How is leukocyte transmigration managed in inflammatory or autoimmune diseases?

Management of Leukocyte Transmigration in Inflammatory and Autoimmune Diseases

Leukocyte transmigration in inflammatory and autoimmune diseases is managed primarily through integrin antagonists like vedolizumab for gut-specific inflammation, TNF-α inhibitors like infliximab for systemic inflammatory conditions, and corticosteroids as first-line immunosuppression, with the specific agent selected based on the target organ and disease severity. 1

Mechanism-Based Therapeutic Targeting

Integrin Antagonists for Tissue-Specific Blockade

Vedolizumab represents the most tissue-selective approach to blocking leukocyte transmigration, binding to α4β7 integrin and preventing T cell migration across the endothelium into inflamed gastrointestinal tissues by blocking interaction with mucosal addressin cell adhesion molecule-1 1. This agent is FDA-approved for ulcerative colitis and Crohn's disease and provides gut-specific immune suppression while theoretically sparing systemic immune responses and antitumor immunity 1.

• Vedolizumab is particularly valuable when systemic immunosuppression must be avoided, such as in cancer patients receiving immune checkpoint inhibitors who develop immune-related enterocolitis 1
• The tissue selectivity distinguishes vedolizumab from systemic agents, making it preferable when inflammation is localized to the GI tract 1

TNF-α Inhibition for Systemic Leukocyte Modulation

Infliximab blocks leukocyte transmigration systemically by inhibiting TNF-α interaction with its receptors, thereby suppressing proinflammatory cytokines (IL-1, IL-6) and modulating activity of leukocytes, neutrophils, and eosinophils 1.

• For steroid-refractory immune-related adverse events, infliximab should be initiated at 72 hours if no response to corticosteroids occurs 1
• Infliximab is particularly effective for immune-related colitis and inflammatory arthritis 1
• Critical caveat: Infliximab is NOT recommended for immune-related hepatitis 1
• Duration is typically a single dose, with a second dose administered 2 weeks later if needed 1

However, paradoxical inflammatory reactions occur with TNF inhibitors, requiring permanent discontinuation of the entire TNF-inhibitor class and switching to vedolizumab or ustekinumab, as these reactions represent a class effect with cross-reactivity 2.

Corticosteroid-Based Management

Corticosteroids remain the mainstay of treatment for most high-grade inflammatory conditions involving aberrant leukocyte transmigration 1. Short-term corticosteroid use does not reduce antitumor efficacy when treating immune-related adverse events 1.

• Slow corticosteroid taper is mandatory to prevent recurrence of inflammatory symptoms 1
• Patients should be tapered off corticosteroids with complete symptom resolution before considering resumption of any immunotherapy 1
• For severe or steroid-refractory conditions not responsive within 48-72 hours, additional immunosuppressive agents are warranted in consultation with relevant specialists 1

Steroid-Sparing Strategies

When early inflammatory complications are mild and transient, steroid-sparing approaches should be explored to protect thymopoiesis and avoid steroid-related toxicity 1:

• High-dose intravenous immunoglobulin for immunomodulation 1
• B-lymphocyte depletion with rituximab 1
• These approaches are particularly important when balancing risks of autoimmune complications against steroid toxicity in developing immune systems 1

Additional Immunosuppressive Agents

Mycophenolate

Mycophenolate preferentially affects T and B lymphocytes by inhibiting the de novo pathway for purine synthesis, which these cells critically depend upon 1, 3. It has demonstrated efficacy in autoimmune hepatitis, myositis, interstitial lung disease, and lupus nephritis 1.

• Typical dosing starts at 500 mg twice daily, increased weekly by 500 mg to reach 1000 mg twice daily (2 g/day) 3
• Doses may increase to 1500 mg twice daily (3 g/day) if tolerated 3
• Requires monitoring of complete blood count and liver function tests for leukopenia and transaminitis 3
• Contraindicated in pregnancy due to teratogenic effects 3

Intravenous Immunoglobulin

IVIG modulates B- and T-lymphocyte activity and effector functions, impacting antigen presentation, pathogenic autoantibodies, complement system, and cytokines 1. It is indicated for neurologic inflammatory conditions including Guillain-Barré syndrome, myasthenia gravis, and neuropathies 1.

Disease-Specific Considerations

Systemic Lupus Erythematosus

For neuropsychiatric SLE with inflammatory mechanisms, glucocorticoids and/or immunosuppressive agents should be used, while anticoagulant/antithrombotic treatment is favored when antiphospholipid antibodies are present 1. Combination therapy may be necessary when both processes coexist 1.

For lupus thrombocytopenia, initial therapy with intravenous methylprednisolone pulses (1-3 days) is encouraged, followed by moderate/high-dose glucocorticoids combined with azathioprine, mycophenolate mofetil, or cyclosporine 1. Rituximab should be considered for patients with no response to glucocorticoids or experiencing relapses 1.

Sepsis-Related Endothelial Dysfunction

In sepsis, the endothelium converts to a procoagulant state that expedites leukocyte recruitment, attachment, and extravasation through disrupted tight junctions 1. This creates a vicious cycle where inflammation induces coagulopathies and endothelial injury 1. Management focuses on source control and supportive care rather than specific anti-transmigration therapy 1.

Monitoring and Safety

• Therapeutic drug monitoring may guide optimization of biologic agents, with objective markers (CRP, fecal calprotectin) used to confirm mucosal healing 2
• Endoscopic assessment should be considered when uncertainty exists about disease activity versus treatment-related complications 2
• Clinical response to vedolizumab should be assessed at 10-14 weeks, while ustekinumab response is evaluated at 8-12 weeks 2

Common Pitfalls to Avoid

• Never switch within the TNF-inhibitor class for paradoxical reactions—this represents a class effect requiring mechanism switch to vedolizumab or ustekinumab 2
• Do not use infliximab for immune-related hepatitis—it is contraindicated in this setting 1
• Avoid premature steroid taper—this leads to recurrence of inflammatory symptoms and requires slow, careful tapering 1
• Do not delay additional immunosuppression beyond 72 hours in steroid-refractory severe inflammatory conditions 1