What management approach is recommended for a patient with a history of autoimmune disease, such as rheumatoid arthritis, who is at risk of developing hypothyroidism and adrenal insufficiency while on Navilumab (anti-CD19 monoclonal antibody) therapy?

Management of Hypothyroidism and Adrenal Insufficiency Risk in Patients with Autoimmune Disease on Immune Checkpoint Inhibitor Therapy

For patients with rheumatoid arthritis receiving immune checkpoint inhibitor therapy (such as anti-CD19 monoclonal antibodies), you should implement routine endocrine monitoring with TSH and free T4 every 4-6 weeks, morning cortisol and ACTH at baseline and when symptomatic, and immediately initiate hormone replacement when deficiencies are confirmed—critically, always replace cortisol before thyroid hormone to prevent precipitating adrenal crisis. 1

Baseline Risk Assessment

Patients with rheumatoid arthritis have an inherently elevated risk for developing endocrine autoimmunity even before starting immunotherapy:

• Pre-existing thyroid disease prevalence: RA patients have a 10.3% prevalence of autoimmune thyroid disease compared to 7.1% in the general population, with risk peaking in the 2-5 years before RA diagnosis. 2
• Adrenal dysfunction: Up to 48% of RA patients on chronic glucocorticoids develop adrenal insufficiency, and even glucocorticoid-naive RA patients may have compromised adrenal reserve due to the "disproportion principle"—inadequate endogenous cortisol production relative to inflammatory stress. 3
• Immune checkpoint inhibitors amplify risk: Patients with preexisting autoimmune conditions are at higher risk for immune-related adverse events (irAEs) or flares of their underlying disease, though this is not an absolute contraindication to treatment. 1

Monitoring Protocol for Hypothyroidism

Asymptomatic Patients

• Check TSH with free T4 every 4-6 weeks as part of routine monitoring during active immunotherapy. 1
• Drawing both TSH and FT4 simultaneously is essential because central hypothyroidism (from hypophysitis) can present with low-normal TSH and low FT4, which would be missed by TSH screening alone. 1

Symptomatic Patients

• Immediately measure TSH and free T4 when patients develop fatigue, weight changes, cold intolerance, or other hypothyroid symptoms. 1
• Median time to onset of endocrine toxicities is 14.5 weeks (range 1.5-130 weeks), so vigilance must continue throughout and after treatment. 1

Management by Grade

Grade 1 (TSH >4.5 and <10 mIU/L, asymptomatic):

• Continue immunotherapy with ongoing TSH/FT4 monitoring every 4-6 weeks. 1

Grade 2 (TSH persistently >10 mIU/L or moderate symptoms):

• May continue or temporarily hold immunotherapy until symptoms resolve. 1
• Initiate levothyroxine replacement at standard doses (1.6 mcg/kg/day). 1
• Critical caveat: If TSH is low with low FT4, this indicates central hypothyroidism from hypophysitis—proceed immediately to adrenal axis evaluation before starting thyroid replacement. 1

Monitoring Protocol for Adrenal Insufficiency

Baseline and Routine Monitoring

• Measure morning (8 AM) cortisol and ACTH at baseline before starting immunotherapy. 1
• For patients on chronic prednisone ≥5 mg daily for RA: recognize they likely already have suppressed adrenal function (39-48% prevalence of adrenal insufficiency). 4
• Monitor for symptoms: fatigue, nausea, vomiting, abdominal pain, hypotension, hyponatremia, hyperkalemia. 1

Diagnostic Approach When Adrenal Insufficiency Suspected

• Draw morning cortisol and ACTH simultaneously to distinguish primary from secondary adrenal insufficiency. 1
• Low morning cortisol (<250 nmol/L or <9 mcg/dL) with elevated ACTH indicates primary adrenal insufficiency (Addison's disease). 1
• Low morning cortisol with low or inappropriately normal ACTH indicates secondary adrenal insufficiency (hypophysitis). 1
• If morning cortisol is equivocal (250-500 nmol/L), perform cosyntropin stimulation test (250 mcg IM/IV) with cortisol measurement at 30 and 60 minutes; peak cortisol <550 nmol/L confirms adrenal insufficiency. 1

Immediate Management of Confirmed Adrenal Insufficiency

This is a medical emergency requiring immediate action:

• Administer hydrocortisone 100 mg IV or IM immediately, followed by 100 mg every 6-8 hours until recovery. 1, 5
• Infuse 0.9% sodium chloride at 1 L/hour initially until hemodynamic improvement. 1, 5
• Never delay treatment to complete diagnostic workup if clinical suspicion is high—secure blood samples for cortisol and ACTH before giving hydrocortisone if possible, but do not wait for results. 1

Long-term Replacement Therapy

Glucocorticoid replacement:

• Hydrocortisone 15-25 mg daily in 2-3 divided doses (first dose immediately upon waking, last dose at least 6 hours before bedtime). 1, 5
• Adjust based on clinical assessment (weight, blood pressure, energy levels, salt cravings), not laboratory values. 1, 6

Mineralocorticoid replacement (for primary adrenal insufficiency only):

• Fludrocortisone 50-200 mcg daily as a single dose. 1, 5
• Monitor blood pressure and serum electrolytes; reduce dose if hypertension develops but do not discontinue. 1

Critical Sequencing: The Life-Threatening Pitfall

The most dangerous error is replacing thyroid hormone before cortisol in patients with combined deficiencies:

• When cortisol is low and thyroid hormone is replaced first, the increased metabolic rate accelerates cortisol metabolism, which can precipitate acute adrenal crisis. 1
• Always evaluate and replace cortisol FIRST when central hypothyroidism is identified, as this indicates hypophysitis with likely concurrent ACTH deficiency. 1
• This is the second most common hormonal loss in hypophysitis after TSH deficiency. 1

Ongoing Surveillance After Diagnosis

For Hypothyroidism

• Monitor TSH and free T4 every 4-6 weeks during dose titration, then every 6-12 months once stable. 6
• Screen for other autoimmune conditions annually (diabetes, pernicious anemia, celiac disease). 6, 5

For Adrenal Insufficiency

• Annual assessment including weight, blood pressure, serum electrolytes (sodium, potassium). 1, 6
• Bone mineral density every 3-5 years to monitor for glucocorticoid-induced osteoporosis. 1, 6
• Do not use serum cortisol or ACTH levels to guide replacement dosing—these are uninterpretable during treatment. 6

Patient Education Essentials

• Provide Medic Alert identification and steroid emergency card. 1, 5
• Supply emergency injectable hydrocortisone (100 mg) with instructions for self-administration during severe illness. 1, 5
• Educate on stress dosing: double or triple oral hydrocortisone during febrile illness, injury, or surgery. 6, 5

Special Considerations for Immunotherapy Continuation

• Endocrine irAEs typically do not require permanent immunotherapy discontinuation once hormone replacement is established. 1
• Grade 1-2 endocrinopathies: continue immunotherapy with hormone replacement. 1
• Grade 3-4 endocrinopathies: temporarily hold immunotherapy until stabilized on replacement, then may resume. 1
• Close multidisciplinary management with endocrinology is essential for patients with preexisting autoimmune disease. 1
• Endocrine irAEs can occur months after immunotherapy discontinuation, so surveillance should continue for at least 1 year post-treatment. 1

Genetic Susceptibility Note

Patients with HLA-DRB104:05 or DRB109:01 haplotypes have increased susceptibility to autoimmune polyendocrine syndrome affecting thyroid and pituitary, which may be relevant in RA patients of Japanese descent receiving immunotherapy. 7