What is the diagnosis and management approach for a 60-year-old woman with rheumatoid arthritis (RA) on methotrexate, tofacitinib (Xeljanz) and sulfasalazine, presenting with chronic cough, tree-in-bud appearance on High-Resolution Computed Tomography (HRCT), deformed joints, dry eyes and dry mouth, and positive Rheumatoid Factor (RF) and anti-Ro antibodies?

Diagnosis

This patient has rheumatoid arthritis-associated bronchiolitis with secondary Sjögren's syndrome, most likely drug-induced or exacerbated by her current DMARD therapy (methotrexate, tofacitinib, or sulfasalazine).

The tree-in-bud appearance on HRCT is pathognomonic for small airways disease/bronchiolitis, not typical interstitial lung disease 1. Combined with chronic cough, dry eyes, dry mouth, and positive anti-Ro antibodies, this indicates secondary Sjögren's syndrome complicating her RA with bronchiolar involvement 1. The clinical picture suggests either drug-induced bronchiolitis or RA-related inflammatory bronchiolitis 1, 2.

Key Diagnostic Features

• Tree-in-bud pattern on HRCT: This finding represents centrilobular nodules connected to distal branching structures, characteristic of bronchiolitis rather than interstitial lung disease 1
• Sicca symptoms with positive anti-Ro antibodies: Confirms secondary Sjögren's syndrome, which commonly causes lymphocytic bronchiolitis 1
• Multiple DMARD exposure: Methotrexate, tofacitinib, and sulfasalazine can all induce or exacerbate lung disease 3, 2

Management Approach

Immediate Steps

Discontinue tofacitinib immediately as it is associated with interstitial lung disease and cough in RA patients, with the FDA label specifically noting dyspnea, cough, and interstitial lung disease as adverse reactions 3. Tofacitinib-related pulmonary toxicity typically occurs early in treatment and can be fatal 2.

Evaluate for Infection

• Obtain bronchoscopy with bronchoalveolar lavage to rule out bacterial infection, particularly Pseudomonas aeruginosa and Haemophilus influenzae, which commonly complicate bronchiolitis 1
• Send sputum cultures if productive cough is present 1
• Consider surgical lung biopsy only if diagnosis remains uncertain after bronchoscopy, as the HRCT pattern is highly suggestive 1

Assess Drug-Induced Versus RA-Related Disease

• Methotrexate pneumonitis: Typically presents with dyspnea, dry cough, and fever within the first 20 weeks of therapy, but can occur at any time 2
• Sulfasalazine: Rare cause of bronchiolitis but documented in case reports 2
• Tofacitinib: Associated with ILD and cough, particularly in older patients 3, 2

Given the tree-in-bud pattern (not typical ground-glass opacities of drug-induced pneumonitis), this is more consistent with inflammatory bronchiolitis rather than classic drug-induced ILD 1.

Treatment Algorithm

Step 1: Corticosteroid Trial (First-Line)

Initiate oral prednisone 0.5-1 mg/kg/day (approximately 40-60 mg daily) for 4-6 weeks as bronchiolitis in inflammatory bowel disease and connective tissue disease responds to corticosteroids 1. Lymphocytic bronchiolitis is more responsive than other forms 1.

• Add inhaled corticosteroids (e.g., fluticasone 500 mcg twice daily) as adjunctive therapy 1
• Reassess after 3-4 weeks; if no improvement, escalate treatment 4

Step 2: Macrolide Antibiotic Therapy

Add azithromycin 250 mg daily or clarithromycin 500 mg twice daily for anti-inflammatory effects, particularly if bacterial superinfection is present 1. Macrolides have demonstrated efficacy in diffuse panbronchiolitis with similar tree-in-bud patterns, improving cough, dyspnea, and radiographic abnormalities within 2-6 months 1.

Step 3: Modify DMARD Regimen

After stabilizing pulmonary disease, restart RA therapy without tofacitinib:

• Continue methotrexate if tolerated (monitor closely for worsening pulmonary symptoms) 2
• Continue sulfasalazine 2
• Add hydroxychloroquine to complete triple DMARD therapy (methotrexate + sulfasalazine + hydroxychloroquine), as no cases of HCQ-induced lung disease have been reported 2

Step 4: If Inadequate Response After 3-6 Months

Switch to biologic therapy, avoiding rituximab since the patient is anti-Ro positive (rituximab works best in seropositive patients) 1, 4:

• First choice: Abatacept (preferred for seronegative or anti-Ro positive patients after JAK inhibitor failure) 1, 4
• Second choice: Tocilizumab (anti-IL-6 receptor antibody, also preferred for seronegative patients) 1, 4
• Avoid TNF inhibitors initially as they can induce or exacerbate ILD in RA patients, with cases occurring within the first 20 weeks of therapy 2

Monitoring Strategy

• Repeat HRCT at 3 months to assess radiographic response 1
• Pulmonary function tests at baseline and 3 months to document improvement in obstructive physiology 1
• Clinical assessment every 4 weeks during corticosteroid therapy 1
• Taper prednisone slowly over 3-6 months once improvement is documented, as long-term corticosteroids beyond 1-2 years increase risks of cataracts, osteoporosis, and cardiovascular disease 1

Critical Pitfalls to Avoid

• Do not assume this is typical RA-ILD: Tree-in-bud pattern indicates bronchiolitis, not the usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) patterns typical of RA-ILD 1, 5
• Do not restart tofacitinib: The FDA label specifically warns of ILD and cough as adverse reactions 3
• Do not use rituximab: It is less effective in anti-Ro positive patients compared to abatacept or tocilizumab 1, 4
• Do not delay infection workup: Bacterial superinfection is common in bronchiolitis and requires specific treatment 1
• Do not continue all three DMARDs if pulmonary disease worsens: Methotrexate and sulfasalazine can both cause lung toxicity, though less commonly than tofacitinib 2

Prognosis

Lymphocytic bronchiolitis associated with connective tissue disease generally responds well to corticosteroids and macrolides 1. However, if left untreated, bronchiolitis can progress to bronchiectasis and respiratory failure 1. The presence of secondary Sjögren's syndrome with anti-Ro antibodies indicates more severe systemic disease and warrants aggressive treatment 1.