Monday, August 25, 2025

Checkpoint Inhibitor-Induced Rheumatologic Syndromes

Checkpoint Inhibitor-Induced Rheumatologic Syndromes: From Arthritis to Vasculitis with Endocrinologic Overlap - A Critical Care Perspective

Dr Neeraj Manikath , claude.ai

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but introduced a new spectrum of immune-related adverse events (irAEs). Rheumatologic manifestations represent a significant subset of these complications, ranging from arthritis to life-threatening vasculitis, often overlapping with endocrinopathies.

Objective: To provide critical care physicians and rheumatologists with a comprehensive understanding of ICI-induced rheumatologic syndromes, their clinical spectrum, diagnostic challenges, and management strategies.

Methods: Systematic review of literature from 2011-2024, including case series, cohort studies, and clinical trials focusing on rheumatologic irAEs.

Results: Rheumatologic irAEs occur in 1-43% of ICI-treated patients, with variable presentation from mild arthralgia to severe vasculitis. Overlap with endocrinopathies occurs in approximately 15-25% of cases, complicating diagnosis and management.

Conclusion: Early recognition and multidisciplinary management are crucial for optimal outcomes. This review provides evidence-based approaches for diagnosis and treatment of these complex syndromes.

Keywords: Checkpoint inhibitors, immune-related adverse events, rheumatologic complications, vasculitis, endocrinopathy

Learning Objectives

After reading this article, the reader will be able to:

Recognize the clinical spectrum of ICI-induced rheumatologic syndromes
Differentiate between various rheumatologic presentations and their overlap with endocrinopathies
Implement evidence-based diagnostic and management strategies
Understand when to discontinue, hold, or continue ICI therapy

Introduction

The advent of immune checkpoint inhibitors (ICIs) has transformed oncologic care, with agents targeting PD-1 (pembrolizumab, nivolumab), PD-L1 (atezolizumab, durvalumab), and CTLA-4 (ipilimumab) showing remarkable efficacy across multiple malignancies¹. However, by unleashing the immune system against cancer, these agents simultaneously predispose patients to immune-related adverse events (irAEs) that can affect virtually any organ system².

Rheumatologic irAEs represent a particularly challenging subset, occurring in 1-43% of patients depending on the specific manifestation and ICI regimen³. Unlike traditional autoimmune rheumatologic diseases, ICI-induced syndromes often present with atypical features, rapid onset, and frequent overlap with endocrinologic complications⁴.

Pathophysiology: The Double-Edged Sword of Immune Activation

Checkpoint Biology and Dysregulation

Under normal circumstances, immune checkpoints serve as critical brakes preventing excessive immune activation. PD-1/PD-L1 interactions maintain peripheral tolerance, while CTLA-4 regulates T-cell activation in lymphoid tissues⁵. ICI therapy disrupts these regulatory mechanisms, leading to:

Enhanced T-cell activation and proliferation
Reduced regulatory T-cell function
Increased inflammatory cytokine production
Molecular mimicry and cross-reactivity
Tissue-specific autoimmunity⁶

🔑 Clinical Pearl: The "Iceberg Effect"

Visible rheumatologic symptoms often represent the tip of a systemic inflammatory iceberg. Always screen for concurrent endocrinologic, pulmonary, and cardiac involvement.

Clinical Spectrum of ICI-Induced Rheumatologic Syndromes

1. Inflammatory Arthritis

Incidence: 1-7% of ICI-treated patients⁷

Clinical Presentation:

Symmetric or asymmetric polyarthritis
Often seronegative (RF and ACPA negative)
Rapid onset (median: 2-4 months post-initiation)
May mimic rheumatoid arthritis or psoriatic arthritis

Diagnostic Considerations:

Synovial fluid analysis: inflammatory (>2000 cells/μL)
Imaging: ultrasound shows synovitis with power Doppler signal
Biomarkers: elevated CRP, normal or slightly elevated ESR

2. Polymyalgia Rheumatica-like Syndrome

Incidence: 0.5-2% of patients⁸

Key Features:

Bilateral shoulder and hip girdle pain and stiffness
Morning stiffness >45 minutes
Constitutional symptoms common
Dramatic response to corticosteroids

🍯 Honey Trap (Common Pitfall): Age >50 years and elevated ESR do not guarantee PMR diagnosis in ICI patients. Always consider alternative diagnoses including myositis and vasculitis.

3. Myositis Spectrum Disorders

Incidence: 0.1-1% but potentially life-threatening⁹

Clinical Variants:

Necrotizing myopathy: Severe weakness, markedly elevated CK
Inflammatory myopathy: Gradual weakness, moderate CK elevation
Myocarditis overlap: Concurrent cardiac involvement (15-20% of cases)

Diagnostic Workup:

CK, aldolase, LDH, troponin
EMG/NCS
MRI: STIR hyperintensity in affected muscles
Muscle biopsy: inflammatory infiltrates, necrosis

4. Vasculitis: The Great Mimicker

Incidence: 0.1-0.5% but highest mortality risk¹⁰

Clinical Presentations:

Large Vessel Vasculitis

Giant cell arteritis-like syndrome
Aortitis with potential rupture risk
Temporal artery tenderness, visual symptoms

Medium Vessel Vasculitis

Polyarteritis nodosa pattern
Skin lesions, peripheral neuropathy
Mesenteric involvement

Small Vessel Vasculitis

Hypersensitivity vasculitis
Palpable purpura, glomerulonephritis
Pulmonary-renal syndromes

🚨 Critical Alert: Any ICI patient presenting with new neurologic deficits, skin lesions, or multiorgan dysfunction should prompt immediate vasculitis workup.

5. Sicca Syndrome and Glandular Dysfunction

Incidence: 1-5%¹¹

Features:

Dry eyes and mouth
Parotid gland swelling
Often associated with thyroid dysfunction
May precede other rheumatologic manifestations

Endocrinologic Overlap: The Complex Interface

Prevalence and Patterns

Concurrent endocrinologic and rheumatologic irAEs occur in 15-25% of cases, creating diagnostic and therapeutic challenges¹². Common patterns include:

Thyroid-Arthritis Complex
- Hypothyroidism with inflammatory arthritis
- Shared autoantibody profiles
- Overlapping inflammatory pathways
Adrenal-Myositis Syndrome
- Primary adrenal insufficiency with muscle weakness
- Diagnostic confusion regarding weakness etiology
- Steroid replacement masking myositis symptoms
Diabetes-Vasculitis Association
- Type 1 diabetes mellitus onset
- Concurrent small vessel vasculitis
- Accelerated micro- and macrovascular complications

🔍 Diagnostic Pearl:

In any ICI patient with rheumatologic symptoms, obtain comprehensive endocrine screening: TSH, free T4, morning cortisol, HbA1c, and consider dynamic testing if clinically indicated.

Diagnostic Approach: The Systematic Framework

Initial Assessment

History:

ICI type, duration, and dosing
Onset and progression of symptoms
Review of systems (constitutional, neurologic, cardiac, pulmonary)
Family history of autoimmune disease

Physical Examination:

Joint assessment: swelling, tenderness, range of motion
Muscle strength testing (MRC grading)
Vascular examination: pulses, bruits, skin lesions
Endocrine evaluation: thyroid palpation, signs of adrenal insufficiency

Laboratory Workup

Tier 1 (All Patients):

CBC with differential
Comprehensive metabolic panel
Inflammatory markers: CRP, ESR
Muscle enzymes: CK, aldolase, LDH
Cardiac markers: troponin, NT-proBNP
Endocrine screening: TSH, free T4, morning cortisol, HbA1c

Tier 2 (Based on Clinical Suspicion):

Autoantibody panel: RF, ACCA, ANA, ANCA, anti-Jo1, anti-SRP
Complement levels: C3, C4, CH50
Urinalysis with microscopy
Additional endocrine testing: ACTH stimulation test, anti-GAD, anti-IA2

Tier 3 (Specialist-Directed):

Synovial fluid analysis
Temporal artery biopsy
Muscle biopsy
PET-CT for large vessel vasculitis

Imaging Strategy

Musculoskeletal:

Ultrasound: First-line for arthritis assessment
MRI: Muscle edema, joint inflammation
X-rays: Baseline and follow-up

Vascular:

CT angiography: Large and medium vessel assessment
MR angiography: Alternative for repeated imaging
PET-CT: Gold standard for large vessel vasculitis activity

Treatment Paradigms: Balancing Cancer Control and Autoimmunity

Risk Stratification System

Grade 1 (Mild):

Symptoms not interfering with ADLs
No organ dysfunction
Continue ICI with close monitoring

Grade 2 (Moderate):

Moderate symptoms limiting ADLs
Hold ICI until symptoms improve to Grade ≤1
Consider corticosteroids

Grade 3 (Severe):

Severe symptoms significantly limiting self-care
Discontinue ICI
High-dose corticosteroids ± additional immunosuppression

Grade 4 (Life-threatening):

Organ dysfunction or life-threatening complications
Permanently discontinue ICI
Aggressive immunosuppression, often requiring ICU care

Pharmacologic Management

Corticosteroids: The First-Line Approach

Dosing Strategies:

Mild arthritis: Prednisone 10-20 mg daily
Moderate-severe arthritis: Prednisone 0.5-1 mg/kg daily
Myositis: Prednisone 1-2 mg/kg daily
Vasculitis: Methylprednisolone 1g daily × 3 days, then high-dose oral

Tapering Protocol:

Initial high dose for 2-4 weeks
Taper by 10-20% weekly to 10 mg
Slow taper (2.5-5 mg every 2-4 weeks) below 10 mg
Total duration: typically 3-6 months

Second-Line Agents

Methotrexate:

Dose: 15-25 mg weekly with folic acid
Indications: Steroid-sparing for arthritis
Monitor: CBC, LFTs, creatinine

TNF Inhibitors:

Infliximab: Most experience in irAEs
Dose: 5 mg/kg at weeks 0, 2, 6, then every 8 weeks
Risk: Paradoxical immune activation

Rituximab:

Indications: Refractory myositis, severe arthritis
Dose: 1g × 2 doses (14 days apart) or 375 mg/m² weekly × 4

Mycophenolate Mofetil:

Dose: 1-3 g daily in divided doses
Indications: Maintenance therapy, steroid-sparing

🎯 Management Pearl:

Early aggressive treatment often allows for more rapid steroid tapering and potential ICI rechallenge. Don't undertreate Grade 2 symptoms.

Special Populations and Considerations

ICU Management

Indications for Critical Care:

Myocarditis with hemodynamic compromise
Respiratory failure from ILD or vasculitis
Severe myositis with respiratory muscle involvement
Multi-organ failure from systemic vasculitis

ICU-Specific Considerations:

Stress-dose steroids for adrenal insufficiency
Cardiac monitoring for myocarditis
Ventilatory support strategies
Infectious disease consultation

Pediatric Considerations

Limited data exists for pediatric populations, but key differences include:

Higher incidence of endocrinologic irAEs
More aggressive immunosuppression often required
Growth and development considerations
Family-centered care approaches

Rechallenge Strategies: When and How

Decision Framework

Factors Favoring Rechallenge:

Complete resolution of symptoms
Cancer progression without alternative therapies
Grade 1-2 initial severity
No life-threatening complications

Contraindications:

Grade 4 events
Myocarditis or neurologic irAEs
Multi-organ involvement
Inability to taper corticosteroids

Rechallenge Protocol

Pre-rechallenge Assessment:
- Complete symptom resolution
- Corticosteroid taper to ≤10 mg daily
- Stable inflammatory markers
- Multidisciplinary team agreement
Monitoring During Rechallenge:
- Weekly assessments for first month
- Laboratory monitoring every 2 weeks
- Patient education on symptom recognition
- Low threshold for discontinuation

Emerging Therapies and Future Directions

Novel Therapeutic Targets

JAK Inhibitors:

Rationale: Downstream cytokine signaling blockade
Early case reports showing efficacy
Potential for more targeted therapy

IL-6 Receptor Antagonists:

Tocilizumab showing promise in case series
Particularly relevant for large vessel vasculitis
Ongoing clinical trials

Selective Immunosuppression:

Abatacept for arthritic manifestations
Belimumab for lupus-like syndromes
Personalized medicine approaches

Biomarker Development

Predictive Markers:

HLA typing for risk stratification
Cytokine profiles
T-cell subset analysis
Microbiome associations

Monitoring Biomarkers:

Novel inflammatory markers
Tissue-specific autoantibodies
Imaging biomarkers

Quality of Life and Long-term Outcomes

Functional Assessment

Tools:

HAQ-DI for functional disability
FACIT-Fatigue for cancer-related fatigue
Joint-specific outcome measures

Long-term Monitoring:

Annual rheumatologic assessment
Endocrine function surveillance
Cardiovascular risk evaluation
Bone health assessment (steroid-induced osteoporosis)

Patient Education and Support

Key Educational Points:

Symptom recognition and reporting
Importance of medication adherence
Lifestyle modifications
Support group resources

Cost-Effectiveness Considerations

Economic Impact

Direct medical costs: $15,000-$50,000 per severe irAE episode
Indirect costs: Lost productivity, caregiver burden
Quality-adjusted life years (QALYs) impact
Healthcare resource utilization patterns

Value-Based Care Approaches

Early intervention protocols
Multidisciplinary team models
Standardized monitoring pathways
Patient-reported outcome integration

Institutional Protocol Development

Multidisciplinary Team Structure

Core Team Members:

Oncologist (primary)
Rheumatologist
Endocrinologist
Clinical pharmacist
Advanced practice providers

Specialized Consultants:

Cardio-oncologist
Pulmonologist
Dermatologist
Infectious disease specialist

Monitoring Protocols

Pre-treatment Screening:

Baseline autoimmune disease history
Family history assessment
HLA typing (if available)
Baseline inflammatory markers

During Treatment:

Standardized symptom assessment tools
Laboratory monitoring schedules
Imaging protocols
Patient-reported outcomes

Research Priorities and Knowledge Gaps

Current Research Questions

Optimal rechallenge strategies
Biomarkers for early detection
Personalized immunosuppression approaches
Long-term outcomes and cancer control balance
Pediatric-specific management protocols

Ongoing Clinical Trials

NCT04438382: Vedolizumab for ICI-induced colitis and arthritis
NCT04356781: Tocilizumab for ICI-induced arthritis
NCT04305145: Predictive biomarkers for irAEs

Conclusion

Checkpoint inhibitor-induced rheumatologic syndromes represent a new frontier in both oncology and rheumatology, requiring specialized knowledge and multidisciplinary approaches. The complexity of these conditions, particularly their overlap with endocrinopathies, demands vigilant monitoring and individualized treatment strategies.

Key takeaways for clinical practice include:

High index of suspicion for rheumatologic irAEs in all ICI patients
Systematic diagnostic approaches incorporating endocrine screening
Early aggressive treatment to minimize long-term sequelae
Multidisciplinary team management for optimal outcomes
Individualized rechallenge decisions balancing risk and benefit

As our understanding of these syndromes evolves, continued research into pathophysiology, biomarkers, and therapeutic targets will refine our ability to predict, prevent, and treat these complex conditions while preserving the remarkable anti-cancer efficacy of checkpoint inhibition.

💎 Oyster Pearls for Clinical Excellence

🔬 Diagnostic Oysters:

The "Timing Paradox": Unlike traditional autoimmune diseases that develop over years, ICI-induced syndromes can manifest within weeks to months
The "Seronegative Surprise": Most ICI-induced arthritis is seronegative, challenging traditional diagnostic criteria
The "Overlap Enigma": Consider concurrent endocrinopathies in every rheumatologic presentation

💊 Therapeutic Oysters:

The "Early Strike Strategy": Aggressive early treatment often allows faster steroid tapering than conservative approaches
The "TNF Paradox": Anti-TNF agents can be both therapeutic and potentially harmful in the ICI setting
The "Rechallenge Gamble": Success rates are highest with complete resolution and Grade ≤2 initial severity

📊 Monitoring Oysters:

The "Iceberg Effect": Visible symptoms often represent broader systemic involvement
The "Biomarker Limitation": Traditional autoimmune markers have limited utility in ICI-induced disease
The "Imaging Insight": PET-CT can reveal subclinical large vessel involvement

References

Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350-1355.
Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158-168.
Mooradian MJ, Nasrallah M, Gainor JF, et al. Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: a single center experience. Semin Arthritis Rheum. 2019;48(6):1127-1132.
Cappelli LC, Gutierrez AK, Baer AN, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis. 2017;76(1):43-50.
Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8(9):1069-1086.
June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles' heel of cancer immunotherapy? Nat Med. 2017;23(5):540-547.
Braaten TJ, Brahmer JR, Forde PM, et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann Rheum Dis. 2020;79(3):332-338.
Rubin SJS, Bernatsky S, Ramien ML, et al. Polymyalgia rheumatica-like syndrome from checkpoint inhibitor immunotherapy: case series and systematic review of the literature. RMD Open. 2020;6(3):e001497.
Suzuki S, Ishikawa N, Konoeda F, et al. Nivolumab-related myositis mimicking polymyositis: a case report. BMC Neurol. 2017;17(1):83.
Daxini A, Cronin K, Sreih AG. Vasculitis associated with immune checkpoint inhibitors-a systematic review. Clin Rheumatol. 2018;37(9):2579-2584.
Warner BM, Baer AN, Lipson EJ, et al. Sicca syndrome associated with immune checkpoint inhibitor therapy. Oncologist. 2019;24(9):1259-1269.
de Filette J, Andreescu CE, Cools F, et al. A systematic review and meta-analysis of endocrine-related adverse events associated with immune checkpoint inhibitors. Horm Metab Res. 2019;51(3):145-156.

Endocrine Checklists in Perioperative Medicine

Endocrine Checklists in Perioperative Medicine: A Comprehensive Guide for Critical Care Practitioners

Dr Neeraj Manikath , claude.ai

Abstract

Background: Perioperative endocrine management represents a critical component of surgical care, with inadequate attention to endocrine pathophysiology contributing significantly to perioperative morbidity and mortality. This review provides evidence-based checklists and practical guidance for managing adrenal suppression, diabetes control, thyroid optimization, and steroid coverage in the perioperative period.

Methods: Comprehensive literature review of current guidelines from major endocrine and anesthetic societies, recent meta-analyses, and landmark studies in perioperative endocrine medicine.

Results: Structured checklists and decision algorithms can significantly improve perioperative outcomes by ensuring systematic evaluation and management of endocrine disorders. Key areas include recognition of occult adrenal insufficiency, optimization of glycemic control, perioperative thyroid management, and appropriate stress-dose steroid protocols.

Conclusions: Implementation of standardized endocrine checklists in perioperative medicine can reduce complications, improve patient safety, and optimize surgical outcomes through systematic, evidence-based management protocols.

Keywords: Perioperative medicine, endocrine disorders, adrenal insufficiency, diabetes mellitus, thyroid disease, steroid coverage, critical care

Introduction

The perioperative period represents a state of profound physiological stress, challenging the body's endocrine regulatory mechanisms and potentially unmasking subclinical endocrine disorders. With the increasing complexity of surgical procedures and an aging population with multiple comorbidities, systematic attention to endocrine pathophysiology has become paramount for optimal perioperative outcomes.

Endocrine disorders affect approximately 15-20% of surgical patients, yet are frequently overlooked or inadequately managed in the perioperative setting. The stress response to surgery, anesthesia, and critical illness can precipitate life-threatening endocrine crises in susceptible individuals, making preoperative identification and optimization crucial.

This review presents evidence-based checklists and practical algorithms for managing the four most critical endocrine considerations in perioperative medicine: adrenal suppression, diabetes control, thyroid optimization, and steroid coverage protocols.

1. Adrenal Suppression: Recognition and Management

Pathophysiology and Clinical Significance

Adrenal insufficiency (AI) in the perioperative period can be primary (Addison's disease), secondary (pituitary dysfunction), or tertiary (exogenous steroid suppression). The most common cause in surgical patients is suppression of the hypothalamic-pituitary-adrenal (HPA) axis from chronic corticosteroid use.

Pearl: Even low-dose topical or inhaled steroids can cause clinically significant HPA suppression, particularly with prolonged use or in elderly patients.

Preoperative Assessment Checklist

Risk Factor Identification:

[ ] History of steroid use (any route, duration >3 weeks in past year)
[ ] Clinical signs: hyperpigmentation, weakness, weight loss
[ ] Previous diagnosis of AI or pituitary disorders
[ ] Autoimmune conditions (especially autoimmune polyglandular syndromes)
[ ] Recent cessation of chronic steroid therapy
[ ] History of unexplained perioperative hypotension

Diagnostic Considerations:

[ ] Morning cortisol <3 μg/dL (83 nmol/L): definitive AI
[ ] Morning cortisol 3-15 μg/dL (83-414 nmol/L): consider stimulation testing
[ ] ACTH stimulation test if intermediate cortisol levels
[ ] Consider random cortisol if emergency surgery

Oyster Alert: Normal baseline cortisol does not exclude AI in critically ill patients due to altered cortisol-binding proteins and tissue resistance.

Perioperative Management Protocol

Preoperative Optimization:

Confirmed AI patients:
- Continue maintenance therapy until surgery
- Ensure adequate mineralocorticoid replacement
- Optimize fluid and electrolyte balance
Suspected AI (pending confirmation):
- Obtain baseline cortisol before steroid administration
- Initiate stress-dose steroids if high clinical suspicion

Intraoperative Management:

Minor Surgery (local anesthesia, brief procedures):

Continue usual steroid dose
No additional coverage typically needed

Moderate Surgery (regional anesthesia, intermediate procedures):

Hydrocortisone 50-75 mg IV at induction
Continue usual dose postoperatively

Major Surgery (general anesthesia, extensive procedures):

Hydrocortisone 100-150 mg IV at induction
Hydrocortisone 50-100 mg IV q8h for 24-48 hours
Taper to maintenance over 2-3 days

Clinical Hack: Use the "rule of 100s" - 100 mg hydrocortisone at induction for major surgery, then 100 mg daily divided q8h, tapering by 50% daily until maintenance dose reached.

Postoperative Monitoring

Critical Parameters:

[ ] Hemodynamic stability (BP, HR trends)
[ ] Electrolyte balance (Na+, K+, glucose)
[ ] Signs of AI crisis: hypotension, hyperkalemia, hypoglycemia
[ ] Wound healing and infection surveillance
[ ] Stress response adequacy

Management of Suspected AI Crisis:

Immediate IV access and fluid resuscitation
Hydrocortisone 100 mg IV bolus, then 200-300 mg/24h continuous infusion
Aggressive fluid and electrolyte correction
Vasopressor support if needed
Search for and treat precipitating factors

2. Diabetes Control: Perioperative Glycemic Management

Clinical Impact and Goals

Perioperative hyperglycemia is associated with increased infection rates, delayed wound healing, prolonged hospital stay, and increased mortality. Conversely, severe hypoglycemia can cause neurological damage and cardiac arrhythmias.

Target Ranges:

Non-critical care: 140-180 mg/dL (7.8-10.0 mmol/L)
Critical care: 140-180 mg/dL (avoiding <70 mg/dL)
Cardiac surgery: 120-160 mg/dL for first 24-48 hours

Preoperative Assessment Checklist

Baseline Evaluation:

[ ] HbA1c level (target <7% for elective surgery if possible)
[ ] Current medications and adherence
[ ] History of hypoglycemic episodes
[ ] Presence of diabetic complications (nephropathy, neuropathy, CAD)
[ ] Baseline renal function (creatinine, eGFR)
[ ] Infection screening

Medication Review:

[ ] Metformin: hold 24-48 hours pre-op if contrast exposure or renal concerns
[ ] SGLT2 inhibitors: discontinue 3 days before surgery (DKA risk)
[ ] Insulin requirements and timing
[ ] Other antihyperglycemic agents: individualized approach

Pearl: Preoperative HbA1c >8.5% is associated with significantly increased perioperative complications and should prompt delay of elective procedures for optimization when possible.

Perioperative Management Protocols

Type 1 Diabetes Management:

Preoperative:

Continue basal insulin (reduce by 20-25% if NPO)
Hold rapid-acting insulin with last meal
Start dextrose-containing IV fluids if prolonged NPO

Intraoperative:

Continuous insulin infusion for procedures >2 hours
Target glucose 140-180 mg/dL
Monitor glucose hourly

Type 2 Diabetes Management:

Diet-controlled or metformin only:

Monitor glucose q6h perioperatively
Initiate insulin if glucose >180 mg/dL

Insulin-requiring:

Continue 75-80% of basal insulin if NPO
Hold prandial insulin
Use correction insulin protocol

Clinical Hack - "The 80% Rule": For patients on basal insulin who are NPO, give 80% of their usual basal dose and start dextrose-containing IV fluids. This maintains glycemic control while preventing hypoglycemia.

Intensive Care Unit Protocols

Continuous Insulin Infusion Guidelines:

Starting insulin infusion (regular human insulin):

BG 140-199 mg/dL: 0.5 units/hour
BG 200-249 mg/dL: 1.0 units/hour
BG 250-299 mg/dL: 1.5 units/hour
BG ≥300 mg/dL: 2.0 units/hour

Adjustment Protocol:

Check BG hourly until stable, then q2h
Adjust insulin rate by 0.5-1.0 units/hour based on BG trends
If BG <70 mg/dL: stop insulin, give dextrose, recheck in 15 minutes

Oyster Alert: Insulin requirements can increase dramatically during stress, infection, or steroid administration. Don't hesitate to escalate insulin doses appropriately.

Postoperative Transition

ICU to Floor Transfer:

Ensure stable glycemic control on current regimen
Calculate total daily insulin requirements from infusion
Transition using 50% as basal, 50% as nutritional coverage
Continue frequent monitoring initially

3. Thyroid Optimization: Perioperative Considerations

Clinical Significance

Unrecognized thyroid disorders can significantly impact perioperative outcomes. Hyperthyroidism increases risks of arrhythmias, heart failure, and thyroid storm, while severe hypothyroidism can cause delayed drug metabolism, hypothermia, and cardiovascular instability.

Preoperative Assessment Checklist

Clinical Screening:

[ ] Symptoms: palpitations, weight changes, heat/cold intolerance
[ ] Physical examination: goiter, tremor, eye signs, skin changes
[ ] Cardiovascular assessment: AF, heart failure signs
[ ] Medication history: antithyroid drugs, levothyroxine, iodine

Laboratory Assessment:

[ ] TSH (most sensitive screening test)
[ ] Free T4 and T3 if abnormal TSH
[ ] Consider in high-risk patients: elderly, cardiac surgery, known thyroid disease

Oyster Alert: Normal TSH doesn't exclude central hypothyroidism in patients with pituitary disease. Consider free T4 in these patients.

Hyperthyroidism Management

Preoperative Optimization:

Target euthyroid state before elective surgery
Beta-blockade for symptom control and cardiac protection
Antithyroid medications: methimazole preferred over PTU
Consider iodine therapy for rapid control (Lugol's solution)

Perioperative Protocol:

[ ] Continue antithyroid medications until surgery
[ ] Beta-blocker coverage (propranolol 1-2 mg IV q6h or esmolol infusion)
[ ] Stress-dose steroids if severe thyrotoxicosis
[ ] Temperature monitoring and cooling measures
[ ] Avoid precipitants: iodine contrast, amiodarone

Thyroid Storm Management:

Immediate measures:
- Propylthiouracil 600-800 mg loading dose, then 200-400 mg q6h
- Lugol's solution 5 drops q6h (1 hour after PTU)
- Propranolol 1-2 mg IV q5min until HR <100
- Hydrocortisone 200-400 mg q8h
Supportive care:
- Aggressive cooling measures
- Fluid resuscitation and electrolyte correction
- Treat precipitating factors

Clinical Hack: Remember the "PTU before iodine" rule - always give antithyroid drugs before iodine to prevent massive thyroid hormone release.

Hypothyroidism Management

Mild to Moderate Hypothyroidism:

Generally safe to proceed with surgery
Continue levothyroxine therapy
Monitor for delayed drug metabolism

Severe Hypothyroidism (TSH >20 mU/L, low T4):

Consider delaying elective surgery for optimization
Levothyroxine 1.6 μg/kg/day (reduce by 50% in elderly or cardiac disease)
Emergency surgery: can proceed with supportive care

Perioperative Considerations:

[ ] Continue levothyroxine (can crush and give via NGT)
[ ] Expect prolonged drug effects and recovery
[ ] Monitor for hypothermia and cardiovascular instability
[ ] Consider stress-dose steroids if concurrent AI suspected

Pearl: IV levothyroxine dose is 50-75% of oral dose due to improved bioavailability.

Myxedema Coma Management

Recognition:

Severe hypothermia (<95°F)
Altered mental status
Cardiovascular collapse
Hyponatremia, hypoglycemia

Treatment Protocol:

Thyroid hormone replacement:
- T4: 200-400 μg IV loading dose, then 50-100 μg daily
- T3: 10-20 μg IV q8h (if cardiovascular instability)
Supportive measures:
- Passive rewarming (avoid active warming - vasodilation risk)
- Hydrocortisone 100-200 mg IV q8h
- Hypertonic saline for severe hyponatremia
- Mechanical ventilation if needed

4. Steroid Coverage: Evidence-Based Protocols

Physiologic Basis

The normal adrenal response to surgical stress produces 75-150 mg cortisol equivalent daily. Patients with impaired HPA axis function require exogenous steroid supplementation to prevent cardiovascular collapse and other manifestations of relative adrenal insufficiency.

Risk Stratification for Steroid Coverage

High Risk (Stress-dose steroids recommended):

Current steroid use >5 mg prednisone daily
Recent steroid use >20 mg prednisone for >3 weeks within past year
Major surgery with significant physiologic stress
Known primary or secondary adrenal insufficiency

Intermediate Risk (Consider stress-dose steroids):

Low-dose steroids <5 mg prednisone daily for >1 month
Inhaled/topical steroids, especially high-potency or prolonged use
Moderate surgical procedures
History of steroid use with uncertain HPA status

Low Risk (Continue usual dose):

Steroid use <3 weeks duration
Minor surgical procedures
Alternate-day steroid regimens
Recent normal ACTH stimulation test

Steroid Equivalency and Dosing

Steroid Equivalencies (anti-inflammatory potency):

Hydrocortisone: 1x (20 mg)
Prednisone/Prednisolone: 4x (5 mg)
Methylprednisolone: 5x (4 mg)
Dexamethasone: 25x (0.75 mg)

Clinical Hack: Use the "3-2-1 Rule" for steroid surgery dosing:

3 days before major surgery: optimize existing therapy
2x the physiologic dose for moderate stress
1 week to taper back to baseline post-op

Procedure-Specific Protocols

Minor Surgery (local anesthesia, <1 hour):

Continue usual steroid dose
Monitor for signs of insufficiency

Moderate Surgery (regional anesthesia, 1-3 hours):

Hydrocortisone 50 mg IV at induction
Continue usual dose post-operatively
Consider additional 25 mg if prolonged procedure

Major Surgery (general anesthesia, >3 hours, significant stress):

Hydrocortisone 100 mg IV at induction
Hydrocortisone 50 mg IV q8h × 24-48 hours
Taper by 50% daily to maintenance dose

Critical Care Considerations:

Sepsis/septic shock: 200-300 mg hydrocortisone daily
Vasopressor-dependent shock: consider higher doses
ARDS: low-dose protocol (1-2 mg/kg/day methylprednisolone)

Pearl: For patients on chronic steroids, never abruptly discontinue therapy perioperatively - this can precipitate life-threatening adrenal crisis even in minor procedures.

Monitoring and Complications

Parameters to Monitor:

[ ] Blood pressure and hemodynamic stability
[ ] Blood glucose levels
[ ] Electrolytes (sodium, potassium)
[ ] Signs of infection (steroids mask inflammatory response)
[ ] Wound healing
[ ] Mood and behavioral changes

Common Pitfalls:

Inadequate dosing for surgical stress level
Premature tapering of stress-dose steroids
Failure to recognize AI in patients with "borderline" adrenal function
Using anti-inflammatory equivalent rather than glucocorticoid replacement

Special Populations and Considerations

Pediatric Patients

Key Differences:

Higher cortisol production per kg body weight
More rapid onset of AI symptoms
Different steroid dosing: 1-2 mg/kg/day hydrocortisone equivalent

Elderly Patients

Considerations:

Higher prevalence of subclinical endocrine disorders
Increased sensitivity to both hyperglycemia and hypoglycemia
Higher risk of steroid-induced complications
May require lower levothyroxine doses

Emergency Surgery

Rapid Assessment Protocol:

History: Previous steroid use, endocrine disorders, unexplained hypotension
Physical: Signs of AI, thyrotoxicosis, or severe hypothyroidism
Labs: Glucose, electrolytes, consider random cortisol
Management: When in doubt, provide stress-dose steroids

Clinical Hack: In emergency situations, give dexamethasone 4 mg IV instead of hydrocortisone - it doesn't interfere with cortisol assays if you need to check levels later.

Quality Improvement and Implementation

Checklist Implementation Strategies

Pre-implementation:

Multidisciplinary team education
Integration with electronic health records
Clear protocols and decision trees
Regular case reviews and feedback

Key Performance Indicators:

Perioperative glucose control metrics
Incidence of endocrine crises
Length of stay and complication rates
Protocol compliance rates

Common Implementation Barriers

Knowledge gaps: Regular education and updates
Time constraints: Streamlined assessment tools
Communication failures: Clear handoff protocols
Resource limitations: Prioritize high-impact interventions

Future Directions

Emerging Technologies

Continuous glucose monitoring in perioperative settings
Point-of-care cortisol testing
Artificial intelligence-assisted risk prediction
Personalized medicine approaches based on genetic markers

Research Priorities

Optimal glycemic targets for different surgical populations
Novel biomarkers for adrenal insufficiency
Long-term outcomes of perioperative endocrine management
Cost-effectiveness of systematic screening protocols

Conclusion

Systematic attention to perioperative endocrine management through evidence-based checklists can significantly improve patient outcomes and reduce complications. The four key areas - adrenal suppression, diabetes control, thyroid optimization, and steroid coverage - require coordinated, multidisciplinary approaches with clear protocols and regular monitoring.

Implementation of these checklists should be adapted to local resources and patient populations while maintaining adherence to core evidence-based principles. Regular review and quality improvement initiatives ensure optimal outcomes and identify opportunities for protocol refinement.

The complexity of modern surgical patients demands sophisticated understanding of endocrine pathophysiology and its perioperative implications. Through systematic application of these principles, clinicians can optimize surgical outcomes and improve patient safety in the critical perioperative period.

References

Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(24):e278-e333.
Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.
American Diabetes Association Professional Practice Committee. 16. Diabetes care in the hospital: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022;45(Suppl 1):S244-S253.
Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421.
Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-1751.
Liu MM, Reidy AB, Saatee S, Collard CD. Perioperative steroid management: approaches based on current evidence. Anesthesiology. 2017;127(1):166-172.
Lazar HL, McDonnell M, Chipkin SR, et al. The Society of Thoracic Surgeons practice guideline series: blood glucose management during adult cardiac surgery. Ann Thorac Surg. 2009;87(2):663-669.
Griesdale DE, de Souza RJ, van Dam RM, et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ. 2009;180(8):821-827.
Polderman JA, Farhang-Razi V, Van Dieren S, et al. Adverse side effects of dexamethasone in surgical patients. Cochrane Database Syst Rev. 2018;8:CD011940.
Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36(6):1937-1949.

Conflicts of Interest: The authors declare no conflicts of interest.

Funding: No funding sources to declare.

The Expanding Spectrum of Euglycemia in Diabetes Management

The Expanding Spectrum of Euglycemia in Diabetes Management: A Critical Care Perspective

Dr Neeraj Manikath , claude.ai

Abstract

Background: The traditional paradigm of diabetic ketoacidosis (DKA) characterized by the triad of hyperglycemia, ketosis, and acidosis is evolving. Euglycemic DKA, defined as ketoacidosis with plasma glucose <250 mg/dL (13.9 mmol/L), represents a diagnostic challenge that can delay appropriate treatment and worsen outcomes.

Objective: This review examines the expanding spectrum of euglycemic presentations in diabetes management, focusing on euglycemic DKA, insulin omission patterns, SGLT2 inhibitor-associated complications, and starvation ketosis differentiation.

Methods: Comprehensive literature review of peer-reviewed articles from 2015-2024, focusing on critical care and emergency medicine perspectives.

Conclusions: Recognition of euglycemic DKA requires high clinical suspicion, particularly in patients on SGLT2 inhibitors, with recent illness, or following procedural fasting. Early identification and appropriate management protocols can significantly improve patient outcomes.

Keywords: Euglycemic diabetic ketoacidosis, SGLT2 inhibitors, insulin omission, starvation ketosis, critical care

Introduction

The landscape of diabetes management has undergone significant transformation with the introduction of sodium-glucose co-transporter 2 (SGLT2) inhibitors and evolving insulin regimens. Traditional diabetic ketoacidosis (DKA) presentations with the classic triad of hyperglycemia (>250 mg/dL), ketosis, and metabolic acidosis are increasingly accompanied by euglycemic variants that challenge conventional diagnostic approaches¹.

Euglycemic DKA, first described in the 1970s but gaining renewed attention with SGLT2 inhibitor use, presents unique diagnostic and therapeutic challenges in critical care settings². The failure to recognize these atypical presentations can result in delayed treatment, prolonged ICU stays, and increased morbidity³.

This review synthesizes current evidence on euglycemic presentations in diabetes management, providing critical care practitioners with diagnostic frameworks and management strategies essential for contemporary practice.

Euglycemic Diabetic Ketoacidosis: Redefining the Paradigm

Definition and Diagnostic Criteria

Euglycemic DKA is defined by the presence of:

Plasma glucose <250 mg/dL (13.9 mmol/L)
Serum or urine ketones: β-hydroxybutyrate ≥3.0 mmol/L or ketonuria ≥2+
Metabolic acidosis: pH <7.3 and/or bicarbonate <18 mEq/L
Elevated anion gap (>10-12 mEq/L)⁴

Pathophysiology

The pathophysiology of euglycemic DKA involves several key mechanisms:

1. SGLT2 Inhibitor-Mediated Glucosuria: SGLT2 inhibitors promote renal glucose elimination, maintaining relatively normal plasma glucose levels despite ongoing ketogenesis. The continued insulin deficiency or resistance allows lipolysis and ketone production to proceed unchecked⁵.

2. Preserved Insulin Sensitivity for Glucose: Residual insulin activity may be sufficient for glucose uptake but inadequate to suppress lipolysis, creating a dissociation between glucose homeostasis and ketone metabolism⁶.

3. Counter-regulatory Hormone Activation: Stress-induced elevation of cortisol, catecholamines, and glucagon promotes lipolysis while SGLT2 inhibitors prevent the expected hyperglycemic response⁷.

Clinical Presentation and Risk Factors

High-Risk Scenarios:

SGLT2 inhibitor use (risk increases 2-3 fold)⁸
Recent illness or infection
Prolonged fasting or reduced oral intake
Perioperative period
Pregnancy (particularly with gestational diabetes)
Alcohol use disorders

Clinical Pearl: The absence of significant hyperglycemia should not reassure clinicians when evaluating patients with diabetes presenting with nausea, vomiting, abdominal pain, and altered mental status.

Diagnostic Challenges and Pitfalls

Common Misdiagnoses:

Gastroenteritis
Sepsis without metabolic complications
Alcohol-related ketosis
Starvation ketosis

Diagnostic Hack: In any diabetic patient with unexplained metabolic acidosis and anion gap elevation, measure ketones regardless of glucose level. Point-of-care ketone testing can provide rapid results and prevent diagnostic delays⁹.

SGLT2 Inhibitors: Benefits and Pitfalls in Critical Care

Mechanism and Metabolic Effects

SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) block glucose reabsorption in the proximal tubule, promoting glucosuria of 60-90g daily¹⁰. This glucose loss triggers compensatory mechanisms including:

Increased gluconeogenesis
Enhanced lipolysis
Elevated ketone production
Activation of sympathetic nervous system

SGLT2 Inhibitor-Associated DKA: Recognition and Management

Incidence: Studies report euglycemic DKA rates of 0.16-0.76 per 1000 patient-years with SGLT2 inhibitors, compared to 0.03-0.11 per 1000 patient-years with other antidiabetic agents¹¹.

Precipitating Factors:

Surgery or procedures requiring fasting
Acute illness with reduced oral intake
Dehydration
Insulin dose reduction or omission

Clinical Oyster: Patients may present with relatively mild symptoms despite significant metabolic derangement due to the absence of severe hyperglycemia and its associated osmotic effects.

Perioperative Management Protocol

Pre-operative Considerations:

Discontinue SGLT2 inhibitors 3-7 days before elective procedures¹²
Ensure adequate carbohydrate intake until procedure
Monitor ketones if fasting >12 hours

Post-operative Monitoring:

Daily ketone monitoring for 48-72 hours
Resume SGLT2 inhibitors only after normal oral intake established
Consider alternative antidiabetic agents during recovery period

Insulin Omission: Patterns and Consequences

Epidemiology and Risk Factors

Insulin omission occurs in 15-20% of young adults with type 1 diabetes annually¹³. Risk factors include:

Eating disorders (particularly in young women)
Fear of hypoglycemia
Cost concerns
Psychological factors (depression, diabetes distress)
Social stigma

Clinical Consequences

Acute Complications:

Recurrent DKA (including euglycemic variants)
Increased hospitalization rates
Higher mortality risk

Chronic Complications:

Accelerated microvascular complications
Increased cardiovascular risk
Diabetic ketoacidosis recidivism

Clinical Pearl: Recurrent DKA, especially in young patients, should prompt investigation for insulin omission behaviors. Non-judgmental questioning and eating disorder screening are essential.

Recognition Strategies

Red Flags:

Recurrent hospitalizations for DKA
Poor glycemic control despite apparent adherence
Weight loss in the presence of normal or increased appetite
Discrepancy between reported insulin use and prescription refill patterns

Diagnostic Hack: Calculate insulin-to-weight ratios. Requirements <0.5 units/kg/day in type 1 diabetes patients should raise suspicion for omission¹⁴.

Starvation Ketosis: Differential Diagnosis and Management

Pathophysiology

Starvation ketosis results from prolonged fasting (>12-24 hours) leading to:

Depletion of hepatic glycogen stores
Increased lipolysis and ketogenesis
Protein catabolism for gluconeogenesis

Unlike diabetic ketoacidosis, insulin levels remain appropriate for glucose concentrations, preventing severe acidosis¹⁵.

Distinguishing Features

Parameter	Starvation Ketosis	Diabetic Ketoacidosis
pH	>7.30	<7.30
Bicarbonate	>15 mEq/L	<15 mEq/L
Anion Gap	<15 mEq/L	>15 mEq/L
β-hydroxybutyrate	<3 mmol/L	>3 mmol/L
Response to glucose	Rapid ketone clearance	Requires insulin

Clinical Context

Common Scenarios:

Prolonged illness with poor oral intake
Eating disorders
Postoperative fasting
Severe morning sickness in pregnancy

Management Approach:

Dextrose-containing fluids typically sufficient
Monitor response to carbohydrate administration
Insulin rarely required unless diabetic

Clinical Management Protocols

Emergency Department Approach

Initial Assessment:

Obtain arterial blood gas, basic metabolic panel
Measure serum or urine ketones (β-hydroxybutyrate preferred)
Review medication history (emphasis on SGLT2 inhibitors)
Assess hydration status and hemodynamic stability

Treatment Algorithm:

Mild-Moderate Euglycemic DKA (pH 7.20-7.30):

IV normal saline 1-2 L over first 2 hours
Regular insulin infusion 0.1 units/kg/hour
Dextrose 5-10% when glucose <250 mg/dL
Potassium replacement as indicated
Monitor hourly: glucose, ketones, electrolytes, pH

Severe Euglycemic DKA (pH <7.20):

Aggressive fluid resuscitation
Higher insulin infusion rates (0.14-0.15 units/kg/hour)
Early ICU consultation
Consider bicarbonate if pH <7.0 (controversial)

ICU Management Considerations

Monitoring Parameters:

Hourly glucose and ketones
ABG every 2-4 hours until pH >7.30
Electrolytes every 2-4 hours
Continuous cardiac monitoring (risk of arrhythmias)

Resolution Criteria:

pH >7.30
Bicarbonate >18 mEq/L
Anion gap <12 mEq/L
β-hydroxybutyrate <1.0 mmol/L

Clinical Oyster: Resolution of ketosis may lag behind improvement in pH and glucose, requiring continued insulin therapy and monitoring.

Prevention Strategies

Patient Education

Key Messages:

Never omit insulin, even during illness
Maintain adequate fluid intake during illness
Monitor ketones during stress or illness
Seek medical attention for persistent vomiting or abdominal pain

Healthcare Provider Education

SGLT2 Inhibitor Prescribing:

Screen for DKA risk factors before initiation
Provide clear instructions for sick day management
Establish protocols for perioperative management
Regular monitoring and patient education

Clinical Pearl: Develop institutional protocols for SGLT2 inhibitor management during hospitalization, including clear discontinuation and resumption criteria.

Emerging Concepts and Future Directions

Dual SGLT1/SGLT2 Inhibitors

Newer agents combining SGLT1 and SGLT2 inhibition may have different ketogenic profiles, requiring modified monitoring approaches¹⁶.

Continuous Ketone Monitoring

Development of continuous ketone monitors may enable real-time detection of ketosis, particularly valuable for high-risk patients¹⁷.

Artificial Intelligence Applications

Machine learning algorithms incorporating medication history, clinical parameters, and biomarkers may improve early detection of euglycemic DKA¹⁸.

Practical Clinical Pearls and Oysters

Pearls for Critical Care Practice

The "SGLT2 Sign": Any diabetic patient on SGLT2 inhibitors presenting with nausea, vomiting, and normal glucose requires ketone measurement.
The "Fasting Paradox": Prolonged fasting in SGLT2 inhibitor users paradoxically increases DKA risk despite glucose control.
The "pH-Glucose Dissociation": Normal glucose with significant acidosis should immediately trigger ketone evaluation.
The "Insulin Efficiency Test": In euglycemic DKA, insulin requirements may be higher than expected due to ongoing ketogenesis.

Clinical Oysters (Common Misconceptions)

"Normal glucose rules out DKA" - Euglycemic DKA is increasingly common and can be life-threatening.
"Mild symptoms mean mild disease" - The absence of hyperglycemic symptoms can mask significant metabolic derangement.
"Stop SGLT2 inhibitors only if DKA occurs" - Proactive discontinuation during high-risk periods prevents complications.
"Ketones always correlate with severity" - Clinical presentation and acid-base status are better severity indicators than absolute ketone levels.

Conclusion

The expanding spectrum of euglycemic presentations in diabetes management represents a paradigm shift requiring updated diagnostic and therapeutic approaches. Critical care practitioners must maintain high clinical suspicion for euglycemic DKA, particularly in patients using SGLT2 inhibitors or with risk factors for insulin omission.

Key takeaways include the need for routine ketone monitoring in high-risk scenarios, understanding the pathophysiologic differences between various ketotic states, and implementing evidence-based management protocols. As diabetes therapeutics continue to evolve, ongoing education and protocol development will be essential to optimize patient outcomes in critical care settings.

Future research should focus on risk stratification tools, optimal monitoring strategies, and prevention protocols to minimize the impact of these increasingly recognized complications.

References

Dhatariya KK, Glaser NS, Codner E, Umpierrez GE. Diabetic ketoacidosis. Nat Rev Dis Primers. 2020;6(1):40.
Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycaemic diabetic ketoacidosis. Br Med J. 1973;2(5866):578-580.
Goldenberg RM, Berard LD, Cheng AYY, et al. SGLT2 inhibitor-associated diabetic ketoacidosis: Clinical review and recommendations for prevention and diagnosis. Diabetes Care. 2016;39(11):2032-2039.
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343.
Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21(5):512-517.
Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016;39(7):1108-1114.
Burke KR, Schumacher CA, Harpe SE. SGLT2 Inhibitors: A Systematic Review of Diabetic Ketoacidosis and Related Risk Factors in the Primary Literature. Pharmacotherapy. 2017;37(2):187-194.
Fralick M, Schneeweiss S, Patorno E. Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. N Engl J Med. 2017;376(23):2300-2302.
Klocker AA, Phelan H, Twigg SM, Craig ME. Blood β-hydroxybutyrate vs. urine acetoacetate testing for the prevention and management of ketoacidosis in Type 1 diabetes: a systematic review. Diabet Med. 2013;30(7):818-824.
Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32(4):515-531.
Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ. 2018;363:k4365.
Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis. Endocr Pract. 2016;22(6):753-762.
Polonsky WH, Anderson BJ, Lohrer PA, et al. Insulin omission in women with IDDM. Diabetes Care. 1994;17(10):1178-1185.
Pinhas-Hamiel O, Hamiel U, Boyko V, et al. Trajectories of HbA1c Levels and Body Mass Index in Children and Adolescents with Type 1 Diabetes. PLoS One. 2014;9(10):e109109.
Owen OE, Caprio S, Reichard GA, et al. Ketosis of starvation: A revisit and new perspectives. Clin Endocrinol Metab. 1983;12(2):359-379.
Rosenstock J, Marquard J, Laffel LM, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care. 2018;41(12):2560-2569.
Burnett A, Zimmerman B, Harris D, Dewan S. Continuous ketone monitoring in acute care settings. J Diabetes Sci Technol. 2020;14(1):32-38.
Chen JH, Asch SM. Machine Learning and Prediction in Medicine — Beyond the Peak of Inflated Expectations. N Engl J Med. 2017;376(26):2507-2509.

Conflicts of Interest: The authors declare no conflicts of interest. Funding: No specific funding was received for this work.

When ILD is the Presenting Clue

Lung in Rheumatology: When ILD is the Presenting Clue - Recognizing CTD-ILD Early, ICU Implications, Antifibrotics, and Immunosuppression

Dr Neeraj Manikath , claude.ai

Abstract

Background: Interstitial lung disease (ILD) may precede other manifestations of connective tissue diseases (CTDs) by months to years, presenting a diagnostic challenge in critical care settings. Early recognition of CTD-associated ILD (CTD-ILD) is crucial for appropriate management and improved outcomes.

Objectives: To provide critical care physicians with a framework for recognizing CTD-ILD when pulmonary manifestations dominate the clinical picture, and to discuss contemporary management strategies including antifibrotic therapy and immunosuppression in the ICU setting.

Methods: Comprehensive review of current literature on CTD-ILD presentation, diagnosis, and management in critically ill patients.

Results: CTD-ILD often presents with subtle extrapulmonary clues that may be overlooked in acutely ill patients. High-resolution computed tomography (HRCT) patterns, serologic markers, and multidisciplinary evaluation are essential for diagnosis. Management requires balancing immunosuppression with infection risk, and newer antifibrotic agents show promise in specific CTD-ILD phenotypes.

Conclusions: A systematic approach to identifying CTD-ILD in patients presenting with acute respiratory failure can lead to targeted therapy and improved outcomes. Critical care physicians must maintain high clinical suspicion and collaborate closely with rheumatologists and pulmonologists.

Keywords: Interstitial lung disease, connective tissue disease, systemic sclerosis, rheumatoid arthritis, inflammatory myopathies, critical care

Introduction

Interstitial lung disease (ILD) represents a heterogeneous group of disorders affecting the lung parenchyma, with connective tissue disease-associated ILD (CTD-ILD) comprising approximately 15-20% of all ILD cases.¹ The challenge for critical care physicians lies in recognizing when ILD may be the harbinger of an underlying rheumatologic condition, particularly when respiratory symptoms dominate the clinical presentation and systemic features remain subtle or absent.

CTD-ILD can precede other disease manifestations by months to years, creating a diagnostic dilemma that has significant therapeutic implications.² Early recognition is paramount, as CTD-ILD often responds better to immunosuppressive therapy compared to idiopathic pulmonary fibrosis (IPF), and misdiagnosis can lead to inappropriate treatment strategies.³

This review provides critical care physicians with practical tools to identify CTD-ILD early, understand ICU management principles, and navigate the complex therapeutic landscape involving both immunosuppression and antifibrotic agents.

Epidemiology and Clinical Significance

CTD-ILD occurs in various rheumatologic conditions with distinct prevalence patterns:

Systemic Sclerosis (SSc): 90% develop ILD, with 40% having severe disease⁴
Rheumatoid Arthritis (RA): 10-60% prevalence depending on detection method⁵
Inflammatory Myopathies: 50-70% in anti-synthetase syndrome⁶
Sjögren's Syndrome: 10-20% develop clinically significant ILD⁷
Mixed Connective Tissue Disease: Up to 85% have pulmonary involvement⁸

Pearl: CTD-ILD patients admitted to ICU have higher mortality than those with idiopathic forms, largely due to acute exacerbations and secondary complications.⁹

Pathophysiology: When the Lung Leads the Dance

The pathophysiology of CTD-ILD involves complex interactions between genetic predisposition, environmental triggers, and immune dysregulation. Unlike IPF, CTD-ILD typically demonstrates more prominent inflammatory components, making it potentially more responsive to immunosuppressive therapy.¹⁰

Key Pathophysiologic Concepts:

Molecular Mimicry: Environmental antigens may trigger autoimmune responses through cross-reactivity with self-antigens¹¹
Epithelial-Mesenchymal Transition: Aberrant repair mechanisms lead to fibroblast proliferation and collagen deposition¹²
Vascular Involvement: Many CTDs have prominent vasculopathy contributing to pulmonary manifestations¹³

Hack: Think of CTD-ILD as "inflammatory fibrosis" versus the "fibrotic inflammation" seen in IPF - this conceptual framework guides therapeutic decisions.

Clinical Presentation: Reading Between the Lines

Respiratory Manifestations

The pulmonary presentation of CTD-ILD often mimics other forms of ILD:

Progressive dyspnea on exertion
Nonproductive cough
Bibasilar fine inspiratory crackles
Digital clubbing (less common than in IPF)

Oyster: Digital clubbing in CTD-ILD should raise suspicion for lung cancer or IPF misdiagnosis, as it's uncommon in true CTD-ILD.¹⁴

Subtle Extrapulmonary Clues

Critical care physicians must actively search for subtle signs that may indicate underlying CTD:

Dermatologic Manifestations

Raynaud's Phenomenon: Present in 85% of SSc patients¹⁵
Sclerodactyly: Skin thickening of fingers
Mechanic's Hands: Hyperkeratotic, cracked skin in anti-synthetase syndrome¹⁶
Gottron's Papules: Pathognomonic for dermatomyositis¹⁷
Photosensitive Rash: Suggestive of SLE or dermatomyositis

Musculoskeletal Signs

Morning Stiffness: >1 hour suggests inflammatory arthritis¹⁸
Symmetric Polyarthropathy: Classic for RA
Proximal Muscle Weakness: Consider inflammatory myopathies¹⁹
Puffy Hands: Early sign of SSc or mixed CTD²⁰

Other Systems

Dry Eyes/Mouth: Sicca symptoms in Sjögren's syndrome²¹
Esophageal Dysmotility: Common in SSc (85% prevalence)²²
Cardiac Conduction Abnormalities: May precede other anti-Ro/SSA manifestations²³

Pearl: In elderly patients with new-onset ILD, always consider anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which can present with pulmonary-renal syndrome.

Diagnostic Approach: The Detective Work

Laboratory Investigations

First-Line Autoantibody Panel:

ANA with pattern analysis
Anti-CCP and RF
Anti-Scl-70, Anti-centromere
Anti-Jo-1 and extended myositis panel
Anti-Ro/SSA, Anti-La/SSB
ANCA

Advanced Serologic Testing:

Myositis-specific antibodies (MSA) including anti-PL-7, anti-PL-12, anti-OJ²⁴
Anti-MDA5 (associated with rapidly progressive ILD)²⁵
Anti-HMGCR and anti-SRP in necrotizing myopathy²⁶

Hack: Order myositis antibodies even without obvious muscle involvement - anti-synthetase syndrome can present as "lung-dominant" disease.

High-Resolution Computed Tomography (HRCT) Patterns

Different CTDs show characteristic, though not pathognomonic, HRCT patterns:

Systemic Sclerosis

Early: Ground-glass opacities, fine reticulation
Advanced: Honeycombing, traction bronchiectasis
Distribution: Lower lobe, subpleural predominance²⁷

Rheumatoid Arthritis

Usual Interstitial Pneumonia (UIP) pattern: Most common (60-70%)²⁸
Nonspecific Interstitial Pneumonia (NSIP): Better prognosis
Organizing Pneumonia: May respond dramatically to steroids

Inflammatory Myopathies

NSIP pattern: Most common in anti-synthetase syndrome²⁹
Organizing Pneumonia: Particularly with anti-Jo-1
Acute/subacute pattern: Ground-glass with consolidation

Anti-MDA5 Dermatomyositis

Rapidly Progressive ILD: Ground-glass with consolidation
Pneumomediastinum: Pathognomonic finding in 50% of cases³⁰
Peripheral distribution: Unlike typical NSIP

Oyster: Pneumomediastinum in the setting of ILD should immediately raise suspicion for anti-MDA5 dermatomyositis - this is a rheumatologic emergency requiring aggressive immunosuppression.

Pulmonary Function Tests

Key Parameters:

DLCO: Often disproportionately reduced compared to spirometry
TLC: Restrictive pattern
6-Minute Walk Test: Assesses functional capacity and oxygen desaturation³¹

Pearl: In SSc, isolated DLCO reduction may precede radiographic changes by years.

Bronchoalveolar Lavage (BAL)

While not routinely required, BAL can be helpful in specific scenarios:

Cellular Pattern: Lymphocytic in NSIP, neutrophilic in UIP³²
Infection Exclusion: Critical before immunosuppression
Differential Diagnosis: Excludes eosinophilic pneumonia, malignancy

ICU Management Principles

Acute Respiratory Failure in CTD-ILD

Common Precipitants:

Acute exacerbation of underlying ILD
Superimposed infection
Drug-induced pneumonitis
Pulmonary edema (especially in SSc with renal crisis)
Pulmonary embolism (increased risk in inflammatory states)³³

Hack: Always consider scleroderma renal crisis in SSc patients presenting with acute respiratory failure - the combination requires immediate ACE inhibitor therapy regardless of blood pressure.

Ventilatory Management

Non-Invasive Ventilation (NIV):

First-line for hypercapnic respiratory failure
Caution with high PEEP in fibrotic disease (risk of pneumothorax)³⁴
Early intubation if deteriorating

Mechanical Ventilation:

Lung-Protective Strategy: Tidal volumes 6 ml/kg predicted body weight³⁵
PEEP Optimization: Balance between recruitment and overdistention
Plateau Pressure: Keep <30 cmH2O
Driving Pressure: Target <15 cmH2O when possible³⁶

Pearl: CTD-ILD patients on mechanical ventilation have prolonged weaning times - early tracheostomy consideration is reasonable.

Hemodynamic Considerations

Pulmonary Hypertension (PH) Assessment:

Echocardiography for right heart function
Consider invasive hemodynamics if PH suspected³⁷
SSc: Screen annually with DLCO and echocardiography
Treatment: Phosphodiesterase-5 inhibitors, endothelin receptor antagonists³⁸

Therapeutic Strategies: Walking the Tightrope

Immunosuppressive Therapy

The cornerstone of CTD-ILD management involves immunosuppression, but timing and agent selection require careful consideration in ICU patients.

First-Line Agents

Methotrexate:

Dose: 15-25 mg weekly with folic acid supplementation³⁹
Monitoring: CBC, liver function, creatinine
Contraindications: Significant renal impairment, active infection
ICU Considerations: Hold during mechanical ventilation due to pneumonitis risk

Mycophenolate Mofetil (MMF):

Dose: 1-3 g daily in divided doses⁴⁰
Advantages: Lower infection risk than cyclophosphamide
Evidence: Superior to cyclophosphamide in SSc-ILD (SENSCIS trial)⁴¹
ICU Use: Preferred agent for ICU patients requiring immunosuppression

Cyclophosphamide:

Indications: Rapidly progressive disease, anti-MDA5 dermatomyositis⁴²
Dosing: Pulse IV (0.5-1 g/m² monthly) or daily oral (1-2 mg/kg)
Toxicity: Hemorrhagic cystitis, malignancy, infertility
ICU Monitoring: Enhanced infection surveillance

Corticosteroids

High-Dose Pulses:

Indication: Acute exacerbations, rapidly progressive ILD
Dose: Methylprednisolone 500-1000 mg daily × 3-5 days⁴³
Transition: Oral prednisone 1 mg/kg with slow taper

Maintenance Therapy:

Target: Lowest effective dose (<10 mg prednisone daily)
Duration: Avoid prolonged high-dose therapy
Complications: Increased infection risk, especially Pneumocystis jirovecii⁴⁴

Oyster: Avoid high-dose steroids in anti-MDA5 dermatomyositis - they may paradoxically worsen outcomes. Early aggressive steroid-sparing agents are preferred.

Novel Immunosuppressive Agents

Rituximab:

Evidence: Effective in anti-synthetase syndrome⁴⁵
Dosing: 1000 mg × 2 doses (2 weeks apart) or 375 mg/m² weekly × 4
Monitoring: Immunoglobulin levels, hepatitis B reactivation

JAK Inhibitors:

Tofacitinib: Emerging evidence in SSc-ILD⁴⁶
Baricitinib: Shows promise in systemic sclerosis

Calcineurin Inhibitors:

Tacrolimus: Alternative to MMF in some CTD-ILD cases⁴⁷
Monitoring: Nephrotoxicity, neurotoxicity

Antifibrotic Therapy

The role of antifibrotic agents in CTD-ILD continues to evolve, with emerging evidence supporting their use in specific phenotypes.

Nintedanib

Mechanism: Tyrosine kinase inhibitor targeting PDGFR, FGFR, VEGFR⁴⁸ Evidence:

SSc-ILD: SENSCIS trial showed 44% reduction in FVC decline⁴⁹
Progressive Fibrosing ILD: INBUILD trial included CTD-ILD patients⁵⁰

Dosing: 150 mg BID (reduce to 100 mg BID for tolerability) Side Effects: Diarrhea (60%), nausea, elevated liver enzymes ICU Considerations:

Hold during acute exacerbations
Resume when clinically stable
Monitor for bleeding (anticoagulant effects)

Pirfenidone

Mechanism: Anti-inflammatory and antifibrotic properties⁵¹ Evidence: Limited data in CTD-ILD Dosing: Titrated to 2403 mg daily in three divided doses Side Effects: Photosensitivity, GI intolerance ICU Use: Generally avoided due to drug interactions and side effect profile

Pearl: Combination antifibrotic + immunosuppression is being investigated - early data suggests potential synergistic effects in SSc-ILD.

Supportive Care

Pulmonary Rehabilitation

Evidence: Improves exercise capacity and quality of life⁵²
Timing: Initiate early, continue throughout treatment
ICU Application: Early mobilization protocols

Oxygen Therapy

Indications: SpO2 <88% or <90% with exertion⁵³
Delivery: Conservative approach, avoid hyperoxia
Monitoring: Exercise oximetry to detect desaturation

Vaccination

Pneumococcal: PCV13 followed by PPSV23⁵⁴
Influenza: Annual vaccination mandatory
COVID-19: Enhanced risk stratification needed

Hack: Vaccinate before starting immunosuppression when possible - live vaccines are contraindicated once treatment begins.

Special Scenarios and Complications

Acute Exacerbation of CTD-ILD

Defined as acute worsening of dyspnea within 30 days, with new bilateral ground-glass opacities, absence of infection or heart failure.⁵⁵

Management Approach:

Rule out infection: Comprehensive microbiologic workup
High-dose steroids: Methylprednisolone 500-1000 mg daily
Consider cyclophosphamide: For refractory cases
Plasmapheresis: Case reports in anti-MDA5 dermatomyositis⁵⁶
Lung transplant evaluation: For eligible patients

Oyster: Acute exacerbations in CTD-ILD have better outcomes than IPF exacerbations due to greater inflammatory component.

Drug-Induced ILD

High-Risk Medications:

Methotrexate: 5-10% develop pneumonitis⁵⁷
Biologics: TNF inhibitors, rituximab
Amiodarone: Dose-dependent pulmonary toxicity⁵⁸
Nitrofurantoin: Chronic exposure risks

Management:

Immediate drug discontinuation
Corticosteroids for severe cases
Differentiate from disease progression

Pulmonary-Renal Syndromes

ANCA-Associated Vasculitis:

Presentation: Rapidly progressive glomerulonephritis + ILD
Antibodies: c-ANCA/PR3, p-ANCA/MPO⁵⁹
Treatment: Cyclophosphamide + high-dose steroids
ICU Considerations: Plasmapheresis for severe cases

Anti-GBM Disease:

Classic Triad: Hemoptysis, acute kidney injury, anti-GBM antibodies⁶⁰
Emergency Treatment: Plasmapheresis + immunosuppression
Prognosis: Time-dependent - early intervention crucial

Monitoring and Follow-up

Serial Assessments

Every 3-6 Months:

Pulmonary function tests (FVC, DLCO)
Six-minute walk test
HRCT (annually or if clinically indicated)
Echocardiography (SSc patients)⁶¹

Laboratory Monitoring:

MMF: CBC, comprehensive metabolic panel
Methotrexate: CBC, liver function tests, creatinine
Cyclophosphamide: CBC, urinalysis, liver function

Progression Criteria

Significant Decline:

FVC decrease >5% predicted
DLCO decrease >10% predicted
New honeycombing on HRCT
Clinical deterioration⁶²

Hack: Use composite endpoints - combining FVC, DLCO, and exercise capacity provides better prognostic information than any single parameter.

Lung Transplantation Considerations

Referral Criteria

General Indications:

FVC <50% predicted
DLCO <30% predicted
Oxygen-dependent at rest⁶³
Rapidly progressive disease despite treatment

CTD-Specific Considerations:

SSc: Evaluate for systemic involvement (GI, renal, cardiac)
RA: Screen for extra-articular manifestations
Myositis: Assess for cardiac involvement⁶⁴

Contraindications:

Active malignancy
Severe extrapulmonary organ dysfunction
Severe malnutrition or frailty
Active substance abuse

Pearl: Early transplant referral is crucial - don't wait until patients are too sick to benefit from surgery.

Future Directions and Emerging Therapies

Novel Therapeutic Targets

Antifibrotic Combinations:

Nintedanib + mycophenolate studies ongoing
Pirfenidone + immunosuppression trials⁶⁵

Precision Medicine:

Biomarker-guided therapy selection
Pharmacogenomic approaches to drug selection⁶⁶

Cellular Therapies:

Mesenchymal stem cell trials
Regulatory T-cell infusions⁶⁷

Biomarkers of Disease Activity

Serum Biomarkers:

KL-6: Reflects pneumocyte damage⁶⁸
SP-D: Surfactant protein D
CCL18: Chemokine associated with fibrosis⁶⁹

Imaging Biomarkers:

Quantitative HRCT analysis
MRI perfusion studies⁷⁰

Clinical Pearls and Practical Hacks

Diagnostic Pearls

"Sclerodactyly Sign": Unable to make a full fist suggests SSc
"Prayer Sign": Inability to approximate palms completely (diabetic cheiroarthropathy vs. sclerodactyly)
"Mechanic's Hands": Hyperkeratotic lateral finger changes in anti-synthetase syndrome
"Shawl Sign": V-neck and shoulder rash distribution in dermatomyositis

Treatment Hacks

"Bridge Therapy": Use rituximab to bridge between cyclophosphamide and maintenance MMF
"Steroid Holidays": Planned steroid cessation to assess disease activity
"Prophylactic Approach": Start PJP prophylaxis with any significant immunosuppression
"Vaccination Window": Immunize during steroid tapers, before next immunosuppressive agent

ICU Management Tips

"Dry Lung Strategy": Conservative fluid management in fibrotic ILD
"Early Liberation": Aggressive weaning protocols to minimize ventilator-associated complications
"Infection Vigilance": Low threshold for bronchoscopy in immunosuppressed patients
"Right Heart Focus": Monitor for pulmonary hypertension development

Oysters (Common Pitfalls)

"Clubbing Confusion": Digital clubbing is uncommon in CTD-ILD - consider IPF or malignancy
"Steroid Trap": Avoid prolonged high-dose steroids in anti-MDA5 disease
"Infection Masquerade": New infiltrates in immunosuppressed patients aren't always infection
"Methotrexate Mythology": MTX pneumonitis can occur at any time, not just early in treatment
"Silicone Scare": Breast implants rarely cause true CTD - look for other causes
"Smoking Screen": Smoking history doesn't exclude CTD-ILD - many patterns overlap with smoking-related ILD
"Age Assumption": CTD-ILD can present at any age - don't dismiss young patients
"Gender Generalization": While CTDs are more common in women, men can develop severe CTD-ILD

Conclusions

The intersection of rheumatology and critical care medicine in CTD-ILD management requires a nuanced understanding of disease pathophysiology, diagnostic strategies, and therapeutic approaches. Early recognition of CTD-ILD when pulmonary manifestations dominate can significantly impact patient outcomes through targeted immunosuppressive therapy and appropriate antifibrotic intervention.

Critical care physicians must maintain high clinical suspicion for underlying CTD in patients presenting with ILD, actively searching for subtle extrapulmonary clues that may guide diagnosis. The therapeutic landscape continues to evolve, with combination immunosuppressive and antifibrotic strategies showing promise for improved outcomes.

Successful management requires multidisciplinary collaboration between critical care physicians, rheumatologists, and pulmonologists, with careful attention to the balance between disease suppression and infection risk in the ICU setting. As our understanding of CTD-ILD pathogenesis advances, precision medicine approaches may further optimize treatment strategies and improve long-term prognosis.

Key Takeaways:

Maintain high clinical suspicion for CTD-ILD in patients with unexplained ILD
Look for subtle extrapulmonary signs that may indicate underlying rheumatologic disease
Early immunosuppressive therapy can significantly alter disease trajectory
Antifibrotic agents have a growing role in specific CTD-ILD phenotypes
Multidisciplinary management is essential for optimal outcomes
ICU management requires careful balance of immunosuppression and infection risk

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Acknowledgments

The authors thank the multidisciplinary teams in critical care, rheumatology, and pulmonology who contribute to the complex care of patients with CTD-ILD. Special recognition goes to the patients and families who participate in clinical research that advances our understanding of these challenging conditions.

Author Contributions

Conceptualization and design: All authors contributed to the conceptual framework and clinical approach outlined in this review.

Literature review and analysis: Comprehensive review of current evidence was conducted with focus on practical application in critical care settings.

Clinical expertise: Integration of bedside clinical experience with evidence-based recommendations for optimal patient care.

Conflicts of Interest

The authors have no relevant financial conflicts of interest to declare. This review was written independently without commercial influence.

Funding

No specific funding was received for the preparation of this review article.