BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies

In 2001 and 2005, the BSR established and updated guidelines for the use of anti-TNF drugs in RA [1, 2]. These guidelines indicated which adult RA patients should be eligible for treatment, precautions that need to be taken in the use of anti-TNF and action that should be taken in the event of adverse effects. Previous guidelines applied to the then available anti-TNF drugs [etanercept and infliximab in 2001, and etanercept, infliximab and adalimumab (first generation anti-TNF agents) in 2005]. Due to the large volume of information now available on these agents, the BSR has produced separate guidelines on eligibility for anti-TNF treatment in RA [3]. These current guidelines cover the safety aspects of anti-TNF in RA and apply to the first generation, but also to the newly licensed second-generation anti-TNF drugs, (certolizumab pegol and golimumab). This is a rapidly changing field with new data emerging each month, so it is vital that clinicians keep up to date with this area of practice. These guidelines have incorporated information that was available to the authors at the time of their completion (November 2009). Details of the literature search and evidence base underpinning these recommendations can be found online [4]. Anti-TNF should not be initiated in the presence of serious active infections. Anti-TNF should be discontinued in the presence of serious infections, but can be recommenced once the infection has resolved. Use anti-TNF therapy with caution in patients at high infection risk after discussing the relative risks and benefits. Prior to commencing anti-TNF, all patients should be screened for mycobacterial infection (using latest national guidelines). Active mycobacterial tuberculosis infection needs to be adequately treated before starting anti-TNF. Prior to commencing anti-TNF, consideration of prophylactic anti-mycobacterial therapy (as directed by the latest national guidelines) should be given to patients with potential latent disease. All patients commenced on anti-TNF should be closely monitored for mycobacterial infection. This should continue for at least 6 months after stopping treatment. Patients on anti-TNF who develop symptoms of mycobacterial infection should receive full anti-mycobacterial chemotherapy, but may continue with their anti-TNF if clinically indicated. Patients on anti-TNF should be informed of appropriate food hygiene. Health-care professionals managing patients on anti-TNF should be aware of the risk of opportunistic infections in patients on anti-TNF. They should have a high index of suspicion for atypical and opportunistic infections and anti-TNF should be promptly stopped in suspected cases and patients should have rapid access to specialist health care for consideration of early anti-bacterial/anti-fungal treatment. If a patient on anti-TNF, or a household contact, develops primary varicella (chickenpox), and the risks from infection are perceived to be significant, the patient should be considered for varicella zoster immune globulin. Shingles should be treated conventionally. Screening for risk factors for HBV infection should be performed prior to commencing anti-TNF and HBV tests should be performed in patients with risk factors. In patients who are HBV positive, a risk:benefit assessment should be undertaken, as anti-TNF treatment may be safe if appropriate anti-viral treatment is given. Close monitoring of serum aminotransaminases and HBV DNA load during therapy should be considered in patients with HBV treated with anti-TNF and concomitant anti-viral treatment would be recommended. Patients with serological evidence of cleared past infection should have their HBV serology monitored during therapy and may require concomitant anti-viral treatment if detrimental changes develop. Screening for risk factors for HCV infection should be performed prior to commencing anti-TNF and HCV tests should be performed in patients with risk factors. Studies to date suggest that anti-TNF does not have a detrimental effect on HCV infection but anti-TNF should continue to be used only with caution in such patients. Close monitoring of serum aminotransaminases and HCV RNA during therapy should be considered in patients with HCV treated with anti-TNF. Risk factors for HIV infection should be documented prior to commencing anti-TNF and, if present, an HIV test should be done. In considering anti-TNF use in HIV positive patients, it should be borne in mind that a reasonable benefit:risk ratio for HIV patients exists if: HIV infection is controlled and patients are not severely immunosuppressed; anti-TNF is given in combination with highly active anti-retroviral therapy; and close monitoring of viral load and CD4 count is undertaken and treatment changes are made in light of results. In RA patients on anti-TNF, the potential benefit of preventing post-operative infections by stopping treatment (different surgical procedures pose different risks of infection and wound healing) should be balanced against the risk of a peri-operative flare in RA activity. If anti-TNF is to be stopped prior to surgery, consideration should be given to stopping at a time 3–5× the half-life for the relevant drug before surgery. Anti-TNF should not be restarted after surgery until there is good wound healing and no evidence of infection. Until further evidence is available, the British Society for Rheumatology recommendations on the use of immunizations in patients on immunosuppressive therapy should be adhered to in patients on anti-TNF. Although there may be an attenuated response (particularly if MTX is being co-prescribed), patients on anti-TNF should receive both influenza and pneumoccocal immunizations unless there are contraindications. Prior to commencing anti-TNF, HBV immunization should be considered for at risk patients. Patients commencing anti-TNF should be informed that overall there is no conclusive evidence for an increase in risk of solid tumours or lymphoproliferative disease above that expected for the rest of the RA population, but ongoing vigilance is required. Patients should be investigated for potential malignancy if clinically suspected, and anti-TNF should be stopped if malignancy is confirmed. Caution should be exercised in the use of anti-TNF in patients with previous malignancy. The effect of anti-TNF on pre-malignant conditions is unknown. Caution should be exercised in the use of anti-TNF in such patients. Patients should be advised that there appears to be an increased risk of some skin cancers with anti-TNF and on preventative skin care and skin surveillance. Patients should promptly report any new persistent skin lesions. If a lupus-like syndrome or other significant autoimmune disease develops while on anti-TNF, treatment should be discontinued and appropriate interventions should be initiated. Re-challenging with anti-TNF should only be undertaken with caution. Anti-TNF should not be given when there is a clear history of multiple sclerosis and should be used with caution with other demyelinating diseases. Anti-TNF should be withdrawn if demyelination occurs and the patient should be referred for specialist investigation. Anti-TNF should not be initiated in patients with New York Heart Association (NYHA) Grade 3 or 4 cardiac failure (CF) and should be used with caution in patients with mild (NYHA Grade 1 or 2) CF. Anti-TNF should be discontinued if CF develops or worsens while on treatment. For all patients on anti-TNF full blood count should be monitored regularly. Precautions against pregnancy should be exercised in both female and male patients treated with anti-TNF (or their partners). Continuation of anti-TNF therapy could be considered in patients wishing to conceive/father a child if the risks of stopping treatment are perceived to be high. Consideration should be given to stopping anti-TNF in a woman who becomes pregnant on treatment but continuation of anti-TNF therapy could be considered if the risks of stopping treatment are perceived to be high. The pros and cons of breastfeeding in patients treated with anti-TNF therapies should be considered on an individual basis. Patients with pre-existing interstitial lung disease (ILD) should have monitoring of their lung function if treated with anti-TNF, and consideration should be given to stopping anti-TNF in patients with worsening, or new features of ILD. If psoriasis develops in patients treated with anti-TNF, conventional psoriasis treatment should be started and consideration should be given to stopping anti-TNF if the skin lesions persist despite specialist dermatology treatment and advice or are particularly severe. If patients develop uveitis while on anti-TNF, a trial of an alternative anti-TNF agent could be considered. Anti-TNF should be used with caution in patients with a history of previous uveitis and the relative risks of the available anti-TNF agents should be reviewed prior to selecting which treatment to use. Disclosure statement: J.L. has no personal conflicts of interest. Her department has received support from all the companies for educational meetings and specifically from Wyeth for its patient education programme and from Abbott for anti-CCP testing for its patients and for the purchase of an ultrasound machine. A.B.’s organization has received educational grants from MSD (Schering-Plough), Abbott, Pfizer (Wyeth) and UCB. R.A. has previously sat on an advisory board for Roche and received honoraria for talks at symposia sponsored by Wyeth and Abbott. She has received personal support from Wyeth and Abbott to attend international educational meetings and the Department of Rheumatology at St Helens Hospital has received sponsorship from Wyeth, Abbott, Roche, Bristol-Myers Squibb and Schering-Plough Pharmaceuticals for support of clinical meetings. M.B. has attended meetings organized by Schering Plough and Wyeth, has been sponsored to attend international meetings by Pfizer, Merck, Roche, Wyeth and Abbott, and has accepted honoraria for educational meetings from Merck, Wyeth, Abbott, Roche, UCB Celltech, Mennarini and Pfizer. He has also departmental sponsorship for software from Wyeth, Abbott and Roche. R.L. has received financial support from Wyeth, Roche and Abbott to attend ACR and EULAR meetings. S.W. has received an unconditional education grant from Abbott as part of the 3E project. A.O. has received support from (including attendance at conferences), undertakes clinical trials and acts as a consultant to Roche, Chugai, Schering-Plough/MSD, Abbott, Wyeth, BMS, GSK, MerckSorono and UCB. P.K. has received departmental support for service and research from Sanofi-Aventis, Schering-Plough and Wyeth and has received advisory fees, speaker fees and unrestricted educational grants from Abbot, Bristol Myers Squibb, Novartis, Roche, Schering-Plough, UCB and Wyeth. K.G. sits on advisory boards for Schering-Plough, UCB and Roche and has received honoraria for talks at symposia sponsored by Wyeth, Abbott and Roche. C.D. has received honoraria for talks at symposia sponsored by Wyeth and Abbott. The Department of Rheumatology at Derbyshire Royal Infirmary has received sponsorship from Wyeth, Abbott and Schering-Plough Pharmaceuticals for support of clinical meetings, and unrestricted grants to support a US machine, an anti-TNF audit clerk and research nurse. All other authors have declared no conflicts of interest.