Additional considerations for specific immunomodulatory drugs

Before starting therapy:

• identify comorbidities that might be exacerbated by corticosteroid therapy (eg diabetes, cardiovascular disease, depression, osteoporosis) and implement a plan for management and monitoring
• evaluate bone health and implement strategies to minimise bone density loss—see Glucocorticoid-induced osteoporosis.

During therapy:

• routine blood tests are not recommended with the exception of those needed to monitor the patient’s disease
• regularly review corticosteroid therapy; to minimise adverse effects use the lowest dose and shortest treatment duration required to achieve treatment goals
• consider adrenocortical suppression—see Glucocorticoid replacement during intercurrent illness and surgery
• in patients who are predisposed to diabetes or are treated with high doses or prolonged courses of systemic corticosteroids, monitor blood glucose concentrations—see Glucocorticoid-induced hyperglycaemia
• monitor and actively manage risk factors for cardiovascular disease, especially with prolonged courses of corticosteroids at daily doses equivalent to 7.5 mg or more of prednisolone—see Atherosclerotic cardiovascular disease risk estimation
• assess the need for antimicrobial prophylaxis in patients planned for treatment with high doses of corticosteroids (20 mg or more per day of prednisolone [or equivalent]) for more than 2 weeks—see Patients taking corticosteroid therapy
• chronic use of corticosteroids in children can have a significant impact on growth and should be used judiciously.

Other considerations:

• the systemic corticosteroids used for autoimmune and autoinflammatory conditions are chosen for their anti-inflammatory (glucocorticoid) effects; equivalent dosages and duration of effect of glucocorticoids are given in Approximate relative potency and duration of effect of glucocorticoids
• the rate at which corticosteroids can be tapered depends on the starting dose and duration of corticosteroid use (which influences the risk of adrenal suppression) and the patient’s risk of disease flare.

apremilast

azathioprine

ciclosporin

cyclophosphamide

hydroxychloroquine

leflunomide

mercaptopurine

methotrexate

mycophenolate

sulfasalazine

tacrolimus

tioguanine

Before starting therapy:

• it is not necessary to undertake investigations to exclude latent tuberculosis because apremilast is not known to cause reactivation
• assess for depression and suicidal ideation (see suicide risk).

During therapy:

• monitor for the development of depression and suicidal ideation (see suicide risk)
• monitor for weight loss.

Before starting therapy:

• perform TPMT genotype (or phenotype) testing, because 1 in 300 individuals have a homozygous genetic mutation causing negligible enzyme activity. In these patients, severe myelosuppression occurs if the dose is not significantly reduced (eg giving 10% of the usual dose or increasing the dosing interval to 3 times weekly)Relling, 2019 [NB1].

During therapy:

• perform liver function tests (to monitor for liver impairment) and check full blood count (to monitor for severe myelosuppression) every 2 weeks during dose escalation, then every 4 to 6 weeks once a stable dose is achieved.

Other considerations:

• during the first few weeks of therapy, azathioprine may cause hypersensitivity reactions that can be mistaken for a flare in the underlying illness.

Before starting therapy:

• measure kidney function, blood pressure, blood glucose concentration and fasting lipid levels.

During therapy:

• regularly assess kidney function, blood pressure and fasting lipid levels.

Other considerations:

• acute kidney impairment associated with ciclosporin treatment is generally reversible if the dose is reduced or treatment stopped; however, chronic kidney impairment associated with long-term ciclosporin treatment is potentially irreversible
• plasma concentration monitoring is generally not performed when ciclosporin or tacrolimus is used to treat autoimmune or autoinflammatory disease. However, ciclosporin and tacrolimus have narrow therapeutic indices and plasma concentration monitoring may be useful, particularly if high doses are used, toxicity is suspected, or response is inadequate (eg to rule out absorption problems and nonadherence).

Before starting therapy:

• consider referral to a reproductive specialist to discuss fertility preservation in all people
• perform urinalysis
• advise patients treated with oral cyclophosphamide to take their dose in the morning to reduce the risk of bladder toxicity
• advise all patients to maintain a fluid intake of 3 litres of water per day and report haematuria or dysuria.

During therapy:

• assess the need for antimicrobial prophylaxis—see Patients taking cyclophosphamide for a nonmalignant condition
• perform monthly urinalysis to check for haematuria and refer for cystoscopy if haemorrhagic cystitis is suspected [NB2]
• check kidney, liver and bone marrow function every 2 weeks for the first 3 months of treatment, then check monthly thereafter. Implement more frequent monitoring of bone marrow function if there is evidence of bone marrow toxicity and consider withholding therapy.

Other considerations:

• perform yearly urinalysis, including urine cytology, once cyclophosphamide therapy has stopped to check for evidence of premalignant or malignant changesChou, 2021
• avoid use within 3 months of attempted conception in males and females
• when possible, avoid use in people of childbearing potential.

Before starting therapy:

• check for history of G6PD deficiency—an alternative drug may be required
• perform baseline ophthalmological review (within 12 months of starting treatment).

During therapy:

• routine blood tests are not recommended with the exception of those needed to monitor the patient’s disease
• after 5 years of continual hydroxychloroquine treatment, annual ophthalmological review may be necessary [NB3].

Before starting therapy:

• measure blood pressure and fasting lipid levels.

During therapy:

• regularly assess blood pressure and fasting lipid levels
• promptly investigate patients reporting new or worsening pulmonary symptoms.

Other considerations:

• leflunomide and methotrexate have synergistic bone marrow, liver and pulmonary toxicity
• if reversal of leflunomide is required, use colestyramine washout:

Before starting therapy:

• assess the patient’s alcohol intake.

During therapy:

• promptly investigate patients reporting new or worsening pulmonary symptoms.

Other considerations:

• methotrexate is given weekly rather than daily, and serious toxicity can occur if taken more frequently. The clinician and patient should agree on which day of the week the patient will take their methotrexate and this should be specified on the prescription
• folic acid or calcium folinate supplementation decreases the risk of adverse effects, including gastrointestinal adverse effects, liver transaminitis and mouth ulcers [NB4]. It should not be taken on the same day as the weekly methotrexate dose
• adverse effects can be limited by administering the methotrexate dose at night, splitting the weekly dose over 2 consecutive days (usually 12 hours apart) or administering the dose subcutaneously
• leflunomide and methotrexate have synergistic bone marrow, liver and pulmonary toxicity
• at the doses typically used in autoimmune and autoinflammatory disorders, there is no risk of toxicity to close contacts of patients taking methotrexate and special precautions in handling bodily fluids are not required.

During therapy:

• check full blood count every week for the first month of treatment, every 2 weeks for the second and third months, monthly for a further 9 months, then as clinically indicated.

Before starting therapy:

• check for history of G6PD deficiency—an alternative drug may be required
• check for history of sulfonamide allergy.

B-cell activating factor inhibitor

B-cell antigen CD20 inhibitor

CTLA-4 immunoglobulin fusion protein

IL-1 inhibitor

IL-6 inhibitor

IL-17 inhibitor

JAK inhibitor

TNF inhibitor

Type 1 interferon inhibitor

Before starting therapy:

• assess for depression and suicidal ideation (see suicide risk).

During therapy:

• monitor for the development of depression and suicidal ideation (see suicide risk).

Before starting therapy:

• measure plasma immunoglobulins and perform a full blood count.

During therapy:

• measure plasma immunoglobulins and perform a full blood count before each treatment cycle
• assess the need for antimicrobial prophylaxis—see Patients taking rituximab for a nonmalignant condition.

During therapy:

• regularly check blood pressure
• assess for skin cancer.

Before starting therapy:

• measure fasting lipid levels in patients treated with anakinra, but not canakinumabRidker, 2017.

During therapy:

• regularly assess fasting lipid levels in patients treated with anakinra, but not canakinumab.

Before starting therapy:

• check for history of diverticulitis
• measure fasting lipid levels.

During therapy:

• regularly assess fasting lipid levels.

Other considerations:

• patients treated with tocilizumab can have normal CRP concentration in the presence of infection.

During therapy:

• monitor for inflammatory bowel disorder manifestations.

Before starting therapy:

• measure fasting lipid levels
• check for a recent history of venous thromboembolic events.

During therapy:

• regularly assess fasting lipid levels
• monitor for herpes zoster.

Other considerations:

• JAK inhibitors should not be prescribed for chronic inflammatory conditions (unless there are no suitable alternatives) in people [NB2]:
  • with a history of cardiovascular disease
  • at increased cardiovascular risk
  • at increased risk of cancer
  • aged 65 years or older.

During therapy:

• perform a baseline test for dsDNA antibodies
• check for a history of heart failure and demyelinating disorders (eg multiple sclerosis).

During therapy:

• monitor for upper respiratory tract infections, bronchitis, and herpes zoster.