need to seek advice from a dermatologist should skin lesions develop or change during the treatment (EO). In patients with known genetic risk factors, discuss the appropriateness of starting TNF␣ antagonist therapy with an oncologist (EO). In patients with pre-malignant lesions, the appropriate specialist should be consulted before starting TNF␣ antagonist therapy. The decision to start TNF␣ antagonist therapy should be based on the risk/benefit ratio assessment and preceded by information of the patient. Follow-up should be provided in accordance with the recommendations of the appropriate specialist (EO). 3.1.1.1.2. Patients with a known history of solid cancer. 3.1.1.1.2.1. Solid cancer in the past 5 years. The initiation of TNF␣ antagonist therapy is not recommended. Preference should be given to other treatment options in this high-risk population (EO). Nevertheless, if the tumor was localized with no evidence of invasion or dissemination and if no alternatives exist to TNF␣ antagonist therapy, the initiation of a TNF␣ antagonist can be considered if agreed upon by the appropriate specialist or oncologist and after obtaining informed consent from the patient (EO).

3.1.1.1.2.2. Solid cancer more than 5 years earlier, believed to be fully eradicated. TNF␣ antagonist therapy can be initiated in patients with a history of solid cancer treated more than 5 years earlier and believed to be fully eradicated (grade C). The decision to start TNF␣ antagonist therapy should be taken jointly with the specialist who provided care for the malignancy or with an oncologist and after obtaining informed consent from the patient (EO). A risk/benefit ratio assessment should be performed in patients with a history of malignancies associated with a high risk of micrometastases, such as breast cancer and melanoma (grade C). TNF␣ antagonist therapy is contraindicated in patients with failure to complete the treatment of the malignancy and in those with lymph node involvement and/or metastatic disease (EO). 3.1.1.1.2.3. Specific case of non-melanoma skin cancer. In basal cell carcinoma, TNF␣ antagonist therapy can be initiated provided the tumor was localized and effectively treated (EO). In patients with treated squamous cell carcinoma, advice should be obtained from a specialist before starting TNF␣ antagonist therapy (EO). 3.1.1.2. Oncological follow-up during TNF˛ antagonist therapy Screening tests for cancer should be performed according to standard recommendations for the relevant gender and age group (EO). Close follow-up should be provided to patients with known premalignant lesions (EO). The skin should be examined at regular intervals and the patient informed of the need to seek advice from a dermatologist if any skin lesions develop (EO). 3.1.1.3. Course of action when cancer is diagnosed during TNF˛ antagonist therapy If a solid malignancy is diagnosed during TNF␣ antagonist therapy, the TNF␣ antagonist should be stopped (EO). A 5-year wait period after obtaining a remission of the malignancy should be respected before restarting TNF␣ antagonist therapy (EO). Nevertheless, if the tumor was localized with no evidence of invasion or dissemination and if no alternatives exist to TNF␣ antagonist therapy, a shorter wait period may be considered after discussion with the appropriate specialist or an oncologist and after obtaining informed consent from the patient (EO). 3.1.2. Hematological malignancies 3.1.2.1. Hematological malignancy in remission In patients in remission of a hematological malignancy, treatment options other than TNF␣ antagonists should be used (EO). In patients with rheumatoid arthritis (RA), preference should be given to combinations of disease-modifying anti-rheumatic drugs (DMARDs) or to rituximab (anti-CD20) (EO). In patients with diseases other than RA, TNF␣ antagonists may be used with the agreement of the hematologist, after an individual assessment of the risk/benefit ratio and after obtaining informed consent from the patient (EO). 3.1.2.2. Hematological malignancy not considered to be in remission In patients with RA and active hematological malignancies, treatment options other than TNF␣ antagonists should be considered to control the underlying inflammatory disease. Options include combined DMARD therapy and rituximab (EO). The use of a TNF␣ antagonist can nevertheless be considered depending on the nature and severity of the hematological

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malignancy, in consultation with a hematologist and after obtaining informed consent from the patient (EO). 3.1.2.3. Course of action when a hematological malignancy is diagnosed during TNF˛ antagonist therapy If a hematological malignancy is diagnosed during TNF␣ antagonist therapy, the TNF␣ antagonist should be stopped (grade C). However, after evaluating the severity of the disease, particularly, in patients with asymptomatic hematological malignancies, such as chronic lymphocytic leukemia, myelodysplastic syndrome with a good prognosis, or stable monoclonal gammopathy of undetermined significance, continued TNF␣ antagonist therapy may be a reasonable decision if taken in consultation with the hematologist and after obtaining informed consent from the patient (EO). 3.1.2.4. Course of action regarding the hematological malignancy before starting TNF˛ antagonist therapy Before starting TNF␣ antagonist therapy, a physical examination should be performed to look for evidence of acute or chronic hematological disease, and laboratory tests should be obtained including absolute and differential blood cell counts and plasma protein electrophoresis (EO). 3.1.2.5. Monitoring patients on TNF˛ antagonist therapy for findings related to hematological malignancies Patients taking TNF␣ antagonist therapy should undergo physical examinations at regular intervals to look for signs suggesting hematological disease (e.g. evidence of anemia, bleeding, or lymphadenopathy), as well as blood sampling for blood cell counts (EO). Particularly close monitoring is appropriate in patients receiving concomitant treatment with immunosuppressants, most notably azathioprine and mercaptopurine, to look for enlargement of the liver and/or spleen (risk of lymphoma) and for early and/or severe cytopenia (grade C). Plasma protein electrophoresis should be performed at regular intervals in patients with monoclonal gammopathy (EO). 4. Infections and TNF␣ antagonist therapy 4.1.1. Human immunodeficiency virus (HIV) TNF␣ antagonist therapy can be considered in HIV positive patients with inflammatory conditions warranting the use of TNF␣ antagonists (EO). In HIV positive patients, TNF␣ antagonist initiation should occur in collaboration with an HIV specialist to assess the risk/benefit ratio in the individual patient (EO). TNF␣ antagonist therapy should be started only if the CD4+ T-cell counts and viral load measurements indicate good immunological and virological disease control (EO). During TNF␣ antagonist therapy, the patient should receive regular clinical and laboratory evaluations from an HIV specialist (EO). Immunizations should be updated in accordance with the specific requirements related to HIV infection and with the contraindications related to TNF␣ antagonist therapy (EO). As no data are available on the potential interactions between antiretroviral drugs and TNF␣ antagonists, serum levels of antiretroviral drugs should be monitored during TNF␣ antagonist therapy (EO). 4.1.2. Varicella–Zoster Virus (VZV) Serological testing for VZV infection should be performed routinely before starting TNF␣ antagonist therapy, to evaluate the risk of VZV infection (EO).

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If the baseline serological test is negative, while on TNF␣ antagonist therapy, the patient should be advised to avoid contact with individuals who have varicella or herpes zoster. Should such contact occur, prophylactic anti-VZV immunoglobulin therapy (temporary marketing authorization in France) should be given within the next 96 h (EO). The varicella vaccine contains a live virus and is consequently contraindicated in patients taking TNF␣ antagonists or other immunosuppressants (EO). In patients with a negative serological VZV test before treatment initiation, administration of the varicella vaccine is recommended provided the resulting delay in initiating the immunosuppressant treatment, particularly with a TNF␣ antagonist, does not compromise the chances of controlling the underlying inflammatory disease (risk/benefit assessment in each individual patient) (EO). The herpes zoster vaccine is not available in France at the time of this writing. It contains a live virus and is therefore contraindicated in patients taking immunosuppressants. In patients who develop varicella or herpes zoster during TNF␣ antagonist therapy, the TNF␣ antagonist should be stopped at least until the infection is fully cleared. Anti-viral therapy should be started as early as possible, in compliance with recommendations for immunocompromised patients (EO). 4.1.3. Herpes simplex virus (HSV) Episodes of uncomplicated orofacial or genital herpes simplex should be managed with early anti-HSV treatment in the doses recommended for immunocompromised patients, while continuing the immunosuppressant treatment (EO). Patients with closely spaced recurrences of orofacial or genital herpes simplex (more than six episodes per year), long-term anti-HSV therapy in the dosage recommended for immunocompromised patients should be started and the situation reevaluated 6 to 12 months later (EO). 4.1.4. Malaria Patients on TNF␣ antagonist therapy who plan to travel to malaria-endemic areas should receive information from a specialist regarding vector control and chemoprophylaxis (EO). All patients on TNF␣ antagonist therapy who travel to areas of Plasmodium falciparum endemicity should receive chemoprophylaxis, even when the modalities of the trip and/or season indicate a low risk of malaria (EO). In patients who develop malaria while taking TNF␣ antagonist therapy, the TNF␣ antagonist should be stopped until full malaria recovery (EO). 4.1.5. Histoplasmosis Before starting TNF␣ antagonist therapy in patients who live in, or plan to travel to, histoplasmosis-endemic areas (e.g. French Guyana or the French Antilles), advice should be obtained from an infectiologist to discuss the possible need for serological screening tests and lung imaging (EO). 4.1.6. Legionellosis The occurrence of a lung infection in a patient on TNF␣ antagonist therapy requires routine testing for the Legionella urinary antigen and lung imaging studies, as well as the initiation of antibiotic therapy active against Streptococcus pneumoniae and Legionella pneumophila (EO).

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When a suspicion of legionellosis persists despite a negative Legionella urinary antigen test, serological tests or microbiological tests for L. pneumophila may be in order (EO). The TNF␣ antagonist should be stopped until full recovery from the infection (EO). 4.1.7. Hepatitis B virus (HBV) Patients scheduled to start TNF␣ antagonist therapy should be screened for HBV infection using tests for the HBsAg, total anti-HBc antibodies, and anti-HBs antibodies (EO). In HBV-seronegative patients, anti-HBV immunization should be performed prior to TNF␣ antagonist initiation (EO). The HBV viral load should be measured in patients at risk for HBV reactivation, i.e. with positive tests for the HBsAg and/or anti-HBs antibodies (EO). In HBsAg-positive patients (active chronic hepatitis or inactive carriage), routine preemptive treatment with a nucleoside or nucleotide analog should be given after consultation with a specialist, and the serum transaminase levels and HBV load should be monitored (after 1 month then every 3 months). If the TNF␣ antagonist is stopped, the preemptive treatment should be continued for 6 to 12 months. Occult hepatitis B2 should be managed in the same way as any chronic infection with positive HBsAg tests (EO). In patients taking nucleoside or nucleotide analogs to treat chronic HBV infection, TNF␣ antagonist therapy should not be started until the HBV-DNA tests revert to negative (EO). In patients with a history of fully eradicated HBV infection in the remote past, serum transaminase, HBsAG, and HBV-DNA levels should be measured after 1 month, then, every 3 months but there is no indication for routine preemptive treatment. In the event of confirmed HBV reactivation, anti-HBV therapy should be given. The TNF␣ antagonist is best stopped, although continued use may deserve discussion on a case-by-case basis (EO). 4.1.8. Hepatitis C virus (HCV) Before initiating TNF␣ antagonist therapy, a test for anti-HCV antibodies should be performed to screen for HCV infection (EO). TNF␣ antagonist therapy can be initiated in patients with HCV infection (EO). Initiation of TNF␣ antagonist therapy does not affect indications for anti-viral therapy (EO). Patients on TNF␣ antagonist therapy should undergo regular monitoring of serum liver enzymes and the HCV load, in consultation with a specialist. These tests should be performed after 1 month then every 3 months (EO). If symptoms suggesting vasculitis develop during TNF␣ antagonist therapy, tests for cryoglobulinemia should be performed (EO). 5. Vaccinations and TNF␣ antagonist therapy 5.1.1. Pneumococcal vaccination Pneumococcal vaccination is recommended every 3 to 5 years in patients on TNF␣ antagonist therapy (EO). The pneumococcal vaccine should be administered before starting TNF␣ antagonist therapy and, ideally, before starting methotrexate or another immunosuppressant (Grade C).

2 Occult hepatitis B is defined as negative HBsAg, positive anti-HBc, negative antiHBs, and detectable HBV-DNA.

5.1.2. Influenza vaccination Influenza vaccination is recommended once a year in patients on TNF␣ antagonist therapy (Grade C). A trivalent inactivated vaccine should be preferred for influenza vaccination (EO). 5.1.3. Vaccination against diphtheria, tetanus, and poliomyelitis (DTPolio) DTPolio vaccination according to the standard immunization schedule is recommended in adults, who should also receive one injection of the pertussis vaccine. DTPolio vaccination should be given to children according to the standard immunization schedule (EO). 5.1.4. Hepatitis B vaccination Patients with negative serological tests for the HBV should receive the HBV vaccine before starting TNF␣ antagonist therapy (EO). 5.1.5. Papillomavirus vaccination Papillomavirus vaccination should be performed according to the standard schedule recommended for the general population, i.e. in adolescents and young women between 11 and 20 years of age (EO). 5.1.6. VZV vaccination In patients with negative serological tests for the VZV, administration of the VZV vaccine 3 weeks before starting immunosuppressive therapy can be considered. However, the resulting delay in achieving control of the underlying inflammatory disease requiring TNF␣ antagonist therapy should be taken into account when evaluating the usefulness of VZV vaccination (EO). VZV vaccines are contraindicated in patients taking TNF␣ antagonists or other immunosuppressants. 5.1.7. Measles–Mumps–Rubella vaccination (MMR) MMR vaccines are contraindicated in patients on TNF␣ antagonist therapy. When the prior history of measles is in doubt, a serological test for measles should be performed (EO). Vaccination 3 weeks before the initiation of immunosuppressive treatment can be considered, but the resulting delay in achieving control of the underlying inflammatory disease requiring TNF␣ antagonist therapy should be taken into account when evaluating the usefulness of the vaccine (EO). 5.1.8. Yellow fever vaccination Yellow fever vaccination is contraindicated in patients on TNF␣ antagonist therapy. 5.1.9. BCG vaccine The BCG is a live vaccine and is consequently contraindicated in patients on TNF␣ antagonist therapy. Neonates at risk for tuberculosis whose mother received TNF␣ antagonist therapy during the pregnancy and who are not breastfed can receive the BCG after the age of 6 months (EO). In children whose mother received TNF␣ antagonist therapy during the pregnancy, and perhaps also those who are breast-fed

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by a mother receiving TNF␣ antagonist therapy, the immunization schedule should be adjusted and the vaccinations delayed to prevent the occurrence of life-threatening complications (EO). 5.1.10. Live attenuated vaccines Live attenuated vaccines are contraindicated in patients receiving TNF␣ antagonists or other immunosuppressants. If a patient is already on TNF antagonist therapy, a period of at least 3 months off is required before vaccination with a live attenuated vaccine. The recovery of the anti-TNF may be prescribed 3 weeks after vaccination. 6. Pregnancy and TNF␣ antagonist therapy The use of an effective contraceptive method appropriate for the patient’s immunological status is recommended in women of childbearing potential. The contraceptive method should be started before TNF␣ antagonist therapy initiation and continued for as long as the drug is used. The choice of the contraceptive method should take into account the increased risk of infection related to the use of immunosuppressants and to the underlying disease (EO). The currently available evidence does not support a recommendation to prefer a specific TNF␣ antagonist in women of childbearing potential with plans to have children in the future (EO). In women on TNF␣ antagonist therapy who want to initiate a pregnancy, after consultation with the specialist who prescribed the TNF␣ antagonist, the use of the contraceptive method can be stopped and the TNF␣ antagonist continued until conception occurs (EO). In men who want to conceive, there is no need to stop the TNF␣ antagonist before conception occurs (EO). As soon as the pregnancy is confirmed, the mother should stop the TNF␣ antagonist (EO). Continued TNF␣ antagonist therapy until the end of the second trimester can, however, be discussed on a case-by-case basis and in consultation with the mother and gynecologist–obstetrician if the level of disease activity puts the mother or the course of the pregnancy at high risk (EO). During the third trimester of pregnancy, TNF␣ antagonist therapy should not be used (EO). In the event of a pregnancy starting in a patient on TNF␣ antagonist therapy, there is no need to recommend termination of the pregnancy (EO). Routine prenatal visits should be provided according to the standard timetables in women on TNF␣ antagonist therapy (EO). Given the immunosuppression induced by TNF␣ antagonists, careful attention to the risk of maternofetal infection is warranted, particularly as there may be no fever (EO). If TNF␣ antagonist therapy was started or continued during the pregnancy, all the healthcare professionals providing care to the neonate must be informed of this fact so that they can adjust the management strategy, particularly, regarding the risk of infection and determination of the optimal immunization schedule (EO). 7. Surgery and TNF␣ antagonist therapy 7.1.1. Scheduled surgery TNF␣ antagonist therapy should be discontinued before scheduled surgery. The time from discontinuation to surgery is 15 days for etanercept and 4 weeks for infliximab, adalimumab, certolizumab, and golimumab (EO).

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With all TNF␣ antagonists, the treatment should be resumed only after full healing of the surgical site and in the absence of any evidence of postoperative infection. Special caution is in order in patients undergoing revision joint replacement surgery (EO).

7.1.2. Emergent surgery When emergent surgery is required, TNF␣ antagonist therapy should be discontinued until the operative site is fully healed. The appropriateness of prophylactic antibiotic therapy should be discussed in patients undergoing surgical procedures at high risk for infection (peritonitis, multiple trauma) (EO).

7.1.3. Oral and dental care Appropriate oral and dental care should be provided before initiating TNF␣ antagonist therapy, in order to minimize the risk of infection (EO). During TNF␣ antagonist therapy, usual dental care (fillings, scaling) does not require treatment discontinuation. Prophylactic antibiotic therapy may be considered depending on the patient’s profile (EO). When a patient on TNF␣ antagonist therapy requires a dental procedure at high risk for infection (dental extraction, periapical granuloma, abscess), the TNF␣ antagonist should be discontinued. Discontinuation should ideally occur at least 15 days before the procedure for etanercept and at least 4 weeks before the procedure for infliximab, adalimumab, certolizumab, or golimumab. However, emergent procedures should not be delayed in order to respect these time intervals. Prophylactic antibiotic therapy is recommended (EO).

8. Older patients and TNF␣ antagonist therapy 8.1.1. Is there an age above which TNF˛ antagonists should not be used? TNF␣ antagonist therapy is not contraindicated in patients older than 65 years of age (EO). The basis for deciding to initiate TNF␣ antagonist therapy, particularly in older patients, is a favorable balance between the expected benefits and the risk of complications, which should be assessed comparatively to that for other treatment options (glucocorticoid therapy, combination DMARD therapy) (EO).

8.1.2. Should TNF˛ antagonist dosages be adjusted in patients older than 65 years of age? No dosage adjustment is warranted based on age older than 65 years (EO). The workup performed as a preliminary to TNF␣ antagonist initiation should include a patient interview for a history of solid cancer and/or hematological malignancy, and the corresponding recommendations should be followed (see the relevant section) (EO). There is no recommendation to conduct intensified screening tests (PSA, breast imaging) before or during TNF␣ antagonist therapy in patients older than 65 years of age compared to the general population of same gender and age (grade C).

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9. Paradoxical adverse events and TNF␣ antagonists

9.1.3. Psoriasis

9.1.1. Lupus

If cutaneous psoriasis develops during TNF␣ antagonist, the advice of a dermatologist should be obtained (EO). In patients who develop psoriasis over less than 5% of their body surface area during TNF␣ antagonist therapy, the TNF␣ antagonist should be continued and topical treatments for the psoriasis should be given concomitantly. If the psoriasis persists, the TNF␣ antagonist should be stopped and another TNF␣ antagonist given (substitution of the soluble receptor for a monoclonal antibody or vice versa) (EO). If psoriasis involving more than 5% of the body surface area or palmoplantar psoriasis develops during TNF␣ antagonist therapy, an alternative treatment option to TNF␣ antagonist therapy should be sought (EO). In patients with severe psoriasis, anti-psoriasis treatment should be given and the TNF␣ antagonist should be stopped. However, if TNF␣ antagonist therapy is indispensable, provided appropriate anti-psoriasis treatment is given, the use of a different TNF␣ antagonist can be considered (substitution of the soluble receptor for a monoclonal antibody or vice versa) (EO).

A physical examination and immunological tests, including an antinuclear antibody (ANA) assay, should be performed before TNF␣ antagonist initiation to look for a preexisting autoimmune disease (grade C). The isolated appearance of ANAs in any titer does not per se warrant TNF␣ antagonist therapy discontinuation. Clinical monitoring is recommended (grade C). The follow-up of patients on TNF␣ antagonist therapy should include regular clinical evaluations for manifestations suggestive of lupus (EO). The following findings should suggest a diagnosis of lupus induced by TNF␣ antagonist therapy: asthenia and/or fever; rash over exposed areas, malar rash, discoid eruption; oral ulcers; chilblains; thrombosis, pleurisy; pericarditis; cytopenia; and exacerbation of joint or muscle pain. Patients with manifestations suggesting TNF␣ antagonistinduced lupus should undergo immunofluorescence testing for ANA, complement assays, an antiphospholipid antibody assay, and renal function tests (proteinuria and urine microscopy and culture), as well as other tests as dictated by the nature of the manifestations (e.g. Coombs test or antiplatelet antibody assay) (grade C). If needed, patients with mild skin manifestations (e.g. lupus chilblains) can be kept on TNF␣ antagonist therapy provided they received closely spaced clinical and laboratory follow-up (EO). TNF␣ antagonist therapy should be stopped in patients who have moderately severe skin and joint manifestations with no other signs pointing to a severe form of drug-induced lupus (grade C). TNF␣ antagonist therapy must be stopped in patients with severe manifestations, such as renal, neurological, cardiac, or hematological abnormalities or marked constitutional symptoms. In most patients, the administration of glucocorticoid and/or immunosuppressive therapy is required also (grade C). If the TNF␣ antagonist is stopped and the manifestations of drug-induced lupus were not severe, the use of another TNF␣ antagonist can be considered. Close clinical and laboratory monitoring is recommended to ensure the detection of a possible recurrence of drug-induced lupus (EO).

9.1.2. Sarcoidosis Before considering a diagnosis of TNF␣ antagonist-induced sarcoidosis, investigations for tuberculosis should be performed (grade B). The following tests are therefore mandatory: intradermal tuberculin test, Quantiferon-TB-Gold test, and the collection of appropriate samples for microscopy and culture to look for the tubercle Bacillus. TNF␣ antagonist therapy should be stopped in patients who develop sarcoidosis during the treatment (EO). In patients with severe manifestations or persistent sarcoidosis despite discontinuation of the TNF␣ antagonist, oral glucocorticoid therapy can be considered after ruling out other diagnoses, most notably an infection (EO). If continued TNF␣ antagonist therapy is indispensable, the TNF␣ antagonist should be changed and preference given to a monoclonal antibody, depending on their recognized indications and drug label specifications. The patient should then be monitored closely for evidence of recurrent sarcoidosis (grade C).

9.1.4. Chronic inflammatory bowel disease (IBD) Before starting TNF␣ antagonist therapy, a history of chronic IBD should be sought (EO). Before starting TNF␣ antagonist therapy in a patient with suspected chronic IBD, advice should be sought from a hepatogastroenterologist to discuss the appropriateness of an endoscopic evaluation of the gastrointestinal tract with collection of biopsy samples (grade C). In patients with chronic IBD related to the disease for which TNF␣ antagonist therapy is being considered, monoclonal antibodies to TNF␣ should be used in compliance with their recognized indications and drug label specifications rather than the soluble TNF␣ receptor (grade C). Patients on TNF␣ antagonist therapy should be investigated for chronic IBD if they develop any of the following symptoms: fever, decline in general health, abdominal pain, ddiarrhoea (particularly with mucus and blood), oral ulcers, anal fissure or abscess, and intestinal pseudo-obstruction (EO). In patients with suspected TNF␣ antagonist-induced chronic IBD, the TNF␣ antagonist should be discontinued and advice sought from a hepatogastroenterologist to discuss the appropriateness of an endoscopic evaluation of the gastrointestinal tract with collection of biopsy samples and/or of computed tomography of the intestinal tract. Investigations should be performed to look for other causes of the symptoms, such as a bacterial, parasitic, or viral infection (stool cultures with or without serological tests) (EO). If chronic IBD develops or worsens during TNF␣ antagonist therapy, substitution of a monoclonal antibody to TNF␣ for the previous TNF␣ antagonist is recommended in compliance with recognized indications and drug label specifications. Additional treatment directed at the chronic IBD may be required and may consist of mesalazine, short-term glucocorticoid therapy, and/or concomitant immunosuppressive agents (grade C). 9.1.5. Ocular manifestations In patients on TNF␣ antagonist therapy who experience a first episode of uveitis with no signs of ophthalmological severity and who are given effective local treatment, TNF␣ antagonist therapy – even with etanercept – can be continued (grade C). In patients on etanercept therapy who experience a first episode of uveitis with signs of ophthalmological severity or a poor response to local treatment, and in those who experience a recurrence after

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a first episode of uveitis, etanercept should be discontinued permanently and a monoclonal antibody to TNF␣ given instead (grade C). 10. Vasculitis and TNF␣ antagonist therapy A history of full recovery from vasculitis or the presence of active rheumatoid vasculitis does not contraindicate TNF␣ antagonist initiation (EO). If strictly cutaneous vasculitis develops during TNF␣ antagonist therapy, the TNF␣ antagonist should be discontinued until the patient recovers and investigations should be performed routinely to look for an infectious cause (grade C). If resumption of TNF␣ antagonist therapy is indispensable, the patient should be switched to a different TNF␣ antagonist (EO). If systemic vasculitis develops during TNF␣ antagonist therapy, the current TNF␣ antagonist should be stopped permanently (EO), investigations for an infectious cause performed (EO), and treatment appropriate for the severity of the vasculitis initiated (EO). The development of rheumatoid vasculitis does not contraindicate continued TNF␣ antagonist therapy (EO). Cases of vasculitis developing during TNF␣ antagonist therapy should be reported to the pharmacovigilance center (EO). 11. Conclusion These recommendations for using TNF␣ antagonists were developed using the methods endorsed by the HAS for establishing Good Practice Guidelines, with the goal of improving the quality and uniformity of practice patterns among physicians in various specialties involved with using TNF␣ antagonists or monitoring patients who require TNF␣ antagonist therapy (the main relevant diagnoses being rheumatoid arthritis, spondyloarthritis, psoriasis, chronic inflammatory bowel disease, and juvenile idiopathic arthritis). Development of these guidelines was commissioned and sponsored by the French Society for Rheumatology (Société fanc¸aise de Rhumatologie, SFR). The guidelines will be updated as mandated by the accumulation of additional published data and by the occurrence of significant changes in clinical practice.

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X. P. has been studies investigator or sub-investigator in partnership with Abbott, Schering Plough and Pfizer. He has also conducted scientifics meetings for those three laboratories. M. A. is clinical trials investigator for Wyeth/Pfizer, UCB and Schering-Plough laboratories. J. S. provided timely interventions (expertises, advices, symposia, clinical studies, training) for Roche, Chugai, Bristol Myers Squibb, Abbott, UCB, GSK, LFB, Actelion, Pfizer, Merck Sharp and Novartis. He also received research grants for Roche, Pfizer, Merck Sharp and Bristol Myers Squibb. Acknowledgments We are grateful to the Société de pathologie infectieuse de langue franc¸aise, Société nationale franc¸aise de médecine interne, and Société franc¸aise de pédiatrie for supporting this work. We thank Dr Christine Revel-Delhom, HAS physician, for her contribution to the close monitoring of the procedures used to develop the recommendations. We are indebted to the members of the task force that revised the recommendations: the rheumatologists Prof Thao Pham (Marseille), Dr Charles Masson (Angers), Prof Xavier Mariette (Kremlin-Bicêtre, AP–HP), Prof Jacques Morel (Montpellier), and Prof Daniel Wendling (Besanc¸on); the internists Prof Mohamed Hamidou (Nantes) and Prof Eric Hachulla: The haematologist: Prof Jean-Pierre Marolleau (Amiens) (Lille); the infectiologists Prof Dominique Salmon-Céron (AP–HP) and Prof Lionel Piroth (Dijon); the dermatologists Prof Hervé Bachelez (AP–HP) and Prof Denis Jullien (Lyon); the hepatogastroenterologist Prof Stanislas Pol (Cochin, AP–HP); the pediatricians Prof Isabelle Koné-Paut (Kremlin-Bicêtre, AP–HP) and Prof Pierre Quartier (Necker, AP–HP); the gynecologist Prof Elisabeth Elefant (CRAT); the patient Mr René Mazar (member of the rheumatoid arthritis patient group AFPric ); the surgeon Prof Yves Panis (Beaujon, AP–HP); and the geriatrician Prof Jean Doucet (Rouen). We thank Ms. Catherine Reillat and the Société franc¸aise de rhumatologie for their active support throughout the project.

Appendix A. Supplementary data Disclosure of interest A. B. received a remuneration from Abbott laboratory as a speaker seminar.

Supplementary data (An appendix to this article is available in French at http://www.sciencedirect.com) associated with this article can be found, in the online version, at doi:10.1016/j.jbspin.2013.09.001.