Biologic Safety Guidelines from the British Society for Rheumatology Save

In the United Kingdom, NICE has looked to the British Society of Rheumatology (BSR) to develop evidence based guidance on the safe use of biologic DMARDs in patients with inflammatory arthritis. This guidance document on biologic safety covers baseline screening, monitoring, effect of co-morbidities, and when or under what circumstances biologic therapy should be interrupted.

This guidance document specifically addresses the safe use of biologis in adults with rheumatoid arthritis (RA) and inflammatory arthritis; but not psoriatic arthritis or ankylosing spondylitis.  Guidance is provided on the use of the following agents: anti-TNF inhibitors: infliximab (IFX); etanercept (ETN); adalimumab (ADA); certolizumab pegol; golimumab; anti-CD20: rituximab (RTX); CTLA4-Ig: abatacept (ABA); anti-IL-6 receptor: tocilizumab (TCZ); and anti-IL-12/IL-23: ustekinumab (does not include Janus-kinase inhibitors).

The following are exerpts from the BSR.

Generic recommendations

• The decision to initiate a biologic should be made in conjunction with the patient/carer and initiated by an expert in the management of rheumatic disease.
• Patients should be provided with education about their treatment to promote self-management.
• Patients should be assessed for co-morbidities as these may influence biologic choice, including evaluation for respiratory disease and screening for infection.
• Patients should have direct access to their specialist centre [e.g. via an advice line (Helpline)] for advice within one working day.
• Clinicians should be encouraged to recruit patients to the appropriate biologic therapy registry, with patient consent.

Pre-treatment investigations

• Baseline assessment for all should include: laboratory evaluation of full blood count, creatinine/calculated glomerular filtration rate (GFR), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), albumin, tuberculin skin test (TST) or IFN-γ release assay (IGRA) or both as appropriate, hepatitis B and C serology and a chest radiograph.
• Patients receiving RTX: baseline immunoglobulins (IgA, IgG and IgM) are recommended prior to initiation.
• Patients receiving TCZ: a baseline lipid profile is recommended prior to initiation. If abnormal, lipid lowering treatment should be initiated as per local guidance.
• Pre-treatment management of and screening for co-morbidity and infection
  • Biologics should not be initiated in the presence of serious active infections (defined as requiring intravenous antibiotics or hospitalization; not including tuberculosis).
  • Use biologics with caution in patients at high infection risk after discussing risks and benefits.
  • Consider using ETN or ABA as a first line biologic therapy in patients at high risk of infection.
  • Mycobacterium tuberculosis: screening for TB before starting a biologic. Screening for TB should include checking for previous TB exposure and treatment, perform a clinical examination, chest X-ray (CXR) and either a TST or IGRA or both, as appropriate.
  • For patients on immunosuppressive therapy with a normal CXR, a TST is not helpful, as immunosuppression hinders interpretation.
  • Patients with an abnormal CXR, previous history of TB or TB treatment should be referred to a specialist with an interest in TB prior to commencing a biologic.
  • Immunocompromised patients screened for latent TB with an IGRA alone or together with a TST and found to have a positive result in either test should be considered for treatment prior to starting biologic therapy.

Specific Considerations

Latent and reactivated TB

• Patients should be treated with prophylactic anti-TB treatment prior to commencing a biologic; therapy may be commenced after completing at least 1 month of anti-TB treatment and patients should be monitored every 3 months.
• Patients who have had previous inadequate treatment for active TB should be investigated for active TB. In these individuals even when active disease has been excluded, the annual risk of TB (reactivation) is much higher than the general population rate, so the risk–benefit analysis favours chemoprophylaxis.
• As TB reactivation risk is higher with anti-TNF mAb drugs (notably ADA and IFX) than for ETN, consider ETN in preference for those who require anti-TNF therapy and are at high risk of TB reactivation.

 Active TB

• Patients with evidence of active TB should be treated before starting a biologic; therapy may be commenced after completing at least 3 months of anti-TB treatment, and there is evidence that the patient is improving with evidence of culture negativity.

 HBV and HCV

• Patients should be screened for HBV and HCV infection.
• In patients who are HBV positive, a risk–benefit assessment should be undertaken, as biologics may be safe if appropriate anti-viral treatment is given, working closely with a hepatologist.
• Studies to date suggest that though biologic therapy does not appear to have a detrimental effect on HCV infection, it should continue to be used only with caution in such patients, following a risk–benefit decision made with a hepatologist.

Malignancy

• Biologic therapies should not be commenced in patients with clinical signs of, or under investigation for, malignancy (basal cell carcinoma excluded).
• 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 on-going vigilance is required.
• There is conflicting evidence regarding the risk of skin cancers with anti-TNF therapy; patients should be advised of the need for preventative skin care, skin surveillance and prompt reporting of new persistent skin lesions.
• Anti-TNF therapy is relatively contraindicated in patients who have had prior treatment with >150 psoralen and ultraviolet A (PUVA) and/or >350 ultraviolet B (UVB) phototherapy. Such patients should be discussed with a dermatologist prior to commencing anti-TNF therapy.
• Caution should be exercised in the use of biologics in patients with previous malignancy. The timing of commencement of biologic therapy post-malignancy is not fixed and will depend on type and stage of malignancy, risk of metastasis and patient views. RTX may be considered as a first-line biologic option in RA patients with previous malignancy.
• The effect of biologics on pre-malignant conditions remains unclear. Caution should be exercised in the use of biologics in such patients. RTX may be considered as a first-line biologic option is these patients.

 Cardiac problems

• Although recent data are reassuring, biologics should be used with caution in patients with class III or IV cardiac failure, working closely with a cardiologist.
• Biologic therapy may be used in patients with previous myocardial infarction or cardiovascular events.

 Respiratory disease

• Pre-existing interstitial lung disease (ILD) is not a specific contraindication to biologic therapy; however, caution is advised in patients with poor respiratory reserve (in whom a significant drop in lung function would be potentially life threatening); in this situation it is advised to work closely with a respiratory physician with a specialist interest in ILD.
• RTX or ABA may be considered a first-line biologic in patients with ILD.

Uveitis

• ADA and IFX can be considered for the treatment of uveitis, in preference to ETN, which appears to be associated with lower rates of treatment success and has been associated with the development of uveitis. The relative risks of the available agents should be taken into account when selecting which treatment to use.

Demyelinating disease

• Anti-TNF therapy should not be given when there is a personal history of multiple sclerosis or other demyelinating diseases. Consider using a non-anti-TNF biologic in this situation.

Diverticular disease

• Exercise caution with TCZ in patients with diverticular disease, particularly when using concurrent NSAIDs and/or steroids. 

Vaccinations

• HBV immunization should be considered for at risk patients.
• Patients >50 years should undergo vaccination against herpes zoster assuming there are no contraindications (e.g. treatment within the past 3 months with >40 mg prednisolone per day for >1 week, >20 mg prednisolone per day for >14 days, MTX >25 mg/week, AZA >3.0 mg/kg/day). This should be administered preferably >14 days before starting biologic therapy.
• Patients who do not have a positive history of varicella zoster (chickenpox) infection should have a varicella zoster virus antibody test. If this is negative, and there are no contraindications (as listed in 3.31), varicella zoster vaccination should be offered prior to biologic commencement.

For patients receiving biologic therapy

Monitoring on Biologic treatment

• All patients should be reviewed for drug safety in a specialist department at least every 6 months. High risk patients (e.g. those at high risk of TB) should be reviewed every 3 months.
• Patients prescribed a biologic (other than TCZ) without concomitant csDMARD (or with csDMARDs that do not require blood test monitoring), should have monitoring blood tests (FBC, creatinine/calculated GFR, ALT and/or AST and albumin every 3–6 months.
• Patients receiving RTX should have serum immunoglobulins (especially IgG and IgM) checked prior to each cycle of RTX. Clinicians and patients should be aware that the risk of infection increases as serum IgG levels fall below normal.
• Patients receiving i.v. or s.c. TCZ, with or without MTX, should have laboratory monitoring every 4 weeks for neutrophils and ALT/AST. Blood tests should ideally be in the week before i.v. TCZ, and in the 3 days before every fourth s.c. injection. Any decision to halt treatment should be made in accordance with the guidance in the TCZ SPC.

Peri-operative care

• The potential benefit of preventing post-operative infections by stopping biologics (different surgical procedures pose different risks of infection and wound healing) should be balanced against the risk of a peri-operative flare in disease activity.
• For most biologics (exceptions: RTX and TCZ), consideration should be given to planning surgery when at least one dosing interval has elapsed for that specific drug; for higher risk procedures consider stopping 3–5 half-lives before surgery (if this is longer than one dosing interval).
• Biologics may be recommenced after surgery when there is good wound healing (typically around 14 days), all sutures and staples are out, and there is no evidence of infection.
• For patients receiving RTX, treatment should ideally be stopped 3–6 months prior to elective surgery.
• For patients receiving TCZ, i.v. TCZ should be stopped at least 4 weeks before surgery; s.c. TCZ should be stopped at least 2 weeks before surgery .