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All organs

CHECKPOINT-INHIBITOR TOXICITY

Endocrine immune-related adverse events

Hormone deficiency, not inflammation to be suppressed: thyroid dysfunction, hypophysitis, primary adrenal insufficiency and insulin-dependent diabetes, each with its own replacement.

Most rungs on these cards are replacement dosing, not immunosuppression, and the ICI is often continued — but not always: SITC withholds it at any grade of adrenal insufficiency and interrupts it for acute hypophysitis. No weight-based corticosteroid range is carried for this organ. Educational reference, not medical advice.

Anchored on the ASCO, ESMO and SITC chapters for this organ. Every source is named beside the position it supports, and labelled with what kind of source it is.

At a glance

ICI-associated hypothyroidism

Also called: IR-hypothyroidism · immune-related hypothyroidism · checkpoint inhibitor thyroiditis · ICI thyroid dysfunction

Pooled any-grade incidence 7.64%, the highest of the endocrine phenotypes the meta-analysis reports, and usually found on a scheduled thyroid panel rather than by symptoms. The treatment is levothyroxine, not corticosteroids — but check the adrenal axis before the first dose.

commonroutineonset: weeks 6–12

Reported frequency

  • 7.64% (95% CI, 6.23-9.17) — any-grade hypothyroidism incidence

    of patients in randomised controlled trials of ICI mono- or combination therapy · 69 randomised controlled trials with 80 independent reports, involving 42 886 patients with solid tumours

    pooled meta-analysis · 37967245

  • 7.81 (95% CI, 5.68-10.74) — risk ratio for any-grade hypothyroidism

    of ICI arms compared with the control arms of the same randomised trials · The same 69-trial pooled corpus. A ratio, not a share — it is how much the risk rises, not how many patients it happens to

    pooled meta-analysis · 37967245

  • 15% — hypothyroidism incidence with combination ICI therapy

    of patients receiving combination ICI therapy · SITC's chapter rate, stated beside 8% for anti-PD-(L)1 and 3% for anti-CTLA-4 — the highest class rate on this card

    guideline · 34172516

Severity and class

  • roughly 0%–2% — grade ≥3 hypothyroidism

    of patients receiving combination ICI therapies · SITC states the share for combination therapy, the class with the highest any-grade rate, and calls grade ≥3 hypothyroidism rare

    guideline · 34172516

  • about 8% with anti-PD-(L)1 therapy, 3% with anti-CTLA-4 therapy and 15% with combination ICI therapy — hypothyroidism by ICI class

    of patients receiving each ICI class · SITC's chapter rates, stratified by class — a three-way comparison, not a single-class figure

    guideline · 34172516

Onset

SITC gives the median time to hypothyroidism as 10 weeks. ASCO's 14.5 weeks with a range of 1.5-130 weeks is not entered as this entity's median because it is the figure for endocrine irAEs AS A GROUP; the far end of that group range is why SITC keeps testing thyroid function every 6-12 months after the ICI has stopped.

Presentation

  • · Usually detected on scheduled testing rather than by symptoms — SITC tests TSH and fT4 every 4-6 weeks during ICI treatment
  • · ASCO's symptom list: cold intolerance, dry skin, constipation, weight gain and/or fatigue
  • · ESMO keys its treatment to whether the patient is symptomatic, and its ICI decision to whether those symptoms are severe
  • · A normal TSH does not exclude it: in hypophysitis TSH can remain within the reference range, so only an FT4 will pick up the presence of hypothyroidism

Differential

  • · Central (secondary) hypothyroidism from ICI hypophysitis — the distinction changes the order of treatment, because a pituitary lesion means cortisol may also be missing, and it changes monitoring: ASCO states TSH is not helpful for monitoring levothyroxine in central hypothyroidism and FT4 should be used instead
  • · The thyrotoxic phase of ICI thyroiditis, which SITC says frequently evolves into hypothyroidism — roughly 90% of patients who develop thyrotoxicosis do not recover full thyroid function
  • · ICI-associated hyperthyroidism, which the same ESMO paragraph manages differently: the ICI is interrupted at symptomatic grade 2 there and only at grade 3 here

Work-up

  • TSH and free T4 every 4-6 weeks during ICI treatment · All patients

    The detection modality for a diagnosis that is usually asymptomatic, and the measurement ESMO titrates the levothyroxine dose against.

    34172516

  • Thyroid function every 6-12 months after the ICI is stopped · All patients

    SITC continues testing after treatment ends, so stopping the ICI does not close the window.

    34172516

  • Morning cortisol before the first levothyroxine dose · All patients

    Decides the ORDER of replacement. SITC tests morning cortisol in patients with hypothyroid symptoms or an elevated TSH with low fT4 to identify concurrent adrenal insufficiency; ASCO states that if thyroid hormone is replaced first when cortisol is low, the increase in cortisol metabolism can trigger an adrenal crisis.

    34172516

  • Free T4 read independently of TSH · If atypical

    A reference-range TSH does not exclude central hypothyroidism; ASCO states only an FT4 will pick it up, and that FT4 rather than TSH should be used to monitor levothyroxine in the central case.

    34724392

Grade ladder

Grade 1

Continue the ICIOutpatient

Grade 1 — asymptomatic biochemical hypothyroidism. The anchor chapters give no endocrine CTCAE table; ESMO's threshold is whether the patient is symptomatic, and the ICI decision turns on whether those symptoms are severe.

No corticosteroid at this grade

No corticosteroid, and no levothyroxine yet either. SITC states that management of thyroid toxicities generally does not require the use of corticosteroid therapy, and that a patient with elevated TSH and normal fT4 should receive repeat testing routinely, with levothyroxine considered only if the pattern persists. ESMO's replacement recommendation is written for symptomatic cases. This is a sourced absence, not a dose that could not be found.

  • · Hydrocortisone before levothyroxine: ASCO calls using hydrocortisone first when multiple pituitary hormones are missing a critical step for preventing harm with hormone replacement.
  • · Continue the ICI — SITC continues immunotherapy as soon as patients are stable, often without interruption, and ESMO interrupts it only if symptoms are severe
  • · Repeat TSH and fT4 routinely rather than waiting for symptoms; SITC considers levothyroxine if the pattern persists

Escalate when: Symptoms appearing, or a persisting elevated TSH — SITC's own trigger for considering levothyroxine.

Grade 2

Continue the ICIOutpatient

Grade 2 — symptomatic hypothyroidism not meeting ESMO's severe threshold. This is the rung ESMO's phrase 'in grade >2 IR-hypothyroidism ... started in symptomatic cases' sits astride; the entry does not resolve whether its wording includes grade 2, and SITC's dose carries no grade qualifier at all.

Hormone replacement — Levothyroxine — the two societies dose it differently, see below

ESMO starts levothyroxine 50-100 μg/day in symptomatic cases and increases the dose over several weeks until thyroid-stimulating hormone levels normalise. SITC states the same drug by patient type instead of by grade: 1.5-1.6 μg/kg/day for young, healthy patients, 25 or 50 μg/day for patients over 65 years of age or with heart disease. Both are carried in full and neither is averaged into the other — a fixed starting dose and a weight-based one are not the same instruction for a 50 kg 80-year-old.

  • · Do not start thyroid hormone before the adrenal axis is covered — if thyroid hormone is replaced first when cortisol is low, the increase in cortisol metabolism can trigger an adrenal crisis (ASCO).
  • · The ICI continues at this rung; ESMO withholds it only for severe symptoms and SITC continues immunotherapy once the patient is stable
  • · Titrate against TSH over several weeks in the primary case — but ASCO states TSH is not helpful for monitoring levothyroxine where the lesion is central, and FT4 should be used instead

Sources differ here

Corticosteroid dose

  • ESMO 2022 (society guideline) — In grade >2 IR-hypothyroidism, hormone replacement therapy (levothyroxine 50-100 μg/day) should be started in symptomatic cases, and the dose should be increased over several weeks until thyroid-stimulating hormone levels normalise
  • SITC 2021 (society guideline) — Levothyroxine should be administered to patients with hypothyroidism at 1.5–1.6 μg/kg/day for young, healthy patients, and should be administered at 25 or 50 μg/day for patients >65 years of age or with heart disease

Escalate when: Symptoms becoming severe — the point at which ESMO interrupts the ICI.

Grade 3

Hold the ICIOutpatient

Grade 3 — severe symptoms. ESMO's stated threshold for interrupting the ICI.

Hormone replacement — Levothyroxine, titrated to normalise TSH in primary hypothyroidism and to FT4 where the lesion is central

Still replacement, not immunosuppression. No anchor chapter prescribes a corticosteroid for IR-hypothyroidism at any grade, and SITC states that thyroid toxicities generally do not require corticosteroid therapy — a weight-based prednisone range on this rung would be a dosing error. The titration target splits: ESMO increases the dose until thyroid-stimulating hormone levels normalise, which is the primary case; ASCO states that TSH is not helpful in monitoring levothyroxine in central hypothyroidism and FT4 should be used instead.

  • · Order of replacement is itself the intervention here: hydrocortisone first when multiple pituitary hormones are missing, then thyroid hormone (ASCO).
  • · Interrupt the ICI — severe symptoms are ESMO's stated trigger, and it is the one endocrine rung on this card where the societies point in different directions
  • · Consider whether the lesion is pituitary rather than thyroidal; a low morning cortisol suggests adrenal insufficiency but does not indicate whether the problem is pituitary or adrenal (ASCO)

Sources differ here

ICI action

  • ESMO 2022 (society guideline) — ICI therapy should be interrupted only if symptoms are severe (grade ≥3) [IV, A]
  • SITC 2021 (society guideline) — Patients experiencing endocrine toxicities should be treated with hormone replacement, and immunotherapy should generally be continued as soon as patients are stable (often without interruption)
  • ASCO 2021 (society guideline) — It is also not essential that patients stop ICPi therapy, as hormone replacement is generally able to restore functional status quickly

Escalate when: Failure to improve on adequate replacement, or a low morning cortisol — which moves the case onto the hypophysitis and adrenal-insufficiency cards.

Grade 4

Hold the ICIConsider admission

Grade 4 — life-threatening consequences. No anchor chapter writes a separate grade-4 recommendation for IR-hypothyroidism, so the treatment repeats grade 3; what changes is the ICI question, which ASCO answers with an explicit carve-out.

Hormone replacement — Levothyroxine, titrated to normalise TSH in primary hypothyroidism and to FT4 where the lesion is central

Unchanged from grade 3: the chapters give no grade-4-specific endocrine dose. The carve-out that matters at this rung is about the ICI, not the replacement.

  • · Check that hydrocortisone was given before levothyroxine; ASCO ties an adrenal crisis to replacing thyroid hormone first when cortisol is low.
  • · ASCO recommends permanent discontinuation with grade 4 toxicities EXCEPT for endocrinopathies that have been controlled by hormone replacement — this organ is the stated exception, and the exception is conditional on control, so the rung holds rather than discontinues while replacement is established
  • · Endocrinology involvement

Escalate when: Already the top rung; failure to control the deficiency on replacement is what reopens the ICI question.

Rechallenge

reasonable

SITC continues immunotherapy as soon as patients are stable, often without interruption, and ASCO states it is not essential that patients stop ICPi therapy because hormone replacement generally restores functional status quickly; ASCO also exempts endocrinopathies controlled by hormone replacement from the grade-4 permanent-discontinuation rule. The question here is not whether the deficiency has resolved — it usually will not — but whether it is replaced and controlled, which is why the renal-derived preconditions in evaluateRechallenge (full recovery, grade 1-2, steroid-responsive) do not govern this card: no rung on it uses a corticosteroid, and recovery is not the endpoint the guidelines test.

  • · Replacement established and the deficiency controlled — ASCO's stated condition for the endocrinopathy carve-out
  • · Symptoms no longer severe, ESMO's threshold for having interrupted the ICI in the first place
  • · The adrenal axis assessed, so that thyroid replacement is not running ahead of an unreplaced cortisol deficit

Deliberately not carried

  • guidelinePmids — Empty although all three anchors are rows in guidelines.ts. Their stored keyRecommendation strings are scoped to ICI-related nephritis/AKI, so linking them would surface kidney dosing on a thyroid card — the substitution assertion 19.5 exists to block. The endocrine chapters are carried in citations with their own quotes.
  • citations[].quote — extraction normalisation — Every quote is a contiguous verbatim span. Two conventions apply throughout the organ: dropped source words are marked ' ... ' with no unmarked elisions, and the retrieved payloads' inline superscript reference numerals are removed with a single space restored where their removal would join two words. No other character is altered.
  • ladder[].steroid.taper — No rung carries a taper, because no rung carries a systemic corticosteroid: IR-hypothyroidism is treated by replacement at every grade and SITC states thyroid toxicities generally do not require corticosteroid therapy. The step-cadence question 19.18 covers therefore does not arise, and no anchor guideline states a cadence for any organ.
  • ladder[].hospitalization — No endocrine chapter states a care setting for hypothyroidism at any grade. The values are this atlas's conservative reading of the grade wording, not a sourced disposition, and grade 4's consider-admission is the clearest instance.
  • gradeDefinition — ASCO's per-organ CTCAE grade tables are images that did not survive extraction into the ledger, so the rungs are described by the thresholds the chapters themselves use — asymptomatic, symptomatic, severe — rather than by a quoted CTCAE definition.
  • mortality — No cited source reports a case-fatality rate for hypothyroidism, and none is derived from the figures that are carried.
  • onset.rangeWeeksLow / onset.rangeWeeksHigh — SITC gives a median time to hypothyroidism with no dispersion. ASCO's 1.5-130 weeks is the range for endocrine irAEs as a group and is stated in the note in those terms rather than entered as this entity's spread.
  • onset — provenance of the 14.5-week figure — ASCO's endocrine chapter bot-blocks automated retrieval; the group median reaches this file through the archive preserved for docs/irae-citation-ledger.md Addendum 4. It is carried in the note as the group figure and is not entered as this entity's median, which comes from SITC.

Sources

  • Haanen J, et al. (2022) Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-upCited for: The treatment of IR-hypothyroidism as hormone replacement rather than immunosuppression, the levothyroxine starting dose and titration target, and the grade at which the ICI is interrupted.Supporting text: the full text
  • Brahmer JR, et al. (2021) Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsCited for: The class-stratified hypothyroidism rates and the grade ≥3 share; the thyroiditis natural history — most patients who pass through a thyrotoxic phase do not recover full thyroid function — and the median time to hypothyroidism; levothyroxine as the standard of care and its dose, which SITC states per patient type rather than per grade; the monitoring cadence during and after ICI therapy; the morning-cortisol test that precedes replacement; and the endocrine panel's two governing statements — that these toxicities are treated by hormone replacement with immunotherapy generally continued, and that thyroid toxicities generally do not require corticosteroids.Supporting text: the full text
  • Schneider BJ, et al. (2021) Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline UpdateCited for: The onset figures for endocrine irAEs AS A GROUP; the hypothyroid symptom list; why a low morning cortisol does not localise the lesion; the free-T4 caution that a reference-range TSH does not exclude central hypothyroidism, and that TSH cannot be used to monitor levothyroxine in the central case; the hydrocortisone-before-levothyroxine ordering rule and the adrenal-crisis mechanism behind it; ASCO's own endocrine position that stopping the ICI is not essential; and the final block, which is ASCO's CROSS-TOXICITY ladder from the guideline abstract rather than endocrine-chapter guidance, cited as such.Supporting text: the full text + the PubMed abstract (checkable at the link above)
  • Vardarli I, Tan S, Brandenburg T, Weidemann F, Görges R, Herrmann K, Führer D (2024) Risk and Incidence of Endocrine Immune-Related Adverse Effects Under Checkpoint Inhibitor Mono- or Combination Therapy in Solid Tumors: A Meta-Analysis of Randomized Controlled TrialsCited for: Pooled any-grade incidence and risk ratio for hypothyroidism and for insulin-dependent diabetes mellitus, the size of the pooled corpus, and the two meta-regression risk factors — combination ICI for hypophysitis/hypopituitarism, ICI agent for adrenal insufficiency. It does NOT carry a pooled incidence for hyperthyroidism, hypophysitis/hypopituitarism or adrenal insufficiency: for those three the abstract records only that the risk is significantly increased, which is an association and not a measured rate.Supporting text: the PubMed abstract (checkable at the link above)

ICI-associated hyperthyroidism

Also called: IR-hyperthyroidism · immune-related thyrotoxicosis · checkpoint inhibitor thyrotoxicosis · ICI thyroiditis

Usually the thyrotoxic phase of a thyroiditis that ends in hypothyroidism — roughly 90% of patients who develop thyrotoxicosis do not recover full thyroid function. The treatment is a beta blocker, and ESMO interrupts the ICI at symptomatic grade 2 rather than grade 3.

commonroutineonset: weeks 1–6

Reported frequency

  • 5% — hyperthyroidism incidence with anti-PD-(L)1 therapy

    of patients treated with anti-PD-(L)1 inhibitors · SITC's chapter rate for anti-PD-1 and anti-PD-L1 agents pooled

    guideline · 34172516

  • 4% — hyperthyroidism incidence with anti-CTLA-4 therapy

    of patients treated with anti-CTLA-4 inhibitors · SITC's chapter rate, stated in the same sentence as the 5% anti-PD-(L)1 figure. SITC gives no combination rate for hyperthyroidism

    guideline · 34172516

Onset

SITC gives the median time to thyrotoxicosis as 5 weeks, and the median time to the hypothyroidism that usually follows it as 10 weeks — this is the earliest endocrine phenotype in the organ. ASCO's 14.5 weeks with a range of 1.5-130 weeks is the figure for endocrine irAEs AS A GROUP and is not entered as this entity's median.

Presentation

  • · Picked up on the same 4-6-weekly TSH and fT4 schedule that detects hypothyroidism, often before symptoms
  • · ASCO's symptom list: palpitations, heat intolerance, insomnia, frequent bowel movements or weight loss
  • · A phase rather than a steady state — SITC describes thyrotoxicosis during the course of thyroiditis, from destruction of thyroid follicles, frequently followed by hypothyroidism
  • · ESMO's management turns on one axis only — symptomatic or not — with a further split for severe symptoms

Differential

  • · Graves' disease, which SITC says ICI therapy may rarely cause and asks be evaluated in patients with persistently low TSH and high fT4 — it is the presentation where an anti-thyroid drug rather than a beta blocker is the treatment
  • · The transition to ICI-associated hypothyroidism, managed in the same ESMO paragraph but with replacement and a higher ICI-interruption threshold
  • · Central thyroid dysfunction from hypophysitis — ASCO states a low TSH may be consistent with either hyperthyroidism or central hypothyroidism, so a free thyroxine level is needed to confirm which

Work-up

  • TSH and free T4 on the 4-6-weekly ICI schedule · All patients

    Detects the thyrotoxic phase before symptoms, and is the measurement ESMO's symptomatic-versus-asymptomatic decision rests on.

    34172516

  • Repeat TSH and fT4 where TSH is low and fT4 normal · All patients

    SITC repeats the pair routinely in this pattern and treats with beta-blockers only if symptoms of hyperthyroidism or a high fT4 develop; persistently low TSH with high fT4 is its trigger to evaluate for Graves' disease.

    34172516

  • Thyroid function every 6-12 months after treatment ends · All patients

    SITC continues testing beyond the end of ICI therapy — and most patients who develop thyrotoxicosis go on to need long-term levothyroxine.

    34172516

  • Morning cortisol before any thyroid hormone is started · All patients

    Applies the moment replacement is contemplated, which on this card is when the thyrotoxic phase gives way to hypothyroidism: replacing thyroid hormone first when cortisol is low can trigger an adrenal crisis, so hydrocortisone goes first when multiple pituitary hormones are missing.

    34724392

Grade ladder

Grade 1

Continue the ICIOutpatient

Grade 1 — asymptomatic thyrotoxicosis. ESMO's recommendation begins at symptomatic grade 2, and states that ICI therapy should be restarted in asymptomatic cases.

No corticosteroid at this grade

SITC states that management of thyroid toxicities generally does not require the use of corticosteroid therapy, and treats this pattern with repeat testing rather than a drug. ESMO's hyperthyroidism recommendation is scoped to symptomatic grade 2 or above. This is a sourced absence, not a dose that could not be found.

  • · Hydrocortisone before levothyroxine: ASCO calls using hydrocortisone first when multiple pituitary hormones are missing a critical step for preventing harm with hormone replacement.
  • · Continue or restart the ICI — ESMO's rule for asymptomatic cases, and SITC continues immunotherapy once the patient is stable
  • · Keep the 4-6-weekly thyroid panel running; the thyrotoxic phase usually ends in hypothyroidism

Escalate when: Symptoms of hyperthyroidism, or a high fT4 — SITC's trigger for beta blockade and ESMO's for interrupting the ICI.

Grade 2

Hold the ICIOutpatient

Grade 2 — symptomatic thyrotoxicosis. ESMO's stated threshold for interrupting ICI therapy.

Dose not carried

No plan renders here because the two anchors take different positions and neither is fillable as an IraeTaper. ESMO's short course is stated without a taper window or a taper-start trigger, both of which IraeTaper requires; SITC states no corticosteroid is generally needed for thyroid toxicities. Both positions are carried below with their own citations — in the rung's supportive measures and in 'Sources differ here' — rather than as a number in this box.

  • · Start beta blocker therapy — ESMO's first named measure at this rung, and SITC treats symptomatic hyperthyroidism or a high fT4 with beta-blockers.
  • · Patients with asthma or chronic obstructive pulmonary disease should be treated with cardioselective beta-blockers such as atenolol or metoprolol (SITC) — the carve-out that decides which beta blocker.
  • · ESMO states oral prednisolone 0.5-1 mg/kg may be required short-term for gland inflammation or if symptoms are severe; SITC states management of thyroid toxicities generally does not require corticosteroid therapy. The societies differ, and neither number is rendered as this rung's plan.
  • · Do not start thyroid hormone before the adrenal axis is covered — if thyroid hormone is replaced first when cortisol is low, the increase in cortisol metabolism can trigger an adrenal crisis (ASCO).
  • · Interrupt the ICI; ESMO restarts it in asymptomatic cases

Sources differ here

Corticosteroid dose

  • ESMO 2022 (society guideline) — Oral prednisolone 0.5-1 mg/kg may be required short-term for gland inflammation or if symptoms are severe
  • SITC 2021 (society guideline) — Management of thyroid toxicities and T1DM generally do not require the use of corticosteroid therapy

ICI action

  • ESMO 2022 (society guideline) — In symptomatic IR-hyperthyroidism (grade ≥2), ICI therapy should be interrupted and beta blocker therapy should be started
  • SITC 2021 (society guideline) — Patients experiencing endocrine toxicities should be treated with hormone replacement, and immunotherapy should generally be continued as soon as patients are stable (often without interruption)

Escalate when: Severe symptoms, or gland inflammation — the two conditions under which ESMO says a short corticosteroid course may be required.

Grade 3

Hold the ICIConsider admission

Grade 3 — severe symptoms. ESMO writes one recommendation for symptomatic grade 2 or above and names severe symptoms only as a trigger within it, so this rung shares that recommendation and differs in the corticosteroid trigger being met.

Dose not carried

Same position as grade 2, with ESMO's severe-symptom trigger now met. No plan renders because the chapter states no taper window and no taper-start trigger, and because SITC's panel takes the opposite position on whether a corticosteroid is needed at all. Both are carried with their citations in the supportive measures and in 'Sources differ here'.

  • · ESMO states oral prednisolone 0.5-1 mg/kg may be required short-term for gland inflammation or if symptoms are severe — this is the rung where that trigger is met; SITC states thyroid toxicities generally do not require corticosteroid therapy.
  • · Beta blockade and ICI interruption remain the stated measures, with cardioselective agents such as atenolol or metoprolol where there is asthma or COPD (SITC).
  • · Order of replacement is itself the intervention once the thyrotoxic phase passes: hydrocortisone first when multiple pituitary hormones are missing, then thyroid hormone (ASCO).

Sources differ here

Corticosteroid dose

  • ESMO 2022 (society guideline) — Oral prednisolone 0.5-1 mg/kg may be required short-term for gland inflammation or if symptoms are severe
  • SITC 2021 (society guideline) — Management of thyroid toxicities and T1DM generally do not require the use of corticosteroid therapy

Escalate when: Failure to settle on beta blockade and, where the societies' short corticosteroid course is used, on that.

Grade 4

Hold the ICIAdmit

Grade 4 — life-threatening consequences. No anchor chapter writes a grade-4 recommendation for IR-hyperthyroidism; the ICI decision comes from ASCO's cross-toxicity statement and its endocrine carve-out.

Dose not carried

No endocrine-chapter sentence addresses grade 4 hyperthyroidism. ESMO's short course is written for gland inflammation or severe symptoms and is not extended here into a grade-4 dose, and the renal ladder's dose is not carried across (D-STEROID).

  • · Check that hydrocortisone was given before levothyroxine; ASCO ties an adrenal crisis to replacing thyroid hormone first when cortisol is low.
  • · ASCO recommends permanent discontinuation with grade 4 toxicities except for endocrinopathies controlled by hormone replacement, so this rung holds rather than discontinues while control is established
  • · Endocrinology involvement

Escalate when: Already the top rung.

Rechallenge

reasonable

ESMO states plainly that ICI therapy should be restarted in asymptomatic cases, and SITC continues immunotherapy as soon as patients are stable, often without interruption. The renal-derived preconditions in evaluateRechallenge (full recovery, grade 1-2, steroid-responsive) do not govern this card: no rung uses a corticosteroid, so steroid-responsiveness is not a test that can be applied, and the endpoint the guidelines use is symptom control rather than recovery of the gland.

  • · Asymptomatic — ESMO's own condition for restarting
  • · Thyroid function still being monitored on the 4-6-weekly schedule after the restart, because most patients who develop thyrotoxicosis go on to hypothyroidism

Deliberately not carried

  • gradeThreePlus — SITC prints a grade ≥3 share for hypothyroidism and for hypophysitis but none for hyperthyroidism, and no other cited source does. The hypothyroidism figure is not borrowed across.
  • agentClassSkew — SITC's 5% and 4% are two class rates in one sentence with no comparison drawn and no combination arm, so they are carried as two incidence rows rather than converted into a skew. Spec §3.5 makes agentClassSkew a measured comparison; there is none stated.
  • mortality — No cited source reports a case-fatality rate for this entity.
  • secondLine — ESMO's recommendation stops at beta blockade, ICI interruption and a possible short corticosteroid course, and SITC's stops at beta-blockers with a cardioselective carve-out. Neither names a second-line agent, and neither names an anti-thyroid drug outside the Graves' evaluation, so no rung carries one.
  • guidelinePmids — Empty although all three anchors are rows in guidelines.ts: their stored keyRecommendation strings are renal-scoped, so linking them would surface kidney dosing on a thyroid card. The endocrine chapters are carried in citations with their own quotes.
  • citations[].quote — extraction normalisation — Every quote is a contiguous verbatim span. Dropped source words are marked ' ... ' with no unmarked elisions, and the retrieved payloads' inline superscript reference numerals are removed with a single space restored where their removal would join two words. No other character is altered.
  • ladder[].steroid.taper — No rung uses kind: 'systemic', so no rung carries an IraeTaper. That is a schema consequence, not a clinical one: ESMO's short-course oral prednisolone is stated with no taper window and no taper-start trigger, both of which IraeTaper requires, and no anchor guideline states a step cadence for any organ. It does not mean no corticosteroid is indicated — the societies differ on that, and both positions are carried on the g2 and g3 rungs.
  • ladder[].hospitalization — No endocrine chapter states a care setting for hyperthyroidism at any grade. The values are this atlas's conservative reading of the grade wording, not a sourced disposition.
  • gradeDefinition — ASCO's per-organ grade tables did not survive extraction, and ESMO writes one recommendation across symptomatic grade 2 and above. The rungs are therefore described by ESMO's own thresholds rather than by a quoted CTCAE definition.
  • onset — provenance of the 14.5-week figure — ASCO's group median and range reach this file through the archive preserved for docs/irae-citation-ledger.md Addendum 4. They are carried in the note as the group figure; this entity's median is SITC's 5 weeks to thyrotoxicosis.

Sources

  • Haanen J, et al. (2022) Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-upCited for: The ICI interruption threshold for symptomatic IR-hyperthyroidism, beta blockade as the first measure, the short-course oral prednisolone dose for gland inflammation, and the restart rule for asymptomatic cases.Supporting text: the full text
  • Brahmer JR, et al. (2021) Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsCited for: The class-stratified hyperthyroidism rates; the thyroiditis natural history — the thyrotoxic phase evolving into hypothyroidism, with most patients not recovering full thyroid function — and the median time to thyrotoxicosis; Graves' disease as a rare alternative the chapter asks be evaluated; the monitoring cadence; beta blockade as the treatment and the cardioselective carve-out for asthma and COPD; and the panel statement that thyroid toxicities generally do not require corticosteroid therapy. SITC's levothyroxine dosing is deliberately NOT cited here: it is hypothyroidism guidance.Supporting text: the full text
  • Schneider BJ, et al. (2021) Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline UpdateCited for: The onset figures for endocrine irAEs AS A GROUP; the thyrotoxicosis symptom list; the TSH/FT4 sentence behind this card's central-versus-primary differential; the hydrocortisone-before-levothyroxine ordering rule, which applies the moment thyroid hormone is contemplated in a patient whose thyrotoxic phase has passed; ASCO's position that stopping the ICI is not essential; and the closing block, which is ASCO's CROSS-TOXICITY ladder from the guideline abstract, not endocrine-chapter guidance.Supporting text: the full text + the PubMed abstract (checkable at the link above)

ICI-associated hypophysitis

Also called: IR-hypophysitis · hypopituitarism · immune-related hypophysitis · checkpoint inhibitor pituitary inflammation

Pituitary inflammation presenting as headache, visual change or secondary adrenal insufficiency, and imaged before it is treated — SITC asks for a pituitary-protocol MRI to separate it from brain metastases. Replace hydrocortisone before levothyroxine: replacing thyroid hormone first when cortisol is low can trigger an adrenal crisis.

uncommoncriticalonset: weeks 6–12

Reported frequency

  • 1% (0% grade ≥3) — hypophysitis incidence with anti-PD-(L)1 therapy

    of patients treated with anti-PD-1 or anti-PD-L1 agents · SITC's chapter rate for anti-PD-1 and anti-PD-L1 agents pooled

    guideline · 34172516

  • 4% (2% grade ≥3) — hypophysitis incidence with anti-CTLA-4 therapy

    of patients treated with anti-CTLA-4 ICIs · SITC's chapter rate, four times the anti-PD-(L)1 rate stated in the same sentence

    guideline · 34172516

  • 9%–11% — hypophysitis incidence with combination ICI therapy

    of patients receiving ICI combination therapy · SITC's chapter rate — the class in which this uncommon diagnosis stops being uncommon

    guideline · 34172516

Severity and class

  • 0% with anti-PD-(L)1 ICIs and 2% with anti-CTLA-4 ICIs — grade ≥3 hypophysitis

    of patients treated with each ICI class · SITC states the grade ≥3 shares in the same sentence as the any-grade rates; it gives no grade ≥3 figure for combination therapy

    guideline · 34172516

  • 1% with anti-PD-(L)1 ICIs, 4% with anti-CTLA-4 ICIs (0% and 2% grade ≥3, respectively), and 9%–11% with combination ICI therapy — hypophysitis by ICI class

    of patients treated with each ICI class · SITC's chapter rates. The pooled meta-analysis independently makes combination ICI an independent risk factor for any-grade hypophysitis/hypopituitarism, and ASCO records the diagnosis as most commonly seen when ipilimumab is used — three sources pointing the same way, only one of which prints rates

    guideline · 34172516, 37967245

Onset

SITC reports a median of 76 days between ICI initiation and diagnosis in an analysis of 689 patients who developed ICI-related hypophysitis. The figure is left in the source's own unit — converting 76 days into weeks would print a number no source did — and the bucket follows it. ASCO's 14.5 weeks with a range of 1.5-130 weeks is the figure for endocrine irAEs AS A GROUP and is not entered here.

Presentation

  • · SITC's symptom list: fatigue, nausea, vomiting, weakness, headache, and gonadotrophic deficiency including loss of libido or erectile dysfunction
  • · ASCO adds headache and visual changes, especially visual field changes in pituitary swelling
  • · Most often secondary adrenal insufficiency from ACTH deficiency, less commonly TSH, FSH and LH deficiency (SITC)
  • · Severe headache, diplopia or other neurological symptoms — ESMO's own grade-3 features
  • · Secondary adrenal crisis, which ESMO treats as grade 3 insufficiency
  • · Deficiency across the adrenal, thyroid and gonadal axes, which is what ESMO asks be replaced at grades 1-2

Differential

  • · Pituitary or brain metastases — SITC calls a brain scan, preferably a pituitary-protocol MRI, vital to distinguish hypophysitis from alternative causes of headache including brain metastases, because ICI therapy and metastasis can both produce this picture
  • · Primary adrenal insufficiency — a low morning cortisol suggests adrenal insufficiency but does not indicate whether the problem is pituitary or adrenal; a simultaneously measured ACTH that is low points to a pituitary cause, and one that is elevated to a primary adrenal one (ASCO)
  • · Iatrogenic suppression of the axis — SITC warns that cortisol and ACTH results may be inaccurate in a patient receiving steroids at baseline, such as dexamethasone premedication with chemo-immunotherapy
  • · Primary hypothyroidism — in hypophysitis TSH can remain within the reference range, so only an FT4 will pick up the presence of hypothyroidism

Work-up

  • Brain scan, preferably a pituitary-protocol MRI · All patients

    SITC calls this vital to distinguish hypophysitis from alternative causes of headache, including brain metastases; typical findings are geographic hypoenhancing lesions in the anterior lobe of the pituitary gland.

    34172516

  • ACTH and morning cortisol, with FSH, LH, TSH, fT4 and sex hormones where both are low · All patients

    SITC's own sequence: a low TSH with normal or low fT4 prompts ACTH and morning cortisol, and low results prompt the full anterior-pituitary panel. A low morning cortisol suggests adrenal insufficiency but does not localise the lesion, and the answer changes which axes need replacing.

    34172516

  • Check whether the patient is already on corticosteroids before interpreting cortisol or ACTH · All patients

    SITC states these results may be inaccurate in patients receiving steroids at baseline — for example dexamethasone premedication with chemo-immunotherapy — which is the commonest way this axis is misread.

    34172516

  • Free T4 rather than TSH alone · All patients

    TSH can remain within the reference range in hypophysitis, so only an FT4 will pick up the hypothyroidism.

    34724392

  • Assessment of the adrenal, thyroid and gonadal axes · All patients

    These are the three axes ESMO asks be replaced where deficient at grades 1-2; an axis not measured is an axis not replaced.

    36270461

Grade ladder

Grade 1

Continue the ICIOutpatient

Grade 1 — asymptomatic. ESMO groups grades 1-2 as 'asymptomatic and symptomatic cases without severe features'; no anchor chapter supplies a CTCAE definition for this diagnosis.

Hormone replacement — Replacement doses of the deficient hormones — adrenal, thyroid and gonadal axes, hydrocortisone first

ESMO initiates replacement doses of deficient hormones across the adrenal, thyroid and gonadal axes in asymptomatic and symptomatic cases without severe features. No replacement dose is rendered: SITC's hypophysitis hydrocortisone figure is dropped rather than transcribed, because its unit did not survive extraction (see the entry's omitted row), and ESMO names no dose.

  • · Hydrocortisone before levothyroxine: ASCO calls using hydrocortisone first when multiple pituitary hormones are missing a critical step for preventing harm with hormone replacement.
  • · SITC interrupts immunotherapy where symptoms of ACUTE hypophysitis are observed; at an asymptomatic rung that trigger is not met, and both SITC and ASCO continue treatment in the stable patient
  • · Image before treating — SITC's brain scan separates hypophysitis from a pituitary or brain metastasis
  • · Measure each axis before replacing any of them

Escalate when: Any severe feature — headache, diplopia or other neurological symptoms — or evidence of adrenal crisis.

Grade 2

Hold the ICIOutpatient

Grade 2 — symptomatic without severe features. ESMO manages it with the same replacement recommendation as grade 1.

Hormone replacement — Replacement doses of the deficient hormones, hydrocortisone first

Unchanged from grade 1: ESMO's replacement recommendation covers asymptomatic and symptomatic cases without severe features together. The order is what changes management, not the dose. SITC adds that patients on hydrocortisone should be given a medical alert device and educated, with their caregivers, on stress doses during hospitalisation or severe illness and on emergency parenteral dexamethasone or hydrocortisone.

  • · Do not start thyroid hormone before the adrenal axis is covered — if thyroid hormone is replaced first when cortisol is low, the increase in cortisol metabolism can trigger an adrenal crisis (ASCO).
  • · SITC interrupts immunotherapy and administers corticosteroids where symptoms of acute hypophysitis are observed; ASCO states it is not essential that patients stop ICPi therapy. The hold at this rung follows SITC's organ-chapter rule — see 'Sources differ here'.
  • · Stress-dose education and a medical alert device before discharge (SITC)
  • · Endocrinology involvement

Sources differ here

ICI action

  • SITC 2021 (society guideline) — If symptoms of acute hypophysitis are observed, immunotherapy should be interrupted and corticosteroids administered (LE: 4)
  • ASCO 2021 (society guideline) — It is also not essential that patients stop ICPi therapy, as hormone replacement is generally able to restore functional status quickly

Escalate when: Severe headache, diplopia or other neurological symptoms, or secondary adrenal crisis.

Grade 3

Hold the ICIAdmit

Grade 3 — severe headache, diplopia or other neurological symptoms, which is how ESMO defines the rung, or secondary adrenal crisis, which it calls grade 3 insufficiency.

Hormone replacement — Stress-dose corticosteroid replacement

ESMO manages secondary adrenal crisis — grade 3 insufficiency — with stress-dose CS replacement. This is the same arm the primary adrenal-insufficiency card uses at its own grade 3, from the same ESMO paragraph, and it renders no weight-based mg/day. ESMO's separate anti-inflammatory indication for severe neurological features is a different question and is carried in the supportive measures, where it can be shown against ASCO's position on it.

  • · ESMO indicates (methyl)prednisolone 1 mg/kg where severe headache, diplopia or other neurological symptoms are present. ASCO states there is no good evidence at this time that high-dose corticosteroids improve the rate of pituitary hormone recovery, and asks that the benefit — possible improvement in headache — be balanced against corticosteroid harms. See 'Sources differ here'.
  • · Order of replacement is itself the intervention here: hydrocortisone first when multiple pituitary hormones are missing, then thyroid hormone (ASCO).
  • · SITC interrupts immunotherapy and administers corticosteroids where symptoms of acute hypophysitis are observed
  • · Stress-dose corticosteroid replacement for adrenal crisis takes precedence over any decision about the ICI

Sources differ here

Corticosteroid dose

  • ESMO 2022 (society guideline) — For IR-hypophysitis, if severe headache, diplopia or other neurological symptoms are present (grade 3), (methyl)prednisolone 1 mg/kg is indicated
  • ASCO 2021 (society guideline) — For example, there is no good evidence at this time that high-dose corticosteroids improve the rate of pituitary hormone recovery. ... Therefore, a clinical judgment is needed to balance benefits, such as the possibility of improved headache, with risks, such as corticosteroid adverse effects, on glycemic control and delay of therapy
  • SITC 2021 (society guideline) — If symptoms of acute hypophysitis are observed, immunotherapy should be interrupted and corticosteroids administered (LE: 4)

Escalate when: Deterioration despite stress-dose replacement, or neurological signs that do not respond.

Grade 4

Hold the ICIAdmit

Grade 4 — life-threatening consequences. No anchor chapter writes a grade-4 hypophysitis recommendation, so the treatment repeats grade 3 and the ICI question is answered by ASCO's carve-out.

Hormone replacement — Stress-dose corticosteroid replacement

Unchanged from grade 3: ESMO's stress-dose replacement for secondary adrenal crisis is written at grade 3 and no chapter extends a separate grade-4 dose. The renal ladder's mg/kg is not carried across (D-STEROID).

  • · Check that hydrocortisone was given before levothyroxine; ASCO ties an adrenal crisis to replacing thyroid hormone first when cortisol is low.
  • · ASCO recommends permanent discontinuation with grade 4 toxicities except for endocrinopathies that have been controlled by hormone replacement — which is why this rung holds while replacement is established rather than discontinuing
  • · Stress-dose corticosteroid replacement for adrenal crisis takes precedence over any decision about the ICI

Escalate when: Already the top rung.

Rechallenge

reasonable

ASCO carves endocrinopathies that have been controlled by hormone replacement out of the grade-4 permanent-discontinuation rule and states it is not essential that patients stop ICPi therapy; SITC continues immunotherapy as soon as patients are stable. Hypophysitis usually leaves permanent deficiencies, so 'controlled' rather than 'resolved' is the condition being tested — which is why the renal-derived preconditions in evaluateRechallenge (full recovery, grade 1-2, steroid-responsive) do not govern this card. The adrenal axis has to be the one that is controlled first.

  • · Replacement established across every deficient axis and the patient stable on it
  • · Hydrocortisone in place before any thyroid hormone, so a rechallenge does not begin with an unreplaced cortisol deficit
  • · A plan for stress dosing at the next intercurrent illness, with the medical alert device and education SITC asks for

Deliberately not carried

  • ladder[].steroid — SITC's hydrocortisone replacement dose — SITC states a hydrocortisone replacement dose for hypophysitis and it is NOT carried. Every retrieved payload renders its unit as milligrams per metre per day, which is not a unit: the denominator is a body-surface-area term whose exponent was lost in conversion, and the payload contains zero superscript characters anywhere, so it cannot be recovered from anything held here. The figure is dropped rather than transcribed or repaired — printing the corrupted string invites reading it as a plain mg/day figure, roughly half a replacement dose, on the one card where under-replacement causes adrenal crisis, and supplying the expected exponent from clinical knowledge is exactly the substitution the citation contract forbids. Needs a human with a browser to read the published article and confirm the exponent before any dose is rendered here (ledger Addendum 5).
  • mortality — No cited source reports a case-fatality rate for hypophysitis, including for the adrenal crisis it can present as.
  • secondLine — No anchor chapter names a steroid-sparing or second-line immunosuppressant for IR-hypophysitis, so no rung carries one. The colitis and hepatitis ladders in the same documents do, and reaching for those agents here would be exactly the cross-organ carry D-STEROID forbids.
  • ladder[].steroid.taper — No rung uses kind: 'systemic', so no rung carries an IraeTaper. ESMO's (methyl)prednisolone 1 mg/kg for severe neurological features has no taper window and no start trigger, and no anchor guideline states a step cadence for any organ; the indication is carried in the g3 supportive measures with its citation instead.
  • ladder[].hospitalization — No endocrine chapter states a care setting for hypophysitis at any grade. Admission at grades 3-4 is this atlas's reading of ESMO's adrenal-crisis wording, not a sourced disposition.
  • gradeDefinition — ASCO's per-organ grade tables did not survive extraction. The rungs use ESMO's own thresholds — asymptomatic, symptomatic without severe features, severe neurological features or secondary adrenal crisis — instead of a quoted CTCAE definition.
  • rechallenge.recurrence — The pharmacovigilance analysis reports a recurrence rate for adrenal events and for three non-endocrine irAEs, but nothing for hypophysitis, and its all-irAE figure is not this entity's rate. None is carried, and that study is not cited on this card.
  • guidelinePmids — Empty although all three anchors are rows in guidelines.ts: their stored keyRecommendation strings are renal-scoped, so linking them would surface kidney dosing on a pituitary card.
  • citations[].quote — extraction normalisation — Every quote is a contiguous verbatim span. Dropped source words are marked ' ... ' with no unmarked elisions, and the retrieved payloads' inline superscript reference numerals are removed with a single space restored where their removal would join two words. No other character is altered.
  • onset — provenance of the 14.5-week figure — ASCO's group median and range reach this file through the archive preserved for docs/irae-citation-ledger.md Addendum 4. They are carried in the note as the group figure; this entity's own figure is SITC's 76-day median, left in days.

Sources

  • Haanen J, et al. (2022) Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-upCited for: The grade-3 features that change management (severe headache, diplopia, other neurological symptoms), the (methyl)prednisolone indication attached to them, stress-dose corticosteroid replacement for secondary adrenal crisis, and replacement across the adrenal, thyroid and gonadal axes at grades 1-2.Supporting text: the full text
  • Brahmer JR, et al. (2021) Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsCited for: The symptom list; secondary adrenal insufficiency as the usual manifestation; the pituitary-protocol MRI that separates hypophysitis from brain metastases and the MRI appearance; the warning that cortisol and ACTH are unreliable in a patient already on steroids; the class-stratified incidence and grade ≥3 share; the median time to diagnosis; the panel's interrupt-and-treat rule for acute hypophysitis; and the stress-dose and medical-alert education. SITC's hydrocortisone replacement figure is NOT cited here — see the entry's `omitted` row for why it is dropped rather than transcribed.Supporting text: the full text
  • Schneider BJ, et al. (2021) Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline UpdateCited for: The onset figures for endocrine irAEs AS A GROUP; the presenting headache and visual-field changes; the agent this diagnosis skews to; why a low morning cortisol does not localise the lesion; the free-T4 caution; the hydrocortisone-before-levothyroxine ordering rule; ASCO's two endocrine-chapter positions on management — that there is no good evidence high-dose corticosteroids improve pituitary hormone recovery, and that stopping the ICI is not essential; and the closing block, which is ASCO's CROSS-TOXICITY ladder from the guideline abstract, not endocrine-chapter guidance.Supporting text: the full text + the PubMed abstract (checkable at the link above)
  • Vardarli I, Tan S, Brandenburg T, Weidemann F, Görges R, Herrmann K, Führer D (2024) Risk and Incidence of Endocrine Immune-Related Adverse Effects Under Checkpoint Inhibitor Mono- or Combination Therapy in Solid Tumors: A Meta-Analysis of Randomized Controlled TrialsCited for: Pooled any-grade incidence and risk ratio for hypothyroidism and for insulin-dependent diabetes mellitus, the size of the pooled corpus, and the two meta-regression risk factors — combination ICI for hypophysitis/hypopituitarism, ICI agent for adrenal insufficiency. It does NOT carry a pooled incidence for hyperthyroidism, hypophysitis/hypopituitarism or adrenal insufficiency: for those three the abstract records only that the risk is significantly increased, which is an association and not a measured rate.Supporting text: the PubMed abstract (checkable at the link above)

ICI-associated primary adrenal insufficiency

Also called: IR-primary adrenal insufficiency · immune-related adrenalitis · checkpoint inhibitor adrenal insufficiency · primary hypoadrenalism

Replacement corticosteroids at every grade and stress doses when the presentation is severe — with a mineralocorticoid alongside them, which is what separates the primary lesion from the pituitary one. SITC withholds the ICI at any grade; ASCO says stopping is not essential.

rarecriticalonset: weeks 6–12

Severity and class

  • 1% with anti-PD-(L)1 or CTLA-4 therapies, and an estimated 5% with combination ICIs — adrenal insufficiency by ICI class

    of patients treated with each ICI class · SITC's chapter rates for adrenal insufficiency as a whole — they are not restricted to the PRIMARY lesion this card covers, and the same chapter says primary adrenal insufficiency is rare in ICI-treated patients. The pooled meta-analysis independently finds ICI agent an independent risk factor for adrenal insufficiency without printing class rates

    guideline · 34172516, 37967245

Onset

SITC gives a median onset of 10 weeks from the first dose of ICI therapy, in a review of case reports. ASCO's 14.5 weeks with a range of 1.5-130 weeks is the figure for endocrine irAEs AS A GROUP and is not entered as this entity's median.

Presentation

  • · Non-specific and hard to diagnose without testing — SITC lists nausea, loss of appetite, weight loss, fatigue, light-headedness, hypoglycaemia and hypotension
  • · ASCO's list overlaps: nausea, vomiting, abdominal pain, weight loss, lightheadedness or orthostasis or syncope, and profound fatigue
  • · Adrenal crisis from vasodilatory shock is the consequence that governs the card; SITC asks for monitoring for haemodynamic instability
  • · High serum ACTH with a low morning serum cortisol is the pattern SITC associates with the primary lesion
  • · ESMO splits the presentation only into asymptomatic or minimally symptomatic cases and severe ones, and the split decides replacement dose versus stress dose

Differential

  • · Secondary adrenal insufficiency from ICI hypophysitis — the same low morning cortisol, a different lesion, and a different set of axes to replace. ASCO: a simultaneously measured ACTH that is low suggests hypophysitis, pituitary mass or an iatrogenic cause, while in primary adrenal insufficiency the morning ACTH will be elevated
  • · Exogenous corticosteroid exposure — ASCO states serum cortisol should not be routinely measured while a patient is on corticosteroid therapy, and that ACTH stimulation testing may be performed if a diagnosis is needed
  • · Any concurrent thyroid deficiency, because replacing that first while cortisol is low is what precipitates a crisis

Work-up

  • ACTH stimulation test · All patients

    SITC calls it the standard of care assessment for adrenocortical insufficiency, because morning cortisol and ACTH levels are not always definitive; it tests AM cortisol and a comprehensive metabolic panel alongside it.

    34172516

  • Morning cortisol with a simultaneous ACTH · All patients

    The pair localises the lesion: high serum ACTH with low morning cortisol marks the primary lesion (SITC), while a low ACTH points to hypophysitis, a pituitary mass or an iatrogenic cause (ASCO). A low cortisol alone does not distinguish them.

    34172516

  • Monitoring for signs of adrenal crisis, such as haemodynamic instability · All patients

    SITC asks for it in every patient with adrenal insufficiency; adrenal crisis from vasodilatory shock is the event this card exists to prevent.

    34172516

  • Review of current corticosteroid exposure before interpreting a cortisol · All patients

    ASCO states serum cortisol should not be routinely measured on corticosteroid therapy because of assay effects, suppressed endogenous levels and the fact that the patient is already treated for any underlying insufficiency.

    34724392

Grade ladder

Grade 1

Hold the ICIOutpatient

Grade 1 — asymptomatic or minimally symptomatic. ESMO groups grades 1-2 under one recommendation and supplies no CTCAE definition.

Hormone replacement — Replacement corticosteroids, with a mineralocorticoid alongside them

ESMO indicates replacement corticosteroids in asymptomatic or minimally symptomatic cases and names no drug, dose or schedule. ASCO adds the part that is specific to the PRIMARY lesion: fludrocortisone is needed in addition to hydrocortisone in most cases of primary adrenal insufficiency, which loses mineralocorticoid as well as glucocorticoid production, and is generally not necessary in secondary or central insufficiency. SITC's hydrocortisone figure is written for hypophysitis — a different diagnosis — and is not carried here.

  • · Withhold the ICI: SITC states that if adrenal insufficiency of ANY grade is diagnosed, immunotherapy should be temporarily withheld and steroid replacement therapy started. ASCO states it is not essential that patients stop ICPi therapy — see 'Sources differ here'.
  • · Hydrocortisone before levothyroxine: ASCO calls using hydrocortisone first when multiple pituitary hormones are missing a critical step for preventing harm with hormone replacement.
  • · Pair the morning cortisol with an ACTH before assuming the lesion is adrenal; the answer decides whether a mineralocorticoid is needed
  • · Provide a medical alert bracelet (SITC)

Sources differ here

ICI action

  • SITC 2021 (society guideline) — If adrenal insufficiency of any grade is diagnosed, immunotherapy should be temporarily withheld and steroid replacement therapy should be started
  • ASCO 2021 (society guideline) — It is also not essential that patients stop ICPi therapy, as hormone replacement is generally able to restore functional status quickly

Escalate when: Symptoms becoming severe, which is ESMO's threshold for stress replacement doses.

Grade 2

Hold the ICIOutpatient

Grade 2 — minimally symptomatic. ESMO manages it with the same replacement recommendation as grade 1.

Hormone replacement — Replacement corticosteroids, with a mineralocorticoid alongside them

Unchanged from grade 1: ESMO writes one recommendation across grades 1-2 and reserves stress doses for severe cases; ASCO's fludrocortisone rule applies at every grade of the primary lesion.

  • · Do not start thyroid hormone before the adrenal axis is covered — if thyroid hormone is replaced first when cortisol is low, the increase in cortisol metabolism can trigger an adrenal crisis (ASCO).
  • · SITC withholds immunotherapy at any grade of adrenal insufficiency and starts steroid replacement
  • · Endocrinology involvement

Escalate when: A severe presentation — ESMO moves to stress replacement doses at grade 3 or above.

Grade 3

Hold the ICIAdmit

Grade 3 — a severe case. ESMO's stated threshold for stress replacement doses.

Hormone replacement — Stress replacement doses of corticosteroid

ESMO requires stress replacement doses in severe cases. Still replacement, not immunosuppression: the chapter states no anti-inflammatory mg/kg for primary adrenal insufficiency at any grade, and none is imported from another organ or another endocrine entity. The mineralocorticoid continues alongside it in the primary lesion (ASCO).

  • · Order of replacement is itself the intervention here: hydrocortisone first when multiple pituitary hormones are missing, then thyroid hormone (ASCO).
  • · Stress dosing comes before any decision about the ICI; SITC withholds immunotherapy at any grade
  • · Monitor for haemodynamic instability — the sign of the adrenal crisis this rung exists for (SITC)

Escalate when: Failure to stabilise on stress replacement doses.

Grade 4

Hold the ICIAdmit

Grade 4 — life-threatening consequences. ESMO's severe-case recommendation is written for grade 3 or above, so this rung repeats it; ASCO's endocrine carve-out is what separates the two rungs.

Hormone replacement — Stress replacement doses of corticosteroid

Unchanged from grade 3 — ESMO writes stress replacement doses for severe cases at grade 3 or above and gives no separate grade-4 dose.

  • · Check that hydrocortisone was given before levothyroxine; ASCO ties an adrenal crisis to replacing thyroid hormone first when cortisol is low.
  • · ASCO recommends permanent discontinuation with grade 4 toxicities except for endocrinopathies that have been controlled by hormone replacement, so this rung holds while control is established rather than discontinuing
  • · Agree a sick-day stress-dosing plan and provide a medical alert bracelet before discharge (SITC)

Escalate when: Already the top rung.

Rechallenge

reasonable

This is the one endocrine entity a rechallenge study reports separately, and it reports it favourably: adrenal events had a LOWER recurrence rate than other irAEs after rechallenge (reporting OR, 0.33; 95% CI, 0.13-0.86), against an all-irAE recurrence of 28.8%. ASCO's carve-out for endocrinopathies controlled by hormone replacement points the same way, and the renal-derived preconditions in evaluateRechallenge (full recovery, grade 1-2, steroid-responsive) do not govern here — the deficiency does not recover and the corticosteroid is replacement rather than treatment, so 'controlled on replacement' is the test. Neither statement licenses rechallenging a patient whose replacement is not established.

  • reporting OR 0.33 (95% CI, 0.13-0.86) — a lower recurrence rate than other irAEs — recurrence of the same irAE after rechallenge, adrenal events versus other irAEs

    of adrenal events against all other irAEs among the 452 informative rechallenges (of 6123 irAEs associated with ICI rechallenges) · An observational, cross-sectional pharmacovigilance cohort read from the World Health Organization database VigiBase. A reporting odds ratio comparing adrenal events with other irAEs, not an absolute recurrence rate for this entity; 130 recurrences (28.8%) were observed across all irAEs

    pharmacovigilance · 32297899

  • · Replacement established and the patient stable on it — ASCO's condition for the endocrinopathy carve-out
  • · A stress-dosing plan in place before the next ICI dose
  • · The lesion localised, so a pituitary cause is not being managed as an adrenal one — and so the mineralocorticoid question is answered

Deliberately not carried

  • incidence — SITC's 1% and 5% describe adrenal insufficiency as a whole rather than the PRIMARY lesion this card covers, and the same chapter calls primary adrenal insufficiency rare without printing a rate for it. They are carried in agentClassSkew with that scope stated, and no incidence row asserts them as this entity's frequency. The pooled meta-analysis records the risk as significantly increased but prints no pooled incidence.
  • gradeThreePlus / mortality — No cited source reports a grade 3 or higher share or a case-fatality rate, including for adrenal crisis.
  • steroid — replacement drug and dose — ESMO names no drug, dose or schedule for primary adrenal insufficiency: it says replacement corticosteroids, and stress replacement doses in severe cases. ASCO names fludrocortisone as an addition without a dose. SITC's hydrocortisone figure belongs to its hypophysitis sentence, is a different diagnosis, and is in any case dropped for the unit problem recorded on that card. No mg/day is rendered anywhere on this card.
  • ladder[].steroid.taper — No rung uses kind: 'systemic', so no rung carries an IraeTaper. Every rung here is replacement, which is not tapered off in the sense IraeTaper models, and no endocrine chapter states a taper window, start trigger or step cadence for any endocrine entity.
  • ladder[].hospitalization — No endocrine chapter states a care setting for adrenal insufficiency at any grade. Admission at grades 3-4 is this atlas's reading of ESMO's severe-case wording and SITC's adrenal-crisis warning, not a sourced disposition.
  • gradeDefinition — ASCO's per-organ grade tables did not survive extraction. The rungs use ESMO's own split — asymptomatic or minimally symptomatic versus severe — rather than a quoted CTCAE definition.
  • guidelinePmids — Empty although all three anchors are rows in guidelines.ts: their stored keyRecommendation strings are renal-scoped, so linking them would surface kidney dosing on an adrenal card.
  • citations[].quote — extraction normalisation — Every quote is a contiguous verbatim span. Dropped source words are marked ' ... ' with no unmarked elisions, and the retrieved payloads' inline superscript reference numerals are removed with a single space restored where their removal would join two words. No other character is altered.
  • onset — provenance of the 14.5-week figure — ASCO's group median and range reach this file through the archive preserved for docs/irae-citation-ledger.md Addendum 4. They are carried in the note as the group figure; this entity's median is SITC's 10 weeks.

Sources

  • Haanen J, et al. (2022) Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-upCited for: Replacement corticosteroids as the treatment of IR-primary adrenal insufficiency at grades 1-2, and stress replacement doses in severe cases.Supporting text: the full text
  • Brahmer JR, et al. (2021) Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsCited for: Adrenal crisis as the consequence that governs this card; the non-specific symptom list; the high-ACTH-with-low-morning-cortisol pattern that marks a primary lesion and the ACTH stimulation test SITC calls the standard of care; the class-stratified rates and the median onset; and the panel rule that the ICI is temporarily withheld and steroid replacement started at ANY grade of adrenal insufficiency.Supporting text: the full text
  • Schneider BJ, et al. (2021) Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline UpdateCited for: The onset figures for endocrine irAEs AS A GROUP; the adrenal symptom list; why a low morning cortisol cannot on its own tell a primary lesion from a secondary one, and the ACTH pattern that can; the MINERALOCORTICOID rule — fludrocortisone in addition to hydrocortisone in most cases of primary adrenal insufficiency, and generally not in the secondary or central case; the caution that serum cortisol should not be measured routinely on corticosteroid therapy; ASCO's position that stopping the ICI is not essential; and the closing block, which is ASCO's CROSS-TOXICITY ladder from the guideline abstract.Supporting text: the full text + the PubMed abstract (checkable at the link above)
  • Vardarli I, Tan S, Brandenburg T, Weidemann F, Görges R, Herrmann K, Führer D (2024) Risk and Incidence of Endocrine Immune-Related Adverse Effects Under Checkpoint Inhibitor Mono- or Combination Therapy in Solid Tumors: A Meta-Analysis of Randomized Controlled TrialsCited for: Pooled any-grade incidence and risk ratio for hypothyroidism and for insulin-dependent diabetes mellitus, the size of the pooled corpus, and the two meta-regression risk factors — combination ICI for hypophysitis/hypopituitarism, ICI agent for adrenal insufficiency. It does NOT carry a pooled incidence for hyperthyroidism, hypophysitis/hypopituitarism or adrenal insufficiency: for those three the abstract records only that the risk is significantly increased, which is an association and not a measured rate.Supporting text: the PubMed abstract (checkable at the link above)
  • Dolladille C, et al. (2020) Immune Checkpoint Inhibitor Rechallenge After Immune-Related Adverse Events in Patients With CancerCited for: The study design and database behind the figure — a pharmacovigilance cohort read from the World Health Organization's VigiBase, which is what makes every number here a reporting quantity rather than an incidence; the lower recurrence rate of adrenal events after rechallenge relative to other irAEs; and the all-irAE recurrence rate that figure sits against. Adrenal events are the only endocrine entity the analysis reports separately.Supporting text: the PubMed abstract (checkable at the link above)

ICI-associated insulin-dependent diabetes

Also called: IR-DM · immune-related diabetes · checkpoint inhibitor diabetes · ICI-induced type 1 diabetes · autoimmune diabetes

Rare, abrupt and permanent insulin deficiency: of the 12 new-onset cases in a PD-1-inhibitor series, 67% presented in ketoacidosis and 83% had low or undetectable C-peptide, and the diabetes did not resolve. The treatment is insulin — ASCO states no immunosuppressive strategy is indicated.

rarecriticalonset: any time on therapy

Reported frequency

  • 0.087% (95% CI, 0.019-0.189) — any-grade insulin-dependent diabetes mellitus incidence

    of patients in randomised controlled trials of ICI mono- or combination therapy · 69 randomised controlled trials with 80 independent reports, involving 42 886 patients with solid tumours

    pooled meta-analysis · 37967245

  • 1.52 (95% CI, 1.07-2.18) — risk ratio for insulin-dependent diabetes mellitus

    of ICI arms compared with the control arms of the same randomised trials · The same 69-trial pooled corpus. The only other risk ratio the abstract prints is 7.81, for hypothyroidism

    pooled meta-analysis · 37967245

  • approximately 1% — ICI-induced diabetes incidence

    of ICI-treated patients · SITC's chapter estimate, stated beside a rate of <1%–2% in patients treated with anti-PD-(L)1 inhibitors; SITC calls CTLA-4-associated diabetes a very rare occurrence

    guideline · 34172516

  • 1.8% — insulin deficiency presenting as new-onset diabetes or worsening of pre-existing type 2 diabetes

    of patients treated with PD-1 inhibitors · Single-centre review of 1444 ICI-treated patients over 6 years, 1163 of whom received PD-1 inhibitors. PD-1 RECIPIENTS ONLY, and a wider case definition than the pooled trial figure above — it counts worsening of pre-existing type 2 diabetes as well as new-onset disease, which is part of why the two numbers are so far apart. They are not reconciled or averaged

    cohort · 30899528

Severity and class

  • 2.2% with pembrolizumab and 1% with nivolumab — ICI-induced diabetes by PD-1 inhibitor

    of patients treated with each agent at one cancer centre · Single-centre review of 1444 ICI-treated patients; the 21 cases came from the 1163 who received PD-1 inhibitors. The same abstract reports ipilimumab at 0%, so the series records no CTLA-4 signal at all — that figure is stated here rather than inside a pd1-stratified value, and nothing here may be rendered as an ICI-class figure

    cohort · 30899528

Onset

SITC states T1DM may develop shortly after the beginning of ICI treatment or as much as 1 year following the start of treatment, which is why the bucket is any-time. New-onset insulin-dependent diabetes developed after a median of four cycles or 5 months in a PD-1-inhibitor series; the units are the paper's, no weeks figure is printed and none is derived here.

Presentation

  • · Often fulminant: SITC describes the initial presentation as fulminant T1DM with diabetic ketoacidosis, and 67% of the 12 new-onset cases in the PD-1 series presented in ketoacidosis
  • · But not always — SITC notes patients may be asymptomatic or present with fatigue, nausea, vomiting, weight loss, polyuria or polydipsia
  • · 83% of those 12 new-onset cases had low or undetectable C-peptide, and autoantibodies were elevated in 5 of 7 (71%) tested at new-onset diabetes; SITC puts the autoantibody yield at up to 53% of cases
  • · Median age 61 years, with a body mass index higher than expected for spontaneous type 1 diabetes — it does not look like the classic phenotype
  • · Other immune-related adverse events occurred in 62% of the 21-case series, most commonly immune-mediated thyroid disease
  • · Diabetes did not resolve during a median follow-up of 1 year

Differential

  • · Worsening of pre-existing type 2 diabetes, which accounted for 9 of the 21 cases in the same series and is a different problem from new-onset insulin deficiency — ASCO frames the clinician's task as distinguishing the two quickly
  • · Corticosteroid-induced hyperglycaemia: ASCO scopes its concern to new-onset hyperglycaemia in a patient WITHOUT risk factors for type 2 diabetes, naming pre-existing disease and corticosteroid exposure as those risk factors — which is the competing explanation on a patient being treated for another irAE
  • · A presentation that resembles spontaneous type 1 diabetes but arrives in an older, heavier patient and progresses faster to severe insulin deficiency

Work-up

  • Urine ketones, acid-base status and electrolytes · All patients

    ASCO's screen for DKA and for the need for inpatient evaluation; SITC hospitalises patients with severe hyperglycaemia or DKA and holds the ICI until the DKA resolves. This is the finding that decides disposition.

    34724392

  • C-peptide, islet autoantibodies and HbA1c · All patients

    SITC's diagnostic panel for new-onset type I diabetes. C-peptide was low or undetectable in 83% of the new-onset cases — the measurement that separates insulin deficiency from worsening type 2 diabetes — and ASCO adds that treatment should not be delayed pending results.

    34172516

  • Thyroid function alongside the diabetes work-up · All patients

    Other irAEs occurred in 62% of the series, most commonly immune-mediated thyroid disease, so a second endocrine axis is more likely than not.

    30899528

  • Endocrinology consultation · All patients

    ASCO asks for it wherever autoimmune diabetes is suspected, even without DKA, because of the complex regimen and education required — and says hospitalisation is appropriate where outpatient endocrinology is not readily available.

    34724392

Grade ladder

Grade 1

Continue the ICIOutpatient

Grade 1 — hyperglycaemia below the grade-2 threshold, without ketoacidosis. ESMO's recommendation is keyed to new-onset IR-DM rather than to a glycaemic grade, so where insulin-dependent diabetes is established the same prompt insulin initiation applies at this rung. No anchor chapter supplies a CTCAE definition here.

Hormone replacement — Insulin

ESMO warrants prompt insulin initiation for new-onset IR-DM and states no grade threshold; ASCO uses insulin wherever the diagnosis is in question. Corticosteroids are not the treatment of this irAE at any grade: SITC states management of T1DM generally does not require corticosteroid therapy and ASCO states no immunosuppressive strategy is approved for type 1 diabetes or considered indicated in checkpoint inhibitor-associated diabetes. A weight-based prednisone range on this card would be a dosing error, not a conservative default.

  • · Check C-peptide and islet autoantibodies rather than assuming worsening type 2 diabetes
  • · SITC holds the ICI until DKA resolves and otherwise continues immunotherapy once the patient is stable; ASCO states stopping is not essential. Without DKA, this rung continues
  • · Screen the thyroid axis at the same time; it is the commonest co-occurring irAE in this series

Escalate when: Ketoacidosis, or a low or undetectable C-peptide indicating established insulin deficiency.

Grade 2

Hold the ICIOutpatient

Grade 2 — hyperglycaemia requiring intervention but without ketoacidosis. ESMO keys its recommendation to new-onset IR-DM rather than to a glycaemic grade, and the ketoacidotic-versus-not axis is the one both ESMO and SITC actually use; no cited source supplies the CTCAE glycaemic bands.

Hormone replacement — Insulin

Unchanged: ESMO's recommendation is prompt insulin initiation for new-onset IR-DM, without a grade-indexed dose or schedule.

  • · The hold at this rung is ASCO's cross-toxicity rule — ICPi therapy may be suspended for most grade 2 toxicities — not an endocrine-chapter statement: SITC's ICI hold is scoped to DKA, and ASCO's own endocrine text says stopping is not essential
  • · Treat this as permanent — the diabetes did not resolve during a median follow-up of 1 year
  • · Diabetes-service involvement from the outset

Escalate when: Ketoacidosis at any point, which ESMO and SITC both send to hospital.

Grade 3

Hold the ICIAdmit

Grade 3 — severe hyperglycaemia or the ketoacidotic presentation, which is the axis ESMO and SITC use: ESMO admits patients presenting with ketoacidosis, and SITC hospitalises severe hyperglycaemia or DKA. 67% of the 12 new-onset cases in the PD-1 series arrived this way.

Hormone replacement — Insulin

Still insulin. ESMO admits patients presenting with ketoacidosis and gives no corticosteroid for this diagnosis; ASCO states no immunosuppressive strategy is indicated in checkpoint inhibitor-associated diabetes. The renal and colitis mg/kg ladders are not carried across (D-STEROID).

  • · Admit — ESMO hospitalises patients presenting with ketoacidosis and SITC hospitalises severe hyperglycaemia or DKA
  • · Hold the ICI until the DKA is resolved (SITC); ASCO states stopping ICPi therapy is not essential once the patient is managed on replacement — see 'Sources differ here'
  • · Establish the insulin regimen before the ICI question is revisited

Sources differ here

ICI action

  • SITC 2021 (society guideline) — Patients with hyperglycemia should be evaluated for DKA and ICIs should be held until DKA is resolved
  • ASCO 2021 (society guideline) — It is also not essential that patients stop ICPi therapy, as hormone replacement is generally able to restore functional status quickly

Escalate when: Failure to correct the ketoacidosis, which is a critical-care question rather than an immunosuppression one.

Grade 4

Hold the ICIAdmit

Grade 4 — life-threatening consequences. No anchor chapter writes a grade-4 IR-DM recommendation, so the treatment repeats grade 3; the ICI question is answered by ASCO's endocrine carve-out.

Hormone replacement — Insulin

Unchanged from grade 3. There is no endocrine-chapter grade-4 dose, and no immunosuppressive arm for this diagnosis in any anchor.

  • · ASCO recommends permanent discontinuation with grade 4 toxicities except for endocrinopathies that have been controlled by hormone replacement — insulin is that replacement, so this rung holds while control is established rather than discontinuing
  • · Correct the ketoacidosis first; the ICI decision does not compete with it
  • · Endocrinology and diabetes-service involvement

Escalate when: Already the top rung.

Rechallenge

reasonable

The deficiency is permanent — the diabetes did not resolve during a median follow-up of 1 year — so recovery is not the test, and the renal-derived preconditions in evaluateRechallenge (full recovery, grade 1-2, steroid-responsive) do not govern this card: no rung uses a corticosteroid. ASCO's carve-out asks instead whether the endocrinopathy is controlled by hormone replacement, and insulin is that replacement; SITC holds only until the DKA has resolved. What a rechallenge must not do is proceed while the glycaemic control that stands in for recovery is not yet established.

  • · Insulin regimen established and glycaemic control stable
  • · Ketoacidosis fully resolved — SITC's own condition for restarting the ICI
  • · The patient able to recognise and act on hypoglycaemia and on intercurrent illness before the next dose

Deliberately not carried

  • incidence — reconciliation of the rates — The pooled randomised-trial incidence, SITC's chapter estimate and the single-centre PD-1 frequency are far apart and are carried separately with their own denominators. They count different things: insulin-dependent diabetes mellitus in trial populations, ICI-induced diabetes as a guideline estimate, and a cohort figure that includes worsening of pre-existing type 2 diabetes. Neither is averaged into the other and no reconciled figure is presented.
  • gradeThreePlus / mortality — No cited source reports a grade 3 or higher share or a case-fatality rate for ICI-associated diabetes. The 67% ketoacidosis figure is a presenting-phenotype share among the 12 new-onset cases and is not repurposed as either.
  • workup — glucose monitoring schedule — No cited source gives a glucose-monitoring cadence during ICI therapy, unlike the 4-6-weekly thyroid schedule SITC states; SITC counsels patients on glucose monitoring without setting an interval. None is invented.
  • onset — unit conversion — The series reports a median of four cycles or 5 months. Converting 5 months into weeks would print a number no source did, and cycles are not a time unit, so medianWeeks and both range bounds stay null and the figures are stated in the note in the terms the paper used.
  • ladder[].steroid.taper — No rung uses kind: 'systemic', so no rung carries an IraeTaper: the replacement here is insulin, and both SITC and ASCO state that corticosteroids and immunosuppression are not the treatment of this diagnosis.
  • ladder.g2.iciAction (organ-chapter position) — The hold at grade 2 runs on ASCO's cross-toxicity ladder rather than an endocrine-chapter rule. SITC's ICI hold for this diagnosis is scoped to DKA, ASCO's endocrine text says stopping is not essential, and ESMO states no ICI action for IR-DM at all — so the g2 rung is the one place on this card where the cross-organ default is doing the work, and it is disclosed rather than presented as endocrine guidance.
  • ladder[].hospitalization — Admission at grades 3-4 is sourced — ESMO admits ketoacidosis and SITC hospitalises severe hyperglycaemia or DKA — but the outpatient values at grades 1-2 are this atlas's reading of the grade wording, not a sourced disposition.
  • gradeDefinition — ASCO's per-organ grade tables did not survive extraction, and no cited source reproduces the CTCAE hyperglycaemia bands. The rungs therefore use the axis ESMO and SITC actually write to — new-onset IR-DM, and ketoacidotic versus not — rather than asserting a CTCAE threshold the entry cannot quote.
  • guidelinePmids — Empty although all three anchors are rows in guidelines.ts: their stored keyRecommendation strings are renal-scoped, so linking them would surface kidney dosing on a diabetes card.
  • citations[].quote — extraction normalisation — Every quote is a contiguous verbatim span. Dropped source words are marked ' ... ' with no unmarked elisions, and the retrieved payloads' inline superscript reference numerals are removed with a single space restored where their removal would join two words. No other character is altered.

Sources

  • Haanen J, et al. (2022) Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-upCited for: Insulin as the treatment of new-onset IR-DM, and hospital admission for patients presenting in ketoacidosis.Supporting text: the full text
  • Brahmer JR, et al. (2021) Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsCited for: The incidence and the PD-(L)1 rate; the window over which T1DM appears; the fulminant DKA presentation and the alternative asymptomatic one; the autoantibody yield; insulin as the treatment; the diagnostic panel; hospitalisation for severe hyperglycaemia or DKA; the DKA-scoped ICI hold; and the panel statement that T1DM generally does not require corticosteroid therapy.Supporting text: the full text
  • Schneider BJ, et al. (2021) Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline UpdateCited for: The onset figures for endocrine irAEs AS A GROUP; the DKA symptom list; the presentation that should raise concern for checkpoint inhibitor-associated diabetes and the screening that follows it; insulin where the diagnosis is in question; the admission trigger; ASCO's statement that no immunosuppressive strategy is indicated for this diagnosis and that stopping the ICI is not essential; and the closing block, which is ASCO's CROSS-TOXICITY ladder from the guideline abstract.Supporting text: the full text + the PubMed abstract (checkable at the link above)
  • Vardarli I, Tan S, Brandenburg T, Weidemann F, Görges R, Herrmann K, Führer D (2024) Risk and Incidence of Endocrine Immune-Related Adverse Effects Under Checkpoint Inhibitor Mono- or Combination Therapy in Solid Tumors: A Meta-Analysis of Randomized Controlled TrialsCited for: Pooled any-grade incidence and risk ratio for hypothyroidism and for insulin-dependent diabetes mellitus, the size of the pooled corpus, and the two meta-regression risk factors — combination ICI for hypophysitis/hypopituitarism, ICI agent for adrenal insufficiency. It does NOT carry a pooled incidence for hyperthyroidism, hypophysitis/hypopituitarism or adrenal insufficiency: for those three the abstract records only that the risk is significantly increased, which is an association and not a measured rate.Supporting text: the PubMed abstract (checkable at the link above)
  • Kotwal A, Haddox C, Block M, Kudva YC (2019) Immune checkpoint inhibitors: an emerging cause of insulin-dependent diabetesCited for: Frequency, per-agent distribution, onset, presenting phenotype and irreversibility of ICI-induced insulin-dependent diabetes. PD-1-INHIBITOR RECIPIENTS ONLY — the cases are drawn from the PD-1 arm of the review, and the same abstract reports ipilimumab at 0%, so nothing here may be rendered as an ICI-class or CTLA-4 figure. Note the scope of the 67% and 83%: the sentence carrying them has NEW-ONSET insulin-dependent diabetes as its subject, so the denominator is the 12 new-onset cases, not the 21-case series. The ellipses mark the structured abstract's section boundaries.Supporting text: the PubMed abstract (checkable at the link above)

Educational use only. Educational synthesis of the published literature — not a treatment protocol, dosing guide, or medical advice. Regimens and agents shown are illustrative of what the literature describes; verify against current guidelines (ASON / KDIGO / ASCO / NCCN) and individualize to the patient. Using this site creates no clinician–patient relationship.

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