Risk management in the use of medications is an important part of pharmacovigilance. This may be defined, in turn, as the activity of public health whose objectives are the identification, quantification, assessment and prevention drug related risks once they are marketed, as collected in the royal decree (RD) 1344/2007.

More specifically, risk management represents the set of pharmacovigilance activities and interventions designed to identify, characterize and prevent or minimize the risks of drugs and evaluate the effectiveness of such interventions. It is everyone's responsibility, regulatory agencies/health authorities, pharmaceutical companies, researchers, health professionals, etc. to work on all.

In recent years, with the use of biological therapies we have identified a number of risks more or less associated with them. Some are identified as significant, that is, those where there is adequate evidence of association with the drug and are very relevant. Other potential risks are important, meaning there are grounds for suspicion, but no confirmation. On the other hand, it should be pointed out that we currently do not have enough relevant information in specific cases, such as in so-called special situations (pregnancy, nursing, etc.).

Based on the above, the management of risk in relation to the use of biologic therapy is present at the following times/circumstances (discussed throughout the document): indication, start of treatment, monitoring and in the assessment of adverse events arising during treatment. In most of these times/circumstances, there is evidence on the best conduct to take.

Finally, remember the legal framework in which we live. The RD 1345/2007 regulates the authorized use of a drug, and RD 1015/2009 the use of medication in special situations. All documentation is accessible on the website of the Spanish Agency for Drugs and Health Products (AEMPS).8

The estimated benefit/risk to an individual patient should be based on all available knowledge from the moment of indication. Therefore:

The panel believes that treatment with biologic therapies must be performed by physicians experienced with them and accustomed to managing the diseases for which they are indicated (LE 5, DR D, DA 100%).

Please refer to the official sheet of all biological agents and comply with its recommendations prior to their use in clinical practice (LE 5, DR D, DA 91%).

There is evidence that off-label uses may be linked to more adverse events than when a drug regimen has been approved for such an indication, and the patient to whom it is prescribed must be as close as possible to the profiled indication.9

It should be remembered that the indication of biologic therapy for patients with a history of uveitis is not currently authorized; therefore, this would constitute an unlicensed indication. In this context the physician should weigh the relative risks derived from the different drugs and consult an ophthalmologist before deciding on whether to start treatment with biologic therapies and if so, which.10,11

A summary of the data sheets of biological therapies is shown in Table 1.

Every patient who starts treatment with biologic therapy should undergo a preliminary assessment to detect and/or prevent potential risks and should be monitored regularly during therapy (LE 5, DR D, DA 100%).

Before starting the first dose, the physician should have gathered enough information about potential risks of the individual patient who has been prescribed the medication. To do so, we advise a series of screening or screening measures destined to look for comorbidity, but also suggest proactive measures to minimize the possible adverse reactions, such as providing good information to patients and staff who will manage the therapy and prophylaxis.

Patient monitoring should be regular and adapted to the characteristics of the patient and department organization, with at least one evaluation recommended per month and then every 1–4 months, regardless of who performs it and how it is performed.

Whenever starting a treatment with biological therapy the patient should be instructed about the warning signs to watch for as possible indicators of risk (LE 5, DR D, DA 91%).

When prescribing biologic therapy, regardless of the disease, the patient should be instructed about symptoms/signs to look for and what to do if they occur. The patient should know and recognize these risks; at least the most frequent ones. Similarly, the physician may indicate lifestyle modifications that help reduce some risks. All this information is available in many rheumatology units or the SER12 website.

The physician who has indicated the drug or one who has been designated for such a purpose should direct the management of risks of treatment with biologic therapies; however, this should involve all of the healthcare staff, including nurses, family physicians, hospital pharmacy and the patient (LE 5, DR D, DA 100%).

The information of the prescribing physician, the one monitoring (if other) and the nurse, must be consistent, for which it is essential to have the support of written documentation, defined processes and clear and precise procedures, brochures, instruction manuals, etc.

In Table 2, the pre-assessment activities recommended at the onset of treatment. Although the safety profile is not identical with different biological therapy options with the information currently available, and except for denosumab, teriparatide and rh-PTH 1–84, the panel considers that the recommendations that follow are applicable to all patients who will undergo biological therapy.

In a patient who's going to start biological treatment, assess the possible existence of an active infection; the presence of the same is a contraindication of biologic therapy (LE 2b, DR B, DA 96%).

The Spanish registry of adverse reactions to biological therapies (BIOBADASER) and other records and/or studies have found an increased incidence of infections in patients with these therapies, regardless of baseline disease.13–28

The use of biological therapies in patients with a history of recurrent infections, sepsis or at high risk of developing an infection, is unreliable and requires appropriate risk-benefit balance and maximum surveillance. Nor should physicians begin treatment with these drugs if there is an active, systemic or localized infection. In this sense, the history of an infected prosthetic joint forces the performance, before the start of biological therapy, of the appropriate therapeutic approach (surgery with radical removal of the infection and, if indicated, the prosthetic replacement).

With a growing immigrant population, and according to their geographical origin, it is recommended that the possible reactivation of unusual infections in our environment be evaluated.

Upon resolution of infection, biological therapy can initiate.

The panel considers it necessary to exclude, in any patient about to undergo biological therapy, the existence of active tuberculosis or recent contact with patients with TB and investigate the possibility of latent tuberculosis infection. It is important to register, in the medical history, any recent contact with TB and TB patients and perform a chest radiograph to rule out active TB or radiographic evidence consistent with an old TB infection, as well as perform a TB skin test (PPD), which must be repeated (re-test) at 1–2 weeks if <5mm (LE 2b, DR B, DA 100%).

A higher incidence of tuberculosis (TB) has been detected in patients receiving TNF antagonists, particularly monoclonal antibodies.5,23,24,29–31 Furthermore, screening has been associated with reduced risk of reactivation of latent TB.5,32 PPD is considered positive in a re-test or in a patient undergoing immunosuppression with an induration greater than or equal than 5mm at 72h. The result should be considered regardless of previous vaccination for tuberculosis. It is also important to educate patients about the risks associated with exposure to patients with active TB.

Treatment should be instituted for latent tuberculosis infection before starting biological therapy in the following circumstances: (1) recent contact with a patient with documented TB, (2) a history of partially treated TB, (3) or positive PPD test or re-test; (4) residual lesions in the chest radiograph. The pattern of choice for treatment of latent tuberculosis infection is isoniazid (5mg/kg/day up to 300mg daily) with vitamin B6 for 9 months (LE 2b, DR B, 96 DA%).

In case of intolerance to isoniazid, rifampicin is recommended in doses of 10mg/kg/day (maximum, 600mg daily) for four months. The effectiveness of these guidelines to prevent reactivation of latent TB has been demonstrated.32 Studies of short treatment courses are emerging33 with various drugs, although we are awaiting confirmation of their efficacy in immunosuppressed patients.

If the patient has received adequate treatment for latent TB infection, active prophylaxis or Mantoux testing is not necessary (LE 5, DR D, DA 96%). However, monitoring is recommended in such patients.

Before starting a biological treatment, the physician must take into account the history of malignancies. When there is a strong history of cancer, its biology and behavior should be assessed, discussing with the oncologist and the patient the risk of recurrence. We do not recommend the use of biologic therapy in patients with a history of lymphoproliferative disease (LE 4, DR C, DA 91%).

There is no current evidence of increased risk of solid tumors in patients undergoing biological therapy18,34,35 although there seems to be an increased risk in relation to non-melanocytic skin tumors (basal), at least in patients with RA.36 Therefore, in patients with a history of solid tumors, indication of biological therapy will be settled on its risks and benefits.

On the other hand, there are conflicting data regarding the risk of developing lymphoproliferative disease with the use of TNF antagonists (see data sheets) in RA,37–41 and there seems to be an association in SA.42 While this issue is not definitively clear, we discourages the use of TNF antagonists if there is a history of lymphoproliferative disease.

Before starting biological treatment, patients should be evaluated for heart failure (LE 4, DR C, DA 91%).

Although the available data (relative to TNF antagonists and RTX) are not entirely consistentes43–45 in patients with mild heart failure, patients should be monitored and discontinuation of treatment carried out in case of worsening heart failure. Do not initiate treatment in patients with a NYHA functional class III or IV.

In general, biological therapy should be individualized for in patients with underlying interstitial lung disease (No. 4, GR C, GA 96%).

The use of biological therapies in patients with interstitial lung disease may be associated with a risk (although little studied and defined) of worsening or fatal outcome.46,47 This risk may be increased in patients with prior history of lung disease, and the worst outcomes have been reported in patients with usual interstitial pneumonitis, so one should pay particular attention to this information.46,47 Pending more evidence about its use, treatment in these patients should be individualized.

Before starting biological treatment, assess the existence of cytopenias, and do not start treatment with until they are resolved (LE 2b, DR B, DA 74%).

In cases of severe cytopenia, it is not recommended to start treatment until resolved. On the other hand, since cytopenia may be due to the activity of the underlying disease their origin should be studied and acted upon accordingly.

Before starting a biological treatment, assess the existence of demyelinating disease and avoid treating patients with a clear history of such processes (LE 2b, DR B, DA 91%).

There have been reports of demyelinating disease with the use of TNF antagonists48–50 and there is, according to their data sheet, a potential risk with TCZ and ABT, although it is unclear whether the use of these drugs actually increases the risk of it. This screening may be done clinically and if in doubt, consultation with a neurologist or specialist performed. In case of prior demyelinating disease, indication of biological therapy should be evaluated individually in the light of its risks and benefits, but generally should be avoided.

Serology marker detection is recommended for HCV and HBV (LE 4, DR C, DA 100%).

In patients with HBV and receiving TNF antagonists cases of reactivation of infection and even liver failure have been reported.51–53 There is no data on reactivation54 regarding the use of RTX. In the case of HCV, it is not clear whether treatment with TNF antagonists or the use of ABT brings about a deterioration of liver function or increased viral load and improvement has even been described in some functional tests.55–59 The case of RTX is not clear.60,61 In connection with the human immunodeficiency virus (HIV), there are series of cases in which biological agents have been effective, but which have also shown an increase in infections.62 Therefore, we believe that each case must be individualized and the risk/benefit ratio assessed. And, especially in the case of HBV, we recommend a preliminary joint assessment by the hepatologist/infectious disease specialist for monitoring the risk of reactivation and evaluating the decision for initiation and maintenance of antiviral drugs.

The following vaccines are recommended for patients undergoing biological therapy: pneumococcal vaccine and influenza vaccine (LE 3b, DR C, DA 96%).

On the other hand, using live attenuated vaccines is contraindicated. Given the degree of immunosuppression induced by biological therapy, the potential risk of infection with their prescription may be important, and their use is discouraged.

In principle, if no other risk factors are present, other vaccines may be prescribed. More information on vaccines may be found in Table 3.

In patients with negative markers for hepatitis B, vaccination is recommended prior to initiation of biological therapy (LE 3b, DR C, DA 78%).

In reference to vaccines, several publications have shown a good humoral response in the case of TNF antagonists and ABT for microorganisms such as the influenza virus, pneumococcus or tetanus toxin,63–66 but is so far contradictory for RTX.67,68 There is insufficient information in relation to other drugs.

In any case, always take into account that these vaccines may be ineffective if the patient undergoes an intense immunosuppression. After initiation of therapy, biological vaccines containing live bacteria should not be used. For more information see Table 3.

Pregnancy and breast-feeding should be discouraged for patients who will initiate biologic therapy; the use of denosumab is contraindicated in pregnancy and lactation (LE 3b, DR C, DA 91%).

In general, although there is not enough evidence,69–71 the use of biological therapy during pregnancy and lactation should be discouraged. It is essential that patients and their doctors discuss the pregnancy planning in relation to the use of these therapeutic agents.

During drug exposure, time intervals for a systematic monitoring of specific events should be established as regularly as possible (LE 5, DR D, DA 100%).

Risk management during treatment with biologic therapies and clinical evaluation includes physical examination and laboratory tests (laboratory, imaging, etc.) depending on each drug and clinical situation (LE 5, DR D, DA 91%).

Treatment should be followed in collaboration and communication with the primary care physician (NE 5, GR D GA 96%).

Close and systematic monitoring has been shown to minimize the adverse effects of any drug. Indeed, close monitoring is standard in clinical trials and adverse effects occur less often. Any means to facilitate communication between primary care and the controller, including the patient with any of these, leads to an expected positive impact on patient safety.

During follow-up special emphasis should be placed on screening for adverse events, especially infections, lung disease, heart failure, as well as on specific cases of laboratory abnormalities (blood alterations, lipids, liver function) as well as monitoring for contact with infectious patients (tuberculosis or chickenpox among others) (LE 5, DR D, DA 96%).

For more details on the management of risk during treatment with biologic therapy refer to Tables 1 and 2.

It is advisable to closely monitor patients with active infection with HBV, HCV or HIV if they initiate biologic therapy (LE 5; DR B, DA 100%).

Although the evidence is still scarce,51,55–58,62 if the physician finally decides to initiate biologic therapy in patients with HBV, HCV or HIV, monitoring should include at least: serology, viral load, CD4 count and liver function test. In the case of HBV the use of antiviral therapy should be assessed and, in the case of HIV, biologic therapy should always be associated with intense antiretroviral therapy (which should begin before the start of treatment). As discussed above, we recommend consulting a specialist if in doubt.

The physician should pay particular attention to the possible development of infections during treatment. In this situation, diagnosis and treatment of cases, and the temporary removal of biological therapy are essential. Once the infection resolved, treatment may be restarted (LE 2b, DR B, DA 100%).

Infections are the most frequent events. They may occasionally be complex and/or serious, and it is essential to always suspect their presence.13,20,29,72–76 There have been cases of diverticulitis with intestinal perforation reported using TCZ,77 so all patients with clinical symptoms of acute abdomen/subacute should be assessed for this possibility.

During follow-up it is recommended to inquire about the possibility of contact with TB patients. If positive or uncertain, repeat the TB skin test or treat exposure with isoniazid (LE 5, DR D, DA 91%).

Even when pretreatment screening or pharmacological prophylaxis has been performed for tuberculosis, the possibility of TB infection still exists, so it is necessary to consider this possibility to follow up and act accordingly.

The QuantiFERON test is an in vitro immune-based rapid assay measuring IFN-γ production by circulating mononuclear cells in response to antigens and is more specific for the detection of tuberculosis infection than PPD. Its use in patients with immune-mediated inflammatory diseases has shown a strong correlation with risk factors for tuberculosis and a low percentage of indeterminate results. However, more studies are needed to assess its use in patients treated with TNF78 antagonists.

There is no evidence that supports a minimum timeframe required for treatment of tuberculosis before initiating biological therapy. Clinical experience makes it advisable to administer it for the longest possible time, always keeping the patients disease activity reasonably low.

If the patient develops cancer during treatment with a biological agent, it should be discontinued (LE 2b, DR B, DA 96%).

Special attention should be paid to the detection of malignant neoplasms.36,39,42,79–82 Among other situations, clinical suspicion should be established when a mismatch is detected between the clinical symptoms and serum levels of acute phase reactants, the leukocyte count or hemoglobin concentration.83

It is also advisable that the patient be explained the importance of observing and reporting any changes in the skin.

The physician should be particularly careful with TNF antagonists and RTX in patients with heart failure, as this condition may worsen considerably, in which case the drug should be discontinued (LE 4, DR C, DA 91%).

Although it requires further evidencia,43,44 in case there is clinical and/or ultrasound evidence of worsening heart failure, medication should be discontinued.

In patients with interstitial lung disease treated with biologic therapy, clinical and lung function should be strictly controlled, and in cases of clinical worsening and extension of lesions, biological therapy should be abandoned (LE 4; DR C, DA 96%).

There have been reports of worsening interstitial lung disease with fatal outcome in patients treated with TNF antagonists,46,47 although recently it has been reported that mortality in patients with RA and interstitial lung disease increases with TNF antagonists compared with traditional DMARDs. The proportion of deaths attributable to interstitial lung disease is higher in patients treated with TNF antagonists, although there may be an information bias.84 This is a little studied subject, in which the cause/effect relationship is poorly defined, so while waiting for more evidence on it, the risk/benefit should be assessed individually.

In case of severe cytopenia during treatment with biologic therapy, this should be discontinued and a search for other possible causes should be explored before attributing it to biological therapy. Once this question has been settled, it may be restored (LE 4, DR C, DA 96%).

There have been rare cases of severe leukopenia or thrombocytopenia and aplastic anemia in patients receiving biologic therapy85; in the event of this happening and if it is due to these drugs, stopping the drug until resolved and assessing its reintroduction is mandatory. Due to its mechanism of action, RTX can cause lymphopenia, which would not (per se) be a reason for suspension. In the case of TZC, cytopenia occurs frequently because of a pharmacodynamic effect and management recommendations exist (in literature and its data sheet). On the other hand, anemia, leukopenia, lymphopenia or thrombocytopenia may result from the disease activity. In any case, the physician should study their origin and decide the course of action based on a benefit/risk ratio.

In case of lupus-like syndrome or other autoimmune disorders occurring, relevant biological therapy treatment should be discontinued (LE 2b, DR B, DA 96%).

Although rare, the possible occurrence of these phenomena should be monitored.86–88 The presence of typical lupus antibodies in the absence of other signs or symptoms, is grounds for suspension.

TNF antagonist agents and TCZ should be discontinued, in a case compatible with demyelinating optic neuritis (LE 2b, DR B, DA 96%).

Treatment with TNF antagonists and TCZ has been associated with the appearance of optic neuritis, multiple sclerosis and other demyelinating disorders,49,50 so drugs must be suspended in the event of occurrence.

In case of activation or the appearance of hepatitis B, C or HIV, antiviral treatment should be associated with biologic therapy (LE 4, DR C, DA 87%).

In the largest series to date, 14 patients with chronic HBV infection, 19 patients vaccinated for HBV and 19 patients with resolved HBV infection received oral antiviral therapy in combination with TNF antagonists. During treatment, levels of HBV surface antibodies disappeared or were reduced. No safety issues were found.89 However, the option of temporarily suspending biological therapy until the establishment of an effective control of virus replication should not be excluded.

In the case of psoriatic lesions in patients with biologic therapy, an appropriate treatment for the lesions should be established and its suspension assessed in case this fails or if skin involvement is severe (LE 4, DR C, DA 96%).

There have been reports of cutaneous psoriasis, mainly on the palms of the hands and soles of the feet, as well as exacerbation or change in morphology of the pre-existing psoriatic lesions using these drugs,90–93 which calls for vigilance against their possible occurrence.

If pregnancy occurs during treatment with biologic therapy, it should be discontinued (LE 4, DR C, DA 78%).

If pregnancy occurs, discontinue treatment with the biological agent.69,70,94 For more information see Table 4. In men, in principle, although the possibility of association with astenoazoospermia and decreased spermatozoid mobility has been suggested,95–98 there is no conclusive evidence of declining fertility in men using TNF antagonists.

In patients with biologic therapy undergoing major elective surgery it is advisable to temporarily suspend treatment (LE 4, DR C, DA 96%).

Although there is no conclusive evidence,99–103 the panel recommends temporarily suspending biological therapy when the patient is to undergo major elective surgery. Although there is no universal agreement on the length of time around the surgery the drug should be discontinued, the physician should take into consideration the different half-life (or duration of immunosuppressive effect) of the agent employed, in order to decide the specific period of interruption. After surgery, the panel believes that if there are no complications or contraindications, treatment may be restored within 10–14 days.