The incidence of serious infection in the TNF group was 4.2/100 patient-years vs 3.2/100 patient-years in the DMARD group. , in a cohort study using the French RATIO registry, found no increased risk of lymphoma in SpA patients receiving anti-TNF compared with the general population. RTX and ABA were not associated with an increased risk of NMSC in a cohort of 6841 patients with RA receiving biologics in a Medicare cohort . Patients should be advised that there is no conclusive evidence for an increased risk of solid tumours or lymphoproliferative disease linked with biologic therapy, but that ongoing vigilance is required (grade 1A, SOA 99%). There is a small amount of evidence regarding the other non-anti-TNF biologics and their effect on response to influenza vaccine. , which both reported an approximate 1.4-fold increased risk of infection in RA patients treated with anti-TNF agents compared with csDMARD controls. Dose: Treatment is usually started at one 50mg tablet daily with or after breakfast for the first week. A higher seroprevalence of 3% for HBV and 2% for HCV infection was recently reported in COMORA, an international cross-sectional study of comorbidities in RA . In the ADACTA study , which was a double-blinded parallel arm trial comparing the efficacy and safety of ADA and TCZ as monotherapy, the rates of serious infection were similar in both groups (3%). Therefore, continuation of biologic therapies in patients at increased risk can be recommended, as, in addition, higher disease activity may predispose to a prothrombotic state . Patients commenced on biologics should be closely monitored for TB while on treatment and for at least 6 months after stopping treatment (grade 2C, SOA 98%). For hepatitis B in particular, additional groups at increased risk include people who may have been exposed to sexually acquired infection. Accreditation is valid for 5 years from 10 June 2013. NICE has accredited the process used by the BSR to produce its guidance on the safety of biologic DMARDs in inflammatory arthritis. A case of severe course of COVID-19 treated with experimental therapy. Over 893 person-years of follow-up, two new genital cancers were observed in the csDMARD group vs no new genital cancers in the anti-TNF group. Liver function test derangement has also, albeit rarely, been associated with anti-TNF therapy. Varicella zoster virus, which causes chickenpox, is more common and serious in immunosuppressed individuals, as they are at risk of severe and potentially fatal disseminated varicella infections [203, 204]. Blinded, prospective studies are therefore needed before firm conclusions can be drawn about the infection risk associated with anti-TNF agents. Data from the BSRBR-RA showed no significant difference in the incidence of first MI between RA patients taking TNF inhibitors and csDMARD-treated RA controls . A description of evidence and full recommendations are given in the full guideline, available at Rheumatology online. Bukhari M, Abernethy R, Deighton C et al. For patients receiving TCZ, i.v. RA patients receiving IFX, ETN or ADA had a 37% higher risk of shingles (adjusted hazard ratio (aHR) 1.37, 95% CI: 1, 2.92) compared with csDMARD users. Separate guidelines covering the use and safety of RTX  and TCZ  in RA were published in 2011 and 2014, respectively. There is insufficient evidence to recommend the use of RTX, TCZ, ABA or UST in patients with HIV infection. Only three of these patients were classifiable as lupus, however. In terms of travel advice, yellow fever is a live vaccine and must not be given, and therefore patients should be advised not to travel to countries requiring this (e.g. Disclosure statement: J.G. It is important that patients are recruited to the appropriate national biologic therapy registries [such as the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) and the British Society for Rheumatology Biologics Register for AS (BSRBR-AS)], to enable long-term collection of real-life safety data on a large scale. Various studies have noted raised transaminases that spontaneously resolved without the need for TCZ dose change [224–228]. A registry-based study, Outcome of tocilizumab treatment in refractory ocular inflammatory diseases, Non-anti-TNF biologic modifier drugs in non-infectious refractory chronic uveitis: the current evidence from a systematic review. Decisions should be made on an individualized basis in conjunction with a respiratory physician, and with full appreciation of the limited evidence base. Similarly, in a French registry, 22% of patients developing CNS demyelination on biologics went on to develop MS despite cessation of biologic therapy . Exercise caution with TCZ in patients with diverticular disease, particularly when using concurrent NSAIDs and/or steroids (grade 2C, SOA 98%). J.M. There are some reports of successful rechallenge with anti-TNF without recurrence of neurological symptoms, but there are also reports of worsening symptoms or recurrence on rechallenge. Screening with TST or IGRA is unhelpful in patients who have had treatment for active or latent TB. Patients on biologics who develop symptoms suggestive of TB should receive full anti-TB treatment but may continue with their biologic if clinically indicated after risk/benefit analysis (grade 2C, SOA 96%). A weak recommendation denotes that the benefits are more closely balanced with the risk or more uncertain. Recommendations based on systematically reviewed evidence are given below. Screening for TB should include checking for previous TB exposure and treatment, performing a clinical examination, chest X-ray (CXR) and either a TST or an IGRA or both, as appropriate (grade 2C, SOA 98%). However, this study is confounded by the simultaneous stopping of NSAIDs on commencement of anti-TNF, perhaps leading to a reduction in insidious GI bleeding. TCZ administration, but the ANC recovered by the next infusion 4 weeks later. Interestingly, these events were not associated with infection. Patients should be assessed for co-morbidities because these may influence DMARD choice, including evaluation for respiratory disease and screening for occult viral infection (GRADE 1C, 97%). While ADA has been shown not to reduce responsiveness to immunization , some studies have suggested that ETN and INF administration is associated with decreased response rates [267, 268]. (Also refer to vaccination recommendations while on biologic therapy). There is a weak evidence base to suggest that ABA and RTX might have less effect on ILD than other biologics [165–167]. A history of previous neutropaenia on csDMARD therapy and a low baseline neutrophil count were shown to be predictors of neutropaenia. AZA: Patients should have baseline thiopurine methyltransferase (TPMT) status assessed (GRADE 1A, 97%). The GWG was composed of rheumatology consultants from various clinical backgrounds, rheumatology specialty trainees, rheumatology nurse specialists and a patient representative. Mean follow-up was 10 months, and all improved. Although this patient was receiving HAART, his CD4 count was significantly lower than other cases (<50 cells/mm3), which may explain the negative outcome.  reported 43 cases of uveitis in patients who were receiving anti-TNF treatment over a period of 8 years. HBV immunization should be considered for at risk patients (grade 2C, SOA 94%). If patients develop uveitis while on a biologic a trial of an alternative biologic could be considered, bearing in mind the latest reported relative risks (grade 1C, SOA 99%). A 2009 meta-analysis of RCTs that included five PsA RCTs and 10 AS RCTs found no significant association . Over the first 5 years of treatment the proportion of patients with IgM but not IgG or IgA below the lower limit of normal continued to increase. IgM response, however, did not change. The use of biologic therapies has transformed the management of inflammatory arthritis, with disease remission becoming an increasingly achievable goal. The mainstay of treatment for inflammatory rheumatic disease involves DMARDs. The literature search excluded any articles not available in English language and any non-human studies. For clinically urgent abnormalities, emergency access to specialist rheumatology advice, with response within one working day, should be available as per National Institute for Health and Care Excellence guidelines. Two recent studies have looked specifically at the risk of recurrence of NMSC in patients receiving anti-TNF; results from these studies have been conflicting. Use biologics with caution in patients at high infection risk after discussing risks and benefits (grade 1B, SOA 99%). The maximum licensed dose for RA is 25mg/week. Data remain scarce for the second-generation TNF inhibitors (CZB and GOL) and some of the newer non-anti-TNF biologic therapies (such as TCZ, ABA and UST). There have been no studies to date assessing the outcome of biologic-treated patients who undergo complete excision of a NMSC and continue with biologic therapy. There are no data for the two-dose schedule for immunocompromised patients, and therefore the three-dose schedule should be given if a girl has already started or is due to start anti-TNF therapy. This advice is for clinicians. Clinicians should be vigilant for progressive multifocal leukoencephalopathy (PML), which has been primarily associated with RTX but has also been reported with anti-TNF therapy. SLE criteria met were most commonly ANA positive, anti-dsDNA positive, malar rash then arthritis, with <10% having renal or CNS involvement. General practitioners, physicians in other specialties and surgeons who manage patients treated with biologic therapies may also find this guideline useful. Kapetanovic MC, Saxne T, Nilsson JA, Geborek P. Elkayam O, Bashkin A, Mandelboim M et al. Clinicians and patients should be aware that the risk of infection increases as serum IgG levels fall below normal. Targeted TB testing programmes are recommended among high-risk groups, with appropriate follow-up care. A higher risk still was identified in a smaller case–control study of 64 patients ; INF and ETN were associated with an OR of 21.8 for surgical site infection (95% CI: 1.231, 386.1; P = 0.036). Lemos LL, de Oliveira Costa J, Almeida AM et al. The aim is to provide evidence-based recommendations, which do not imply a legal obligation, for clinicians to follow when prescribing synthetic, non-biologic, anti-rheumatic drugs commonly used in management of multisystem rheumatic conditions. Recent results from several further meta-analyses of both RCTs [26, 109–115] and observational studies [116, 117] have been reassuring and have failed to find a significant association between anti-TNF use and overall malignancy in patients with RA. Data on the use of TCZ or UST in patients with a history of malignancy are lacking. Relatively fewer studies have focused on varicella zoster (chickenpox) risk and anti-TNF therapy. After adjustment, the incidence-rate ratio (IRR) compared with the ETN-treated patients was 3.1 (95% CI: 1.0, 9.5) for INF and 4.2 (95% CI: 1.4, 12.4) for ADA. In the UK, the 2016 guidance from NICE [76, 77] recommends testing all immunocompromised patients for latent TB with an IGRA alone or together with a TST—a positive result in either test should prompt consideration for treatment. Finally, the guideline does not specifically cover the safety of biosimilar preparations of branded biologics; until further clinical data are available, the safety recommendations we propose for originator biologics can be applied to their biosimilar counterparts. Kubota A, Nakamura T, Miyazaki Y, Sekiguchi M, Suguro T. Ruyssen-Witrand A, Gossec L, Salliot C et al. This advice is for clinicians. The association between anti-TNF treatment and various disorders of peripheral nerves such as Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy and mononeuropathy multiplex has been highlighted in various case series and case reports . Exposure to measles should be treated with immunoglobulin regardless of prior immunization . Several studies have found a significant association between anti-TNF therapy and risk of HZ. The audit tool can be accessed via the BSR website. Ongoing MTX was predictive of reduced response. One subgroup led the anti-TNF section, another the RTX and abatacept (ABA) section, and the third group led the TCZ and ustekinumab (UST) sections. TCZ has been noted to cause an initial rise in serum lipids [187, 221, 231], but long-term extension studies have shown them to broadly stabilize within 3 months . Most patients receiving concomitant HAART had good clinical outcomes [104–106]; the sole exception is a case report of an HIV patient with PsA in whom ETN had to be stopped due to recurrent infections . Similarly, a retrospective review of the Mayo clinic experience identified 56 RA patients who developed psoriasis while receiving anti-TNF treatment . In these studies anti-viral treatment was generally given if HBV DNA level was >105 IU/ml, although we recommend that thresholds of treatment should be decided working with a hepatologist given that European Association for the Study of the Liver guidelines recommend treatment based on a combination of raised ALT, HBV DNA level >2000 IU/ml and severity of liver disease . A significantly higher risk of NMSC was found in the psoriasis group (HR = 6.0, 95% CI: 1.6, 22.4) with a shorter time to first NMSC compared with the RA group. Patients need to be informed about the delayed action of these drugs and the need to persevere with the treatment (in the absence of side effect). In individuals due to start biologic therapy who are not in the above category, varicella zoster vaccination is recommended, in addition to vaccination of healthy susceptible close household contacts of immunocompromised patients (e.g. Higher rates of hospitalized chickenpox and shingles compared with the general population have been observed in a study combining the BIOBADASER registry with the Spanish national hospital discharge database . Studies to date continue to show that biologic (especially anti-TNF) therapies do not have a detrimental effect on HCV infection [99, 101], but it would be prudent to work closely with a hepatologist and arrange monitoring. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. There is a paucity of data specific to non-anti-TNF biologics and peri-operative care. Further research is very unlikely to change confidence in the estimate of effect. A systematic review by Levy [168, 169] concluded that ADA and INF can be considered as second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy and scleritis in patients requiring immunomodulation who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. A systematic review by Simonini et al. For Permissions, please email: email@example.com. C.C. 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