Patients with RA are treated with csDMARDs, bDMARDs, or tsDMARDs with the aim of achieving clinical remission or, failing that, a disease with a low inflammatory load. During the course of treatment, efficacy and safety parameters are taken into consideration. There is some evidence that the use of bDMARDs and tsDMARDs is associated with increased infection rates compared to csAMARDs and/or placebo. The data comes from both RCTs and real-life post-marketing data. Sometimes, these real-life studies do not include the existing comorbidities or concomitant drugs (glucocorticoids, among others) of these patients, which undoubtedly influence a higher or lower rate of infections. The increased susceptibility to infections in patients with RA has been attributed to the pathophysiology of the disease, associated comorbidities, lifestyle factors such as smoking and obesity, and the use of drugs such as glucocorticoids and immunomodulators.16

Patients with RA treated with standard-dose bAMARDs (with or without csAMARDs) have a higher incidence of serious infections compared to those treated with cFMARD (OR: 1.31; CI 95%: 1.09–1.58). Therefore, it is advisable to screen prior to the start, an indication that assesses each case individually, and frequent monitoring of clinical and biological parameters.17

For tsDMARDs, the data show that the short- and long-term safety of JAK inhibitors was comparable to that of bDMARDs. As potent immunosuppressive agents, the incidence rates of infections, including opportunistic infections, are comparable to those of bDMARDs, with the exception of the rate of herpes zoster infections, which is slightly higher for JAK inhibitors. Analyses of subsequent RCTs on baricitinib and upadacitinib have suggested a possible dose-dependent infection risk pattern.18 Thus, in the current context, it has been shown that JAKi are clearly superior in efficacy compared to placebo in improving signs, symptoms and health-related quality of life in patients with RA in the short term. However, safety analyses have shown that the risk of adverse effects and infections is slightly higher in the case of the four tsDMARDs: tofacitinib, baricitinib, upadacitinib and filgotinib, especially with regard to the reactivation of herpes zoster.19

The perception of the safety of JAKi has changed following the publication of the results of the ORAL Surveillance post-marketing safety study. Because of potential safety concerns seen with higher doses of tofacitinib, the FDA ordered this study, which compares tofacitinib 5 mg and 10 mg twice daily with anti-TNFs in patients with active RA and insufficient response to methotrexate. Similarly, due to initial data suggesting an increased risk of thromboembolic events with higher doses of baricitinib, the FDA is requesting two post marketing safety studies that are still in development. ORAL Surveillance included patients who were ≥50 years of age and had at least one cardiovascular risk factor. The two primary targets were major adverse cardiac events and malignancies, excluding non-melanoma skin cancer. Other cardiovascular events, including venous thromboembolism, deep vein thrombosis, and pulmonary embolism and infections, were included as secondary endpoints. The study was designed as a non-inferiority comparison with the non-inferiority margin established as the upper limit of CI 95% at <1.8 for the primary comparison between the two combined doses of tofacitinib versus anti-TNF6.

The study failed to achieve its primary endpoint, i.e., tofacitinib did not demonstrate non-inferiority to anti-TNFs for MACE and malignancies. The upper limit for both crossed the 1.8 margin. In addition, there was an increased incidence of venous thromboembolism, deep vein thrombosis, and pulmonary embolism with tofacitinib, observed mainly in the 10 mg20 group. The risk of infection also increased with both doses of tofacitinib versus TNF inhibitors, especially herpes zoster.21

More recently, the European Pharmacovigilance Risk Assessment Committed (PRAC) has issued a recommendation based on these results to minimise risks in patients with inflammatory diseases and the use of tsDMARDs. These risks are considered class effects for all tsDMARDs indicated in inflammatory diseases. In the case of treating a patient with any of the aforementioned risk factors because no other therapeutic alternative is available, the dose should be reduced.22

One of the most effective measures to minimise risks while maintaining efficacy has been the optimisation of drug doses, once the therapeutic objective has been achieved and guided by the clinical, serological/biological status, or imaging methods. Optimisation ensures an optimal dose of the drug, with a reduction in possible adverse effects attributed to it. However, the evidence of its benefit/risk balance should be better evaluated. In addition, the observation that frail elderly patients have higher infection rates than younger patients has increased precautionary measures in this population.23–25

Thus, there is a clear need to analyse the available evidence on the risk of serious infections associated with the use of targeted biological and synthetic drugs used in these patients.

Recommendation 4. In patients with RA who are about to start treatment with biological DMARDs or targeted synthetic DMARDs, it is recommended that a prior holistic assessment of the risk of infection be done, considering factors such as age, concomitant treatment and the existence of comorbidities and administration of vaccines to correctly estimate the potential risk factors for severe infection. (BPC recommendation.)

Recommendation 5. In patients with RA without risk factors for infection, targeted biological or synthetic DMARDs could be used safely. (Weak recommendation in favour.)

Recommendation 6. In patients with RA aged ≥65 years and with pulmonary comorbidity or a history of smoking, the use of JAK inhibitors is suggested only in the event that there are no suitable therapeutic alternativess (BPC recommendation.)

Recommendation 7. In patients with RA who have risk factors for severe infection, where targeted synthetic DMARDs have to be used, it is suggested that the lowest dose be used and other risk factors monitored. (BPC recommendation.)

Hepatitis B is an immune-mediated disease caused by the hepatitis B virus (HBV). A cytotoxic and humoral response to infected hepatocytes is produced, triggering cytolysis leading to hepatitis. Therefore, the immune status of the patient who suffers from it is extremely important, since the response to the virus and viral replication depends on this being competent.

HBsAg positivity for more than 6 months is the marker of chronic HBV infection. Chronic hepatitis B is a dynamic process, between virus replication and host immune response. Since it is a non-cytopathic virus, liver injury is caused by the immune response, and the increase in the level of transaminases indicates the presence of inflammation (hepatitis).40

To identify hepatitis B infection, the presence of the HBV core antigen (anti-HBc) and HBV surface antigen (HBsAg) antibody must be determined. In all patients with positive anti-HBc Ac, it should also be determined whether HBsAg is negative, Ac anti-HBs (anti-HBs seroconversion). In patients with chronic hepatitis B, it is important to determine HBeAg and its antibody, anti-HBe, since the HBeAg-positive or negative forms have a different evolution and their treatment may be different and quantify viral DNA by PCR (viral replication marker and only mode of detection of occult infections in patients with positive anti-HBc and negative anti-HBs antigen).

In its natural history, four phases of active infection can be differentiated - not necessarily sequential (Table 3), and a phase of functional healing.

• 1

  Phase of chronic HBeAg positive infection (before, immunotolerance). This is characterised by the presence of HBeAg, very elevated HBV-DNA levels, normal ALT values, mild necroinflammatory activity or normal liver on liver biopsy, and slow or no progression of fibrosis. This phase is typical of young people (<40 years) who have acquired the virus by vertical transmission, when the immune system is still immature.

• 2

  Chronic hepatitis phase or HBeAg positive immune activity. This is characterised by the presence of HBeAg, a decrease in the level of HBV-DNA compared to those observed in the previous phase, high or fluctuating ALT values, and an increase in histological activity with progression of fibrosis.

• 3

  Chronic hepatitis phase HBeAg negative. In some patients with chronic HBV infection, inflammatory activity persists in the absence of HBeAg positivity. This phenomenon is mostly due to infection by viruses that have certain mutations in the genome that prevent infected hepatocytes from producing HBeAg. Chronic HBeAg-negative hepatitis B is very common in the Mediterranean area and the East and is currently the most common form of chronic hepatitis B in our environment.

• 4

  Chronic infection phase HBeAg negative (formerly, inactive carrier). It is defined by having HBeAg negative and anti-HBe positive, persistently normal ALT values with low HBV-DNA levels (generally less than 2000 IU/mL). Quantification of HBsAg (qHBsAg) level may be useful to differentiate this phase from patients in the grey area (normal ALT or <1.5 times the upper limit of normal with oscillating HBV-DNA >20,000 IU/mL). qHBsAg levels below 1000 IU/mL are highly suggestive of chronic HBeAg-negative infection. The long-term prognosis of patients in this phase is generally good, although sometimes reactivations of the infection occur with elevations in the level of HBV-DNA and ALT, so it is advisable to monitor these parameters at least once a year.

• 5

  Functional healing phase after loss of HBsAg. It is defined by HBsAg-negative with or without anti-HBs, anti-HBc-positive, and is characterised by normal ALT values and usually undetectable serum HBV-DNA levels. Loss of HBsAg in patients without advanced fibrosis is associated with minimal risk of cirrhosis, decompensation, and hepatocellular carcinoma (HCC), and improved survival.

People with chronic infection (HBsAg positive) or previous contact with HBV (HBsAg negative and anti-HBc positive regardless of anti-HBs) who receive immunosuppressive treatments or biological drugs are at risk of reactivation of the infection, the severity of which can range from asymptomatic and transient elevation of transaminases to fulminant hepatitis.

HBV reactivation is defined as an increase in viral replication (usually >1 log of HBV-DNA) in people with detectable viral load or as HBV-DNA positivity in people with undetectable viral load or resolved infection. Host, virus, and type of immunosuppressive therapy factors associated with an increased risk of HBV reactivation have been described. The level of immunosuppression required to produce reactivation in HBsAg-positive patients is lower than in those with HBsAg-negative and anti-HBc-positive.

In situations of immunosuppression, patients with a serological pattern of chronic infection or functional cure may have an elevated viral load in the blood (known as reactivation), with reappearance of surface antigens and elevation of transaminases, which can lead to acute or even acute liver failure.41

Treatment of RA includes immunomodulatory and immunosuppressive drugs (DMARDs) that have changed the prognosis of the disease. However, it is a priority to know what the risk of these treatments is, since the inhibition of certain inflammatory pathways can also lead to reactivation of infections that had previously been stopped by a competent immune system. Cases of HBV reactivation have been observed in patients with RA in relation to the administration of csDMARD,42 or with bDMARD43 or DMARDs. But it is necessary to know what the real risk of activation is with all the drugs used.

Recommendation 8. In patients with RA who are about to start treatment with biological DMARDs or targeted synthetic DMARDs, it is recommended that their serological status of hepatitis B be asked for by determining HBsAg and anti-HBc. (BPC recommendation.)

Recommendation 9. In HBsAg positive cases, patients should be referred to the specialist for evaluation and diagnosis to establish which phase of HBV infection they are in. In HBsAg-negative and anti-HBc-positive cases, the study should be completed by determining HBV-DNA and, if this is detectable, patients should be managed as for the HBsAg-positive group. (BPC recommendation.)

Recommendation 10. In patients with RA with an inactive carrier pattern or functional cure due to HBV, what is suggested is the use of anti-TNF-alpha, IL-6R inhibitors, or JAK inhibitors. (BPC recommendation.)

Recommendation 11. In patients with RA with a pattern of chronic infection or functional cure for HBV, it is suggested that rituximab be avoided and, although the available evidence is insufficient, the development group suggests also avoiding abatacept, if prophylaxis is not desired. (Weak recommendation against.)

Recommendation 12. In those patients with a pattern of chronic infection or functional cure of HBV, in whom treatment with rituximab or abatacept is considered necessary, the developing group suggests the use of HBV reactivation prophylaxis. (BPC recommendation.)

Recommendation 13. In patients with RA with a pattern of chronic infection or functional cure of HBV, treated with targeted biological or targeted synthetic DMARDs, where viral reactivation prophylaxis has not been given, liver enzyme monitoring is necessary every 3 months. (BPC recommendation.)

Recommendation 14. In patients with chronic HBV hepatitis, it is recommended that initiating reactivation prophylaxis be considered (together with the hepatologist) before initiating treatment. (BPC recommendation.)

The SR has identified only observational studies,44–63 many of them retrospective, where most are along the same lines, showing that the risk of HBV reactivation in patients with past infection is very low when treated with anti-TNF, anti-IL-6R and tsDMARDs. The use of this type of drug in the management of RA has amply shown its benefits for the joints, as well as mortality and cardiovascular risk. The recommendation is weak due to the small number of studies and the quality of the available evidence, however it is in favour of treatment with these drugs, as the benefits outweigh the risks of HBV reactivation.

Regarding the use of abatacept and rituximab, although the data are inconclusive due to the types of studies identified (with probable patient selection bias), the mechanism of action of these drugs and the recommendations of the expert groups, together with the availability of other drugs that appear to be safer, makes them unadvisable for use in patients with a history of past HBV infection, if prophylaxis cannot be given. In the case of rituximab, based on the evidence identified, consensus documents and its own criteria, the Panel considers that the risk-benefit ratio advises against its use in these patients unless prophylaxis is previously initiated to avoid HBV reactivation, and that prophylaxis should be extended at least one year after the end of treatment with rituximab.

Finally, the group considers that there is not enough evidence to issue treatment recommendations in patients with chronic HBV infection, although it is specified that the assessment of prophylaxis together with the hepatologist may be beneficial. This could improve patients' chances of treatment.

A detailed description of the evidence considered and the process that has led from evidence to recommendations can be found in Appendix B's Supplementary material.

Herpes zoster (HZ) is caused by the chickenpox-zoster virus, the same virus that causes chickenpox. After having chickenpox, the virus lies dormant in the dorsal ganglia near the spinal cord. The virus is kept under control, however when it undergoes change, the virus can reactivate as HZ or “shingles”, which is characterised by a painful, unilateral vesicular rash, usually in a single dermatome that can spread in cases of profound immunosuppression. HZ causes a great deal of morbidity, including pain, depression, and long-term disability in the form of post-therapeutic neuralgia, pain that continues after the rash has subsided or disappeared.

The incidence rates of HZ in the healthy general population aged 50–59 years are 6.7 cases per 1000 person-years,64 and in the 60−90 year age group, it is approximately 10 cases per 1000 person-years in the unvaccinated group.65 The risk and severity of HZ increases with age and in situations where cellular immunity, responsible for keeping the chickenpox virus under control, such as systemic lupus erythematosus (SLE) and RA, is impaired. In SLE and RA, the incidence rates per 1000 patient-years are about 20 and 13 cases, respectively.66,67

Antiviral medications approved for the treatment of HZ include acyclovir, valacyclovir or famciclovir, which reduce the severity and duration of HZ but may not prevent pain caused by HZ or the development of postherpetic neuralgia, which can persist for years and may be refractory to treatment.68

The increased risk of HZ infection from immune-mediated diseases may be caused by the inflammatory disease itself, as well as by the use of immunosuppressive treatments. This increase has been described in association with the use of corticosteroids, especially in relation to dose and DMARDs, which are related to their mechanism of action. bDMARDs increase the risk of HZ compared to csDMARDs, and tsDMARDs can increase this up to 3 fold.

Recommendation 15. In patients with RA who are going to start treatment with biological DMARDs or targeted synthetic DMARDs, it is recommended that the risk of reactivation of herpes zoster infection be assessed, considering: age, vaccination status, concomitant treatment with steroids and their dose, the presence of other comorbidities, and a history of previous infection. (BPC recommendation.)

Recommendation 16. In patients with RA on treatment with modifier drugs, whether classical, biological or targeted synthetic drugs, it is recommended that administration of the vaccine with attenuated viruses be avoided due to the risk of zoster infection associated with immunosuppression. (BPC recommendation.)

Recommendation 17. In patients with RA who are going to start treatment with biological DMARDs, it is recommended that the need for vaccination be assessed according to the treatment indicated and the presence of other risk factors described above. (BPC recommendation.)

Recommendation 18. In patients with RA who are about to start treatment with targeted synthetic DMARDs, vaccination with recombinant herpes zoster vaccine is recommended. (BPC recommendation.)

The SR has identified a total of 15 studies, including RS29,69,70 RCTs71–75 and observational studies9,76–81 that have focussed on evaluating the reactivation of herpes zoster infection, the spread of the infection to other areas, and the occurrence of serious events such as postherpetic neuralgia. None of the identified studies recorded any cases of postherpetic neuralgia. Additional considerations derived from two other studies have been included.21,82

The evidence is conclusive regarding the frequency of HZ infection in patients treated with tsDMARDs in comparison with the csDMARDs or between them. Additional considerations from the ORAL Surveillance study showed an increased risk of HZ reactivation in patients over 65 years compared to those between 50  and 65 years, in all treatment groups. However, the development group has considered the favourable benefit-risk balance in favour of the use of b/tsDMARDs in patients with RA, since these drugs have great benefits for the patient, without this meaning a high risk of reactivation of the HZ, in most cases and especially now that there is a recombinant vaccine.

The Panel has taken into account safety studies and registries that have identified other factors influencing the risk of HZ reactivation. Age, sex, use of glucocorticoids (SLN), place of origin (Asia vs. Europe) or previous infections are factors that appear to be associated with an increased risk of HZ.66,67,83,84

In general, live attenuated vaccines should be avoided in patients on immunosuppressive therapy, as these vaccines contain live attenuated microorganisms that could theoretically cause infections in the immunocompromised population. Regarding vaccination against HZ, a study in patients with immune-mediated diseases has evaluated the safety of live attenuated vaccine. In patients aged 60 years or older treated with immunosuppressants, including bDMARDs, no increase in the incidence of vaccine-related HZ was demonstrated in the first few days after vaccination.85 Finally, the 2019 update of the EULAR recommendations on vaccination in patients with immune-mediated diseases also includes similar recommendations on HZ vaccination.10

Thus, the development group, based on the evidence, their clinical experience and their own criteria, has issued a recommendation that is in favour of evaluating the possible risks of reactivation of HZ infection and another against the administration of the vaccine with attenuated viruses due to immunosuppression and the fact that a recombinant vaccine already exists. In addition, a PCB recommendation has been issued in favour of recombinant vaccine prior to treatment with bDMARDs, depending on risk factors, and another in favour of vaccine before tsDMARDs in all cases. As there is a recombinant vaccine suitable for everyone, the Panel has ruled out the possibility of not recommending certain treatments in patients at high risk of HZ reactivation.

No data have been found on the effect of recombinant vaccine in reducing the incidence of HZ in RA patients treated with bDMARDs or tsDMARDs.

A detailed description of the evidence considered and the process that has led from evidence to recommendations can be found in Appendix B's Supplementary material.

The association between cancer and RA was first described in 1978 when it was identified that RA patients had an elevated risk of lymphoma.86 Since then, multiple studies have been published on the incidence of cancer in RA patients, sometimes with mixed results. A 2015 meta-analysis, which included 23 observational studies, comparing cancer risk in RA patients versus the general population, calculated an overall standardised incidence rate (SIR) for all cancer types of 1.09 (95%CI 1.06–1.13) for patients with RA.87 The overall SIR for lymphoma was 2.46 (95% CI 2.05–2.96), 3.21 (95% CI 2.42–4.27) for Hodgkin lymphoma, and 2.26 (95% CI 1.82–2.81) for non-Hodgkin lymphoma. It was also suggested that there is an increased risk of melanoma in patients with RA (SIR: 1.23; CI 95%: 1.01–1.49), although a more recent analysis of several European registries has not confirmed this association.88

Following the large increase in immunosuppressive drugs available for the treatment of RA, interest has been aroused in the effect that new therapies may have on the development of cancer. There are numerous registries and observational cohorts analysing the relationship between biological therapies and the development of cancer in patients with RA.89–93 The evidence from these observational studies does not show that there is an increased risk of cancer in general, however it is possible that there is a greater risk of specific neoplasms.94 Therefore, a specific assessment of the risk of certain cancers is required in RA patients treated with advanced therapies, including skin cancer and haematological malignancies.

Recommendation 19. In patients with RA who are about to start treatment with biological or targeted synthetic DMARDs, a history of cancer should be taken into account. (BPC recommendation.)

Recommendation 20. In patients with RA and a history of non-melanoma skin cancer, who need treatment with targeted biological or synthetic DMARD, periodic dermatological follow-up is recommended to detect recurrences. (BPC recommendation.)

Recommendation 21. In patients with RA and advanced age, in whom it is considered necessary to initiate treatment with targeted synthetic DMARDs, a periodical medical review is recommended to rule out the development of non-melanoma skin cancer.t (BPC recommendation.)

Recommendation 22. In patients with RA and a history of blood cancer/lymphoma requiring biological therapy, rituximab is preferentially recommended. (BPC recommendation.)

Recommendation 23. There is insufficient evidence to recommend the use of targeted synthetic anti-TNFs or targeted synthetic DMARDs in patients with a history of blood cancer. (BPC recommendation.)

The SR has identified 15 studies including 3 RS82,95,96 one RCT and one extension study6,97 and 12 observational studies37,98–108 with data on the development of melanoma, non-melanoma skin cancer and different types of blood cancer.

Studies with bDMARDs do not show an increased risk of skin or blood cancer in patients receiving biologicals compared to csDMARDs, except for abatacept, which has shown a slightly higher risk of non-melanoma skin cancer in several studies.82,104

Clinical trials with tsDMARDs have not shown an increased risk of developing non-melanoma skin cancer,6,95 although there does seem to be a trend. In the SR by Sepriano et al.82 we did not specifically analyse this outcome, however we did review the safety aspects of the studies included in general, noting that there were a higher number of cases of non-melanoma skin cancer in patients treated with JAKi compared to those treated with placebo or active comparator. The SR by Solipuram et al.95 did not find a significant increase in non-melanoma skin cancer in patients treated with JAKi. In the ORAL Surveillance6 study, tofacitinib did not meet non-inferiority criteria for cancer development compared to anti-TNFs. Subsequent sub-analysis detected a non-significant increase in non-melanoma skin cancer in patients receiving tofacitinib compared with anti-TNFs, when both doses of tofacitinib were compared together and also separately. In addition, this sub-analysis found that 10 lymphomas occurred in the group of 2911 patients who received tofacitinib (both doses) compared to a single case of lymphoma in the 1451 patients who received anti-TNF97. In the real-world STAR-RA study,108 the HR for non-melanoma skin cancer development in patients treated with tofacitinib compared with patients receiving anti-TNF was 1.15 (95% CI 0.96–1.39). This study also evaluated the occurrence of lymphatic and hematopoietic cancers, with the HR for tofacitinib compared to anti-TNF being 0.91 (CI 95%: 0.53–1.58); however, the disadvantage of this study is that the duration of treatment was much shorter than that of the ORAL Surveillance study, so the results were inconclusive.

Regarding the recommendation made for elderly patients, it is true that all DMARDs used in the treatment of RA (including methotrexate) are associated with a small incremental risk of nonmelanoma skin cancer. This recommendation is made only by the Spanish Agency for Medicines communiqué, which the Panel does not agree with, and it has been proposed to the SER that they suggest this be deleted.22

The recommendations issued are weak because the quality of the available evidence was low or moderate. In any case, the evidence supports the use of biological drugs and JAKi for the treatment of RA, as the benefits for disease control and prognosis far outweigh the risk of cancer.

A detailed description of the evidence considered and the process that has led from evidence to recommendations can be found in Appendix B's Supplementary material.

Different epidemiological studies have shown that patients with RA have a 2–3 times higher risk of thromboembolic disease (TED) than the general population, even when statistically adjusted for confounding factors, such as the presence of other cardiovascular risk factors.109 In fact, an interdependence has been established between inflammation and the elevation of certain pro-inflammatory cytokines, such as IL-6 and IL-8, and the activation of coagulation pathways responsible for the thrombotic tendency. In addition, it has been reported that endothelial dysfunction and venous stasis occur in relation to sustained inflammation, which provokes activation of the coagulation cascade.110–112

Given the link with the inflammatory activity of the disease, the use of drugs capable of controlling this reduces the risk of TED but does not completely eliminate it, and TEDs have been described during treatment with different cs/b/tsDMARDs.70,82,113 In RA, in addition to the classic risk factors for TED, such as a sedentary lifestyle, obesity, post-surgical status, the intake of contraceptives or COX2 inhibitors, it should be borne in mind that one of the most important factors is the activity of the disease, so its reduction, regardless of treatment, should be a factor in the prevention of TED.114 It is therefore necessary to analyse the available evidence on the risk of TED associated with the use of targeted biological and synthetic drugs to improve the care of our patients.

Recommendation 24. In patients with RA who are about to start treatment with biological or targeted synthetic DMARDs, it is recommended that a prior evaluation be done to estimate the presence of risk factors for thromboembolic disease. (BPC recommendation.)

Recommendation 25. In patients with RA without risk factors for thromboembolic disease, biological and targeted synthetic DMARDs may be used interchangeably. (Weak recommendation in favour.)

Recommendation 26. In RA patients with elevated risk factors for thromboembolic disease, targeted synthetic DMARDs are suggested with caution.u (BPC recommendation.)

Recommendation 27. In patients with RA who have risk factors for thromboembolic disease in which targeted synthetic DMARDs need to be used, it is suggested that the lowest dose be used and the other risk factors be controlled.v (Weak recommendation in favour.)

The SR has identified 23 studies including 5 SRs70,82,115–117 2 RCTs 118,119 and 16 studies including long-term extension analyses, administrative registries or databases, and other observational,77,79,120–132 that assess the risk of venous thromboembolic events (VTEs), including deep vein thrombosis (DVT) and pulmonary embolism (PE). Studies with bDMARDs are along the same lines, showing a similar risk of thromboembolic event in patients who receive these drugs, versus placebo or csDMARDs. In studies with tsDMARDs, the risk is maintained, although a greater trend is observed, which does not reach statistical significance, in the groups with higher cardiovascular risk and higher doses. However, the Oral Surveillance study in the population over 50 years of age with risk factors for cardiovascular disease has shown an increased incidence of TED from tofacitinib compared to anti-TNF, and especially with high doses of 10 mg twice daily. All TEDs occurred in patients with significant risk factors, especially having had a previous event of these characteristics. Risk factors for PD in the treatment groups included a history of VTE, use of oral contraceptives or hormone replacement therapy, a body mass index ≥ 30 kg/m2, an age ≥ 65 years, and a history of hypertension.129,133 Although this study is limited to tofacitinib until more information is available on the other molecules with a similar mechanism of action, it should not be used in patients at risk of TED, according to the resolution FROM the PRAC, if there are other alternatives.

The recommendations issued are weak or on good clinical practice due to the quality of the available evidence, however they are in favour of the use of these drugs, which can have great benefits for the patient, without posing a high risk of thromboembolic events. Nonetheless, the EG highlights the importance of prior patient evaluations to estimate whether there are risk factors for thromboembolic disease, in which case it is suggested that tsDMARDs should be avoided.

A detailed description of the evidence considered and the process that has led from evidence to recommendations can be found in Appendix B's Supplementary material.

There is particular interest in human papillomavirus (HPV) infection, precancerous disease, and cancerous cervical changes in women with RA in relation to the effects of bDMARDs and tsDMARDs on RA and immunosuppressive therapy.

The global prevalence of HPV infection is estimated at 11.7% (95%CI: 11.6–11.7), with considerable regional differences and higher incidence rates in sub-Saharan Africa (24%), Eastern Europe (24%), and Latin America (16%).134 The highest prevalence is in women under 25 years of age. Studies on immune-mediated inflammatory diseases have shown that patients with systemic lupus erythematosus have a higher incidence of HPV compared to RA and scleroderma. In a small cohort of RA patients treated with anti-TNF (for 6 months), the risk of exacerbation and/or progression of HPV135 was not increased.

It is a priority to establish what the risk of bDMARDs and tsDMARDs is, since the inhibition of certain inflammatory pathways can also cause reactivation of infections that had previously been halted by a competent immune system

Recommendation 28. In patients with RA, the HPV vaccination recommendations indicated in the general population should be followed, that is:

• 1

  Universal immunisation is recommended for girls, ideally at 12 years of age.

• 2

  Vaccination is recommended in adult patients with excisional treatment of the cervix and/or WHIM syndrome (warts, hypogammaglobulinemia, infections and myelocathexis syndrome), as well as in those under 26 years of age in prostitution, those with HIV infection, and men who have sex with men (BPC recommendation).

Recommendation 29. In women with RA, the usual gynaecological check-ups are recommended and, if HPV infection is detected, that extreme precautions be taken, although there is no evidence that any treatment is better than another (BPC recommendation).

The SR has identified 7 observational studies,135–141 most of them prospective based on cohort or registry follow-up, that evaluate the risk of HPV progression in RA patients treated with bDMARDs. No evidence has been identified to assess the impact of treatment with tsDMARDs. The use of these types of drugs in the management of RA has amply demonstrated their benefits.

The Panel considers that there is not enough evidence to issue recommendations for or against some drugs or others, but the recommendations for HPV vaccination indicated for the general population for this type of patient with RA are endorsed.

The HPV vaccine is commonly used in our environment and is currently included in the Spanish vaccination schedule for the general female population,142 in addition to being considered for people of both sexes with certain risk pathologies or some risky sexual practices.142–144 Routine vaccination programmes against HPV in adolescent women, and specifically in those focussed on risk groups of both sexes (men who have sex with men, HIV, prostitution, Whim syndrome and conization) have achieved high effectiveness in reducing the incidence of infections by the genotypes included in the vaccines that cause anogenital warts. precancerous lesions (cervix and other anogenital locations) and cervical cancer, resulting in highly cost-effective treatment.

Systematic HPV vaccination programmes in men have not yet been shown to be sufficiently cost-effective in relation to these results, although they would be possible if we consider other parameters: a lower price for the vaccine and/or broadening the objectives of these programmes (also considering the prevention of other tumours: oropharynx, head and neck), provided that high vaccination coverage (close to 90%) is achieved. Almost half of European countries have incorporated this type of programme since 2020, considering other criteria such as equity, homogeneity or confidence in vaccines, in line with recommendations from the World Health Organisation and the European Union. In Spain, at the time of writing, this type of programme is already in place in three regions (Galicia, Valencia and Catalonia), and, in accordance with these criteria, the Ministry of Health has decided to approve funding in the remainder of the regions from 2023 onwards.145,146

A detailed description of the evidence considered and the process that has led from evidence to recommendations can be found in Appendix B's Supplementary material.