What could be the reason for worsening symptoms and high ESR (Erythrocyte Sedimentation Rate) in a 60-year-old female with Rheumatoid Arthritis (RA) on Tofacitinib (tofacitinib), with a history of diabetes (5 years), hypertension (5 years), and hypothyroidism (15 years), and early Interstitial Lung Disease (ILD)-like changes on High-Resolution Computed Tomography (HRCT)?

Worsening RA Symptoms with High ESR and Early ILD: Causes and Management

The most likely reason for worsening symptoms and very high ESR (140) in this patient with RA on tofacitinib is progression of interstitial lung disease (ILD), which requires immediate multidisciplinary evaluation and adjustment of treatment strategy.

Clinical Assessment of the Current Situation

The patient presents with:

• 60-year-old female with multiple comorbidities:
  • Diabetes (5 years)
  • Hypertension (5 years)
  • Hypothyroidism (15 years)
• RA diagnosis with high RF, anti-CCP, and ESR
• Initial response to tofacitinib followed by:
  • Worsening pain
  • Extremely elevated ESR (140)
  • Early ILD-like changes on HRCT
• Tingling and numbness in left leg for 8 months
• Pain in bilateral knee, ankle, and wrist for 6 months

Potential Causes for Worsening Symptoms

1. Progression of RA-ILD

• RA-ILD occurs in approximately 3-5% of RA patients 1
• Tofacitinib has been associated with ILD events at a rate of 0.18 per 100 patient-years 2
• The patient's extremely high ESR (140) suggests active inflammatory disease

2. Tofacitinib Treatment Failure

• Primary or secondary treatment failure can occur with JAK inhibitors 1
• High inflammatory markers suggest inadequate disease control

3. Medication-Related Complications

• JAK inhibitors like tofacitinib carry risks of:
  • Infections (higher in RA-ILD patients) 3
  • Thromboembolic events 1
  • Liver function abnormalities 4

4. Comorbidity Interactions

• Diabetes, hypertension, and hypothyroidism may complicate RA management
• Age >65 years and smoking are risk factors for ILD progression in patients on tofacitinib 2

Diagnostic Approach

Pulmonary Assessment

1. Complete PFTs including spirometry and DLCO

   • Recommended for monitoring RA-ILD 1
   • Assess for deterioration in lung function

2. Follow-up HRCT

   • Essential to evaluate progression of ILD 1
   • Compare with previous imaging to assess progression rate

3. Ambulatory Desaturation Testing

   • Conditionally recommended for monitoring SARD-ILD 1
   • Should be performed every 3-12 months

Rheumatologic Assessment

1. Disease Activity Evaluation

   • Comprehensive joint examination
   • Assessment of extra-articular manifestations

2. Laboratory Testing

   • Complete blood count to assess for cytopenias
   • Liver and kidney function tests (tofacitinib can affect both) 1
   • Lipid profile (JAK inhibitors can alter lipid levels) 5

Management Recommendations

Immediate Actions

1. Refer for Multidisciplinary Evaluation

   • Rheumatology and pulmonology consultation is essential 1
   • Consider ILD expert center referral for progressive disease

2. Adjust Current Therapy

   • Consider switching from tofacitinib to alternative DMARD therapy based on the progression of ILD
   • JAK inhibitors have been associated with ILD events 2

Treatment Options

1. For Progressive RA-ILD

   • Consider adding antifibrotic therapy (nintedanib) which has been shown to slow RA-ILD progression 1
   • Evaluate balance between inflammatory and fibrotic ILD process 1

2. For Inadequate RA Control

   • Consider alternative bDMARD if tofacitinib is failing 1
   • Adjust glucocorticoid dosing temporarily to control inflammation

Monitoring Plan

1. Pulmonary Monitoring

   • PFTs every 3-12 months (more frequently during first year) 1
   • HRCT when clinically indicated 1
   • Ambulatory desaturation testing every 3-12 months 1

2. Rheumatologic Monitoring

   • Regular assessment of disease activity
   • Monitor for adverse effects of therapy

Special Considerations

Risk Factors for ILD Progression

• Age >65 years
• Smoking history
• High disease activity (DAS28-ESR) 2
• High-titer RF and anti-CCP antibodies 1

Cautions with JAK Inhibitors

• Increased risk of serious infections 6
• Thromboembolic events, especially in patients with risk factors 1
• Liver enzyme elevations and lipid changes 4

Comorbidity Management

• Ensure optimal control of diabetes, hypertension, and hypothyroidism
• These conditions may complicate RA management and contribute to overall inflammation

The extremely high ESR (140) and worsening symptoms despite tofacitinib therapy, combined with early ILD changes, strongly suggest progressive RA-ILD requiring prompt multidisciplinary evaluation and treatment adjustment.