Examples of auto immune/immune mediated diseases with different responses to meds by sex?

In light of the fact that the Daratumumab pilot trial was all females, wondering if there are examples of immune mediated diseases with very different responses to particular medications by sex? I know some people here don’t like it when I ask AI, but here we go—deep seek.


Yes, there are several autoimmune and immune-mediated diseases where males and females exhibit **different responses to the same medication**, influenced by biological sex differences in pharmacokinetics, immune function, and hormonal effects. Below are key examples:

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1. Rheumatoid Arthritis (RA)**
- **Drug: Methotrexate (MTX)**
- **Sex Difference**: Women are more likely to discontinue MTX due to side effects (e.g., nausea, hepatotoxicity) and may require dose adjustments.
- **Why?**: Higher body fat percentage in women affects drug distribution, and estrogen may influence folate metabolism (MTX is a folate antagonist).

- **Drug: TNF inhibitors (e.g., adalimumab, infliximab)**
- **Sex Difference**: Women have **lower drug persistence** (more frequent discontinuation due to inefficacy or side effects).
- **Why?**:
- Higher immunogenicity in women (more anti-drug antibodies).
- Estrogen enhances B-cell activity, potentially reducing drug efficacy.

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2. Systemic Lupus Erythematosus (SLE)**
- **Drug: Mycophenolate Mofetil (MMF) for Lupus Nephritis**
- **Sex Difference**: Men may require **higher doses** for the same therapeutic effect.
- **Why?**: Testosterone may upregulate drug-metabolizing enzymes (e.g., UGTs), leading to faster clearance.

- **Drug: Belimumab (B-cell inhibitor)**
- **Sex Difference**: Women (especially premenopausal) may respond better due to estrogen’s role in B-cell activation.

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3. Multiple Sclerosis (MS)**
- **Drug: Interferon-beta (IFN-β)**
- **Sex Difference**: Men show **better clinical responses** (fewer relapses) than women.
- **Why?**: Testosterone may enhance IFN-β signaling, while estrogen blunts it.

- **Drug: Dimethyl Fumarate (DMF)**
- **Sex Difference**: Women report **more flushing and GI side effects**.
- **Why?**: Estrogen may enhance mast cell activation (contributing to flushing).

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4. Inflammatory Bowel Disease (IBD) – Crohn’s & Ulcerative Colitis**
- **Drug: Anti-TNFs (e.g., infliximab, adalimumab)**
- **Sex Difference**: Women have **lower drug levels** and higher immunogenicity (more anti-drug antibodies).
- **Why?**:
- Estrogen increases IgG production (leading to faster drug clearance).
- Body weight/composition differences affect dosing.

- **Drug: Thiopurines (azathioprine/6-MP)**
- **Sex Difference**: Women experience **more leukopenia and hepatotoxicity**.
- **Why?**: Lower TPMT enzyme activity (key for drug metabolism) in some women.

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5. Psoriasis/Psoriatic Arthritis**
- **Drug: IL-17 Inhibitors (e.g., secukinumab)**
- **Sex Difference**: Men often show **better skin clearance** than women.
- **Why?**: Androgens enhance Th17 pathway suppression.

- **Drug: Methotrexate**
- **Sex Difference**: Women report **more nausea and fatigue**.

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6. Ankylosing Spondylitis (AS)**
- **Drug: TNF inhibitors**
- **Sex Difference**: Men tend to have **better spinal symptom relief** than women.
- **Why?**: Women more often have peripheral arthritis, which may respond differently.

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Key Mechanisms Behind Sex-Specific Responses:**
1. **Hormonal Effects**:
- Estrogen → ↑ B-cell activity, ↑ drug immunogenicity.
- Testosterone → ↓ inflammation, ↑ drug metabolism.
2. **Pharmacokinetics**:
- Women often have lower lean body mass, affecting drug distribution.
- CYP450 enzymes (drug metabolism) are influenced by sex hormones.
3. **Immunogenicity**:
- Women mount stronger immune responses to biologics (higher anti-drug antibodies).

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Clinical Implications:**
- **Dosing**: Weight-based dosing may disadvantage women (e.g., fixed dosing for anti-TNFs might be better).
- **Monitoring**: Women may need closer side-effect monitoring (e.g., MTX toxicity, leukopenia with thiopurines).

 

It's an interesting question, but are these responses "very different"?

They might be, but my impression is that the drugs tend to be used in both sexes regardless of some differences in response.

I guess it depends what aspect of it you want to dig into?