Juvenile idiopathic arthritis toxicity criteria and severity descriptors

Toxicity criteria and severity descriptors for the listing of biological agents for juvenile idiopathic arthritis on the PBS.

Azathioprine

Only valid for adult patients. Azathioprine must be at a dose of at least 1 mg per kg per day.

Adverse event Brief description of minimum grade National Institutes of Health
common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin <80 g per L 3 (or higher)
Leukopenia Total white cell count <3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets <50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils <1.0 x 109 per L 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering <50% of body surface or localised desquamation or other lesions covering <50% of body surface 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools per day over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Pancreatitis Abdominal pain with pancreatic enzyme elevation 3 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Hepatic
Bilirubin > 1.5 x upper limit of normal 2 (or higher)
Transaminases Alanine aminotransferase or aspartate aminotransferase >2.5 x upper limit of normal oralanine aminotransferase or aspartate aminotransferase >1.5 x upper limit of normal on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x upper limit of normal 2 (or higher)
Neurology or senses
Headaches (severe) Severe pain, pain or analgesics severely interfere with activities of daily living 3 (or higher)
Pulmonary
Pneumonitis or pulmonary infiltrates Radiographic changes, respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Other
Allergic reaction Urticaria, drug fever >38°C  or bronchospasm 2 (or higher)
Fatigue, malaise Severe, loss of ability to perform some activities 3 (or higher)
Fever (in the absence of neutropenia) Body temp >39°C (oral or tympanic) 2 (or higher)
Infection Severe or systemic infection, requiring intravenous antimicrobial treatment or hospitalisation 3 (or higher)
Secondary malignancy Secondary malignancy present 4

Cyclosporin

Only valid for adult patients. Cyclosporin must be at a dose of at least 2 mg per kg per day.

Adverse event Brief description of minimum grade National Institutes of Health
common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin <80 g per L 3 (or higher)
Leukopenia Total white cell count <3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets <50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils <1.0 x 109 per L 3 (or higher)
Cardiovascular
Hypertension Recurrent or persistent rise of >20 mmHg diastolic blood pressure or rise to >150/90 on 2 occasions if blood pressure previously normal 2 (or higher)
Fluid retention Symptomatic, limiting function, unresponsive to therapy or requiring drug discontinuation 3 (or higher)
Dermatology or skin
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering <50% of body surface or localised desquamation or other lesions covering <50% of body surface 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools per day over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Pancreatitis Abdominal pain with pancreatic enzyme elevation 3 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Weight gain or loss 20% or more weight gain or loss 3 (or higher)
Hepatic
Bilirubin >1.5 x upper limit of normal 2 (or higher)
Transaminases Alanine aminotransferase or aspartate aminotransferase >2.5 x upper limit of normal or alanine aminotransferase or aspartate aminotransferase >1.5 x upper limit of normal on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x upper limit of normal 2 (or higher)
Musculoskeletal
Muscle weakness Symptomatic and interfering with function 2 (or higher)
Neurology or senses
Ataxia (incoordination) Mild symptoms interfering with function but not interfering with activities of daily living 2 (or higher)
Decreased level of consciousness Somnolence or sedation interfering with function but not interfering with activities of daily living 2 (or higher)
Headaches (severe) Severe pain, pain or analgesics severely interfere with activities of daily living 3 (or higher)
Hearing Tinnitus or hearing loss not requiring hearing aid or treatment 2 (or higher)
Mood alteration Moderate mood alteration interfering with function but not interfering with activities of daily living 2 (or higher)
Neuropathy - sensory Objective sensory loss or paraesthesia interfering with function but not interfering with activities of daily living 2 (or higher)
Seizure(s) Seizures in which consciousness is altered 3 (or higher)
Vision Symptomatic and interfering with function but not interfering with activities of daily living 2 (or higher)
Renal
Haematuria Macroscopic (or dipstick +++) confirmed on 2 separate occasions 2 (or higher)
Proteinuria >1.0 g per 24 hours, elevated urine protein-creatinine ratios, dipstick protein ++ or greater, confirmed on 2 separate occasions 2 (or higher)
Renal impairment Creatinine >1.5 × upper limit of normal or creatinine clearance <30 mL per min 2 (or higher)
Other
Allergic reaction Urticaria, drug fever >38°C or bronchospasm 2 (or higher)
Fatigue, malaise Severe, loss of ability to perform some activities 3 (or higher)
Fever (in the absence of neutropenia) Body temp >39°C (oral or tympanic) 2 (or higher)
Hyperkalaemia Potassium >6 mmol per L 3 (or higher)
Infection Severe or systemic infection, requiring intravenous antimicrobial treatment or hospitalisation 3 (or higher)
Secondary malignancy Secondary malignancy present 4

Sodium aurothiomalate

Only valid for adult patients. Sodium aurothiomalate must be at a dose of at least 50 mg weekly.

Adverse event Brief description of minimum grade National Institutes of Health
common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin <80 g per L 3 (or higher)
Eosinophilia Persistent or unexplained eosinophilia > 1 x 109 per L  
Leukopenia Total white cell count <3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets <50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils <1.0 x 109 per L 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering <50% of body surface or localised desquamation or other lesions covering <50% of body surface 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools per day over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Hepatic
Bilirubin >1.5 x upper limit of normal 2 (or higher)
Transaminases Alanine aminotransferase or aspartate aminotransferase >2.5 x upper limit of normal or alanine aminotransferase or aspartate aminotransferase >1.5 x upper limit of normal on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x upper limit of normal 2 (or higher)
Neurology or senses
Decreased level of consciousness Somnolence or sedation interfering with function but not interfering with activities of daily living 2 (or higher)
Neuropathy - sensory Objective sensory loss or paraesthesia interfering with function but not interfering with activities of daily living 2 (or higher)
Seizure(s) Seizures in which consciousness is altered 3 (or higher)
Syncope (fainting) Present 3 (or higher)
Vision Symptomatic and interfering with function but not interfering with activities of daily living 2 (or higher)
Vision – cornea or retina Symptomatic corneal or lenticular changes present 1 (or higher)
Pulmonary
Cough (severe) Severe cough or coughing spasm, poor control or unresponsive to treatment. Evidence of reversal on cessation of treatment. 3 (or higher)
Pneumonitis or pulmonary infiltrates Radiographic changes, respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary fibrosis Respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary symptoms - new or worsening (probable drug-induced pneumonitis) Development of syndrome consistent with drug-induced pneumonitis (such as cough, dyspnoea, fever, hypoxaemia) with lung infiltrates on imaging
(refer to Searles McKendry criteria)
 
Renal
Haematuria Macroscopic (or dipstick +++) confirmed on 2 separate occasions 2 (or higher)
Proteinuria >1.0 g per 24 hours, elevated urine protein-creatinine ratios, dipstick protein ++ or greater, confirmed on 2 separate occasions 2 (or higher)
Renal impairment Creatinine >1.5 × upper limit of normal or creatinine clearance <30 mL per min 2 (or higher)
Other
Allergic reaction Urticaria, drug fever >38°C or bronchospasm 2 (or higher)
Fever (in the absence of neutropenia) Body temp >39°C (oral or tympanic) 2 (or higher)

Hydroxychloroquine

Only valid for adult patients. Hydroxychloroquine must be at a dose of at least 200 mg daily

Adverse event Brief description of minimum grade National Institutes of Health
common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin <80 g per L 3 (or higher)
Leukopenia Total white cell count <3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets <50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils <1.0 x 109 per L 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering <50% of body surface or localised desquamation or other lesions covering <50% of body surface 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools per day over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Hepatic
Bilirubin >1.5 x upper limit of normal 2 (or higher)
Transaminases Alanine aminotransferase or aspartate aminotransferase >2.5 x upper limit of normal or alanine aminotransferase or aspartate aminotransferase >1.5 x upper limit of normal on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x upper limit of normal 2 (or higher)
Musculoskeletal
Muscle weakness Symptomatic and interfering with function 2 (or higher)
Neurology or senses
Headaches (severe) Severe pain, pain or analgesics severely interfere with activities of daily living 3 (or higher)
Hearing Tinnitus or hearing loss not requiring hearing aid or treatment 2 (or higher)
Neuropathy - motor Objective weakness interfering with function but not interfering with activities of daily living 2 (or higher)
Seizure(s) Seizures in which consciousness is altered 3 (or higher)
Vision Symptomatic and interfering with function but not interfering with activities of daily living 2 (or higher)
Vision – cornea or retina Symptomatic corneal or retinal changes present 1 (or higher)
Other
Allergic reaction Urticaria, drug fever >38°C or bronchospasm 2 (or higher)

Leflunomide

Only valid for adult patients. Leflunomide must be at a dose of at least 10 mg daily.

Adverse event Brief description of minimum grade National Institutes of Health
common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin <80 g per L 3 (or higher)
Leukopenia Total white cell count <3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets <50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils <1.0 x 109 per L 3 (or higher)
Cardiovascular
Arrhythmia Symptomatic and requiring therapy 3 (or higher)
Hypertension Recurrent or persistent rise of >20 mmHg diastolic blood pressure or rise to >150/90 on 2 occasions if blood pressure previously normal 2 (or higher)
Fluid retention Symptomatic, limiting function, unresponsive to therapy or requiring drug discontinuation 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering 50% of body surface or localised desquamation or other lesions covering 50% of body surface 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools per day over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Weight gain or loss 20% or more weight gain or loss 3 (or higher)
Hepatic
Bilirubin >1.5 x upper limit of normal 2 (or higher)
Transaminases Alanine aminotransferase or aspartate aminotransferase 2.5 x upper limit of normal or alanine aminotransferase or aspartate aminotransferase >1.5 x upper limit of normal on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x upper limit of normal 2 (or higher)
Neurology or senses
Headaches (severe) Severe pain, pain or analgesics severely interfere with activities of daily living 3 (or higher)
Mood alteration Moderate mood alteration interfering with function but not interfering with activities of daily living 2 (or higher)
Vision Symptomatic and interfering with function but not interfering with activities of daily living 2 (or higher)
Pulmonary
Cough (severe) Severe cough or coughing spasm, poor control or unresponsive to treatment. Evidence of reversal on cessation of treatment. 3 (or higher)
Pneumonitis or pulmonary infiltrates Radiographic changes, respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary fibrosis Respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary symptoms - new or worsening (probable drug-induced pneumonitis) Development of syndrome consistent with drug-induced pneumonitis (such as cough, dyspnoea, fever, hypoxaemia) with lung infiltrates on imaging (refer to Searles McKendry criteria) Not applicable
Renal
Haematuria Macroscopic (or dipstick +++) confirmed on 2 separate occasions 2 (or higher)
Proteinuria >1.0 g per 24 hours, elevated urine protein-creatinine ratios, dipstick protein ++ or greater, confirmed on 2 separate occasions 2 (or higher)
Renal impairment Creatinine >1.5 × upper limit of normal or creatinine clearance <30 mL per min 2 (or higher)
Other
Allergic reaction Urticaria, drug fever >38°C or bronchospasm 2 (or higher)
Fatigue, malaise Severe, loss of ability to perform some activities 3 (or higher)
Fever (in the absence of neutropenia) Body temp >39°C (oral or tympanic) 2 (or higher)
Hypokalaemia Potassium <3 mmol per L 3 (or higher)
Infection Severe or systemic infection, requiring intravenous antimicrobial treatment or hospitalisation 3 (or higher)
Secondary malignancy Secondary malignancy present 4

Methotrexate

Only valid for adult patients. Methotrexate must be at a dose of at least 20 mg weekly.

Adverse event Brief description of minimum grade National Institutes of Health
common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin <80 g per L 3 (or higher)
Leukopenia Total white cell count <3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets <50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils <1.0 x 109 per L 3 (or higher)
Cardiovascular
Pericardial effusion or pericarditis Pericarditis (pericardial rub, electrocardiogram changes or chest pain) 2 (or higher)
Thrombosis or embolism Requiring anticoagulant therapy 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering <50% of body surface or localised desquamation or other lesions covering <50% of body surface 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools per day over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased, and symptoms do not improve with at least 2 of the following measures:
  1. reduction of the methotrexate dose
  2. folinic acid or folic acid supplementation
  3. switching from oral to intramuscular dosing
  4. dividing the methotrexate dose over 12 hours

A minimum of 3 doses of methotrexate should have been trialled

2 (or higher)
Pancreatitis Abdominal pain with pancreatic enzyme elevation 3 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Hepatic
Bilirubin >1.5 x upper limit of normal 2 (or higher)
Transaminases Alanine aminotransferase or aspartate aminotransferase >2.5 x upper limit of normal or alanine aminotransferase or aspartate aminotransferase >1.5 x upper limit of normal on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x upper limit of normal 2 (or higher)
Musculoskeletal
Osteonecrosis
(avascular necrosis)
Symptomatic and interfering with function 2 (or higher)
Osteoporosis Symptomatic and requiring treatment 3 (or higher)
Neurology or senses
Decreased level of consciousness Somnolence or sedation interfering with function but not interfering with activities of daily living 2 (or higher)
Headaches (severe) Severe pain, pain or analgesics severely interfere with activities of daily living 3 (or higher)
Hearing Tinnitus or hearing loss not requiring hearing aid or treatment 2 (or higher)
Mood alteration Moderate mood alteration interfering with function but not interfering with activities of daily living 2 (or higher)
Seizure(s) Seizures in which consciousness is altered 3 (or higher)
Vision Symptomatic and interfering with function but not interfering with activities of daily living 2 (or higher)
Pulmonary
Cough (severe) Severe cough or coughing spasm, poor control or unresponsive to treatment. Evidence of reversal on cessation of treatment 3 (or higher)
Pneumonitis or pulmonary infiltrates Radiographic changes, respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary fibrosis Respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary symptoms - new or worsening (probable drug-induced pneumonitis) Development of syndrome consistent with drug-induced pneumonitis (such as cough, dyspnoea, fever, hypoxaemia) with lung infiltrates on imaging (refer to Searles McKendry criteria) Not applicable
Renal
Haematuria Macroscopic (or dipstick +++) confirmed on 2 separate occasions 2 (or higher)
Renal impairment Creatinine >1.5 × upper limit of normal or creatinine clearance <30 mL per min 2 (or higher)
Other
Allergic reaction Urticaria, drug fever >38°C or bronchospasm 2 (or higher)
Fatigue, malaise Severe, loss of ability to perform some activities 3 (or higher)
Fever (in the absence of neutropenia) Body temp >39°C (oral or tympanic) 2 (or higher)
Infection Severe or systemic infection, requiring intravenous antimicrobial treatment or hospitalisation 3 (or higher)
Nodulosis (following introduction of methotrexate therapy) Development of multiple new nodules causing significant local pressure symptoms and distress to patient  
Secondary malignancy Secondary malignancy present 4

Sulfasalazine

Only valid for adult patients. Sulfasalazine must be at a dose of at least 2 g daily.

Adverse event Brief description of minimum grade National Institutes of Health
common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin <80 g per L 3 (or higher)
Leukopenia Total white cell count <3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets <50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils <1.0 x 109 per L 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering <50% of body surface or localised desquamation or other lesions covering <50% of body surface 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools per day over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Pancreatitis Abdominal pain with pancreatic enzyme elevation 3 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Hepatic
Bilirubin >1.5 x upper limit of normal 2 (or higher)
Transaminases Alanine aminotransferase or aspartate aminotransferase >2.5 x upper limit of normal or alanine aminotransferase or aspartate aminotransferase >1.5 x upper limit of normal on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x upper limit of normal 2 (or higher)
Neurology or senses
Headaches (severe) Severe pain, pain or analgesics severely interfere with activities of daily living 3 (or higher)
Hearing Tinnitus or hearing loss not requiring hearing aid or treatment 2 (or higher)
Mood alteration Moderate mood alteration interfering with function but not interfering with activities of daily living 2 (or higher)
Neuropathy - sensory Objective sensory loss or paraesthesia interfering with function but not interfering with activities of daily living 2 (or higher)
Seizure(s) Seizures in which consciousness is altered 3 (or higher)
Pulmonary
Cough (severe) Severe cough or coughing spasm, poor control or unresponsive to treatment. Evidence of reversal on cessation of treatment 3 (or higher)
Pneumonitis or pulmonary infiltrates Radiographic changes, respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary fibrosis Respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Renal
Haematuria Macroscopic (or dipstick +++) confirmed on 2 separate occasions 2 (or higher)
Proteinuria >1.0 g per 24 hours, elevated urine protein-creatinine ratios, dipstick protein ++ or greater, confirmed on 2 separate occasions 2 (or higher)
Renal impairment Creatinine >1.5 × upper limit of normal or creatinine clearance <30 mL per min 2 (or higher)
Other
Allergic reaction Urticaria, drug fever >38°C or bronchospasm 2 (or higher)
Fever (in the absence of neutropenia) Body temp >39°C (oral or tympanic) 2 (or higher)

Page last updated: 21 July 2016

This information was printed Monday 5 December 2016 from humanservices.gov.au/health-professionals/enablers/juvenile-idiopathic-arthritis-toxicity-criteria-and-severity It may not include all of the relevant information on this topic. Please consider any relevant site notices at humanservices.gov.au/siteinformation when using this material.