Is immunotherapy an option for a patient with melanoma and a history of rheumatoid arthritis (RA) and ulcerative colitis (UC)?

Immunotherapy for Melanoma in Patients with Rheumatoid Arthritis and Ulcerative Colitis

Immunotherapy is a viable option for melanoma patients with pre-existing rheumatoid arthritis and ulcerative colitis, though it requires careful patient selection and close monitoring, with anti-PD-1 monotherapy (pembrolizumab or nivolumab) preferred over combination therapy due to lower toxicity risk. 1

Evidence Supporting Use in Autoimmune Disease

The largest retrospective series demonstrates that checkpoint inhibitors can be safely administered to patients with pre-existing autoimmune conditions:

• In 30 patients with advanced melanoma and autoimmune disorders (including 6 with inflammatory bowel disease and 6 with rheumatoid arthritis) treated with ipilimumab, the objective response rate was 20%, consistent with the general population 1
• Critically, 50% of patients experienced neither autoimmune disease flare nor high-grade immune-related adverse events 1
• Among those who did experience complications, 27% had autoimmune condition exacerbation and 33% developed conventional immune-related adverse events, most managed successfully with corticosteroids 1

For anti-PD-1 therapy specifically:

• Studies of PD-1 inhibitors in melanoma patients with pre-existing autoimmune disease showed 42% experienced autoimmune flares and 16% developed new immune-related adverse events 1
• Importantly, no patients with gastrointestinal autoimmune conditions (n=11) experienced disease flares in one cohort 1
• Response rates remained at 33%, mirroring outcomes in patients without autoimmune disease 1

Treatment Algorithm

Step 1: Assess Disease Activity and Immunosuppression Requirements

Do NOT proceed with immunotherapy if: 1

• Currently active autoimmune disease requiring systemic immunosuppressive medication
• Receiving corticosteroids >10 mg/day prednisone equivalent
• Life-threatening autoimmune manifestations (severe colitis with complications, severe extra-articular rheumatoid disease)

May proceed with caution if: 1

• Autoimmune disease controlled on low-dose prednisone (≤10 mg/day) or hydroxychloroquine alone
• Rheumatoid arthritis stable on disease-modifying agents without recent flares
• Ulcerative colitis in remission or with mild activity

Step 2: Select Appropriate Immunotherapy Regimen

First-line recommendation: Anti-PD-1 monotherapy (pembrolizumab or nivolumab) 1, 2

• Lower risk of immune-related adverse events compared to combination therapy
• Maintains efficacy with response rates of 20-40% in autoimmune populations 1
• Preferred for unresectable or metastatic melanoma 2

Avoid combination ipilimumab/nivolumab unless: 1

• Rapidly progressive disease requiring maximal response
• Patient can tolerate significantly higher toxicity risk (25% colitis rate vs 2.9% with monotherapy) 1, 3

Step 3: Pre-Treatment Optimization

For patients with ulcerative colitis: 4, 5

• Assess current disease activity and extent
• Consider elective colectomy in patients with severe, refractory ulcerative colitis before initiating immunotherapy 4
• One case report demonstrated excellent tumor response after prophylactic colectomy without UC flare 4
• If colitis is mild-moderate and controlled, proceed with anti-PD-1 monotherapy with intensive monitoring 5

For patients with rheumatoid arthritis: 6

• Ensure disease is controlled on stable medication regimen
• Document baseline joint involvement and inflammatory markers
• Anti-PD-1 therapy has been used successfully even in poorly controlled RA with manageable outcomes 6

Step 4: Monitoring During Treatment

Monitor for autoimmune flares: 1

• Assess for recurrent or enhanced pre-existing symptoms at each visit
• Most flares present as worsening of baseline autoimmune symptoms rather than new manifestations
• 27% of patients experience autoimmune exacerbation, typically manageable with corticosteroids 1

Monitor for new immune-related adverse events: 1, 7

• Diarrhea, abdominal pain (colitis occurs in 2.9% with anti-PD-1 monotherapy) 1
• Arthralgias distinct from baseline RA pattern
• Respiratory symptoms (pneumonitis in 3.1% of patients) 7
• Liver function tests before each dose 7

Management of Complications

For autoimmune disease flares: 1

• Most managed successfully with corticosteroids (prednisone 0.5-1 mg/kg/day)
• Rarely require addition of infliximab or other immunosuppressants
• Importantly, immunosuppression for immune-related adverse events does not appear to decrease checkpoint inhibitor efficacy when started after onset 1

For severe immune-mediated colitis: 7, 3

• Initiate high-dose corticosteroids (1-2 mg/kg/day prednisone equivalent) immediately
• If corticosteroid-refractory, add infliximab 7
• Rule out CMV reactivation in corticosteroid-refractory cases 7
• Permanently discontinue immunotherapy for Grade 3-4 colitis 7

For concurrent autoimmune flare and immune-related adverse event: 1

• Occurs in small subset of patients
• Requires high-dose corticosteroids
• May necessitate permanent discontinuation of immunotherapy

Critical Pitfalls to Avoid

Do not exclude patients solely based on autoimmune diagnosis 1

• Half of patients with pre-existing autoimmune disease experience no complications
• Response rates remain comparable to general population
• Risk-benefit analysis favors treatment in most cases of advanced melanoma

Do not use baseline corticosteroids >10 mg/day during immunotherapy initiation 1

• Associated with decreased objective response rate, progression-free survival, and overall survival in retrospective analysis 1
• Taper to ≤10 mg/day before starting checkpoint inhibitors if possible

Do not assume all autoimmune patients will flare 1

• Gastrointestinal autoimmune conditions may not flare as frequently as expected
• One study showed zero flares in 11 patients with GI/neurologic autoimmune conditions 1

Do not delay treatment for prophylactic immunosuppression 1

• No evidence supporting prophylactic corticosteroids or other immunosuppressants
• Treat complications as they arise rather than preemptively

Do not continue immunotherapy through Grade 3-4 immune-related adverse events 7

• Permanent discontinuation required for severe toxicity
• Fatal outcomes reported, particularly with myocarditis (39.7% fatality rate) and colitis 1

Special Consideration: Surgical Intervention

For patients with severe, active ulcerative colitis: 4, 5

• Elective colectomy before immunotherapy initiation is a reasonable strategy
• Enables full-dose checkpoint inhibitor therapy without risk of life-threatening colitis
• Case reports demonstrate excellent tumor responses post-colectomy without UC flare 4, 5
• Consider in consultation with gastroenterology and surgical oncology for high-risk UC patients