Podcast Summary: Derms on Drugs – The Causes of Chronic Spontaneous Urticaria
Date: September 26, 2025
Hosts: Dr. Matt Zirwas, Dr. Laura Ferris, Dr. Tim Patton
Guest: Dr. Mark Sirota (Pediatrics, Dermatology, Allergy)
Episode Focus: Understanding the mechanisms, diagnosis, and latest treatment advances for chronic spontaneous urticaria (CSU).
Main Theme and Purpose
This episode of Derms on Drugs dives deep into the shifting understanding of chronic spontaneous urticaria (CSU), highlighting the latest research on its mechanisms (endotypes), practical diagnostic pearls, and evolving therapeutic strategies. Featuring insights from triple-boarded expert Dr. Mark Sirota, the discussion blends clinical wisdom, new data, and lively banter.
Key Discussion Points & Insights
1. Mechanisms of CSU: Endotypes and Their Clinical Implications
[01:21 – 05:30]
- Three Proposed Endotypes:
- Type 1 ("Auto-allergy"):
- Patients are "allergic to themselves," with IgE directed against endogenous antigens (e.g., double-stranded DNA).
- Not true autoimmunity but "auto-allergy."
- Responds rapidly to omalizumab (Xolair); often have higher IgE, concurrent asthma/allergies.
- Type 2B (Autoimmune):
- Presence of pathogenic IgG directed at either IgE or the IgE receptor.
- Frequently seen in patients with additional autoimmune conditions (e.g., positive ANA, joint pain).
- Lower IgE levels, slower response to omalizumab, may benefit from BTK inhibitors like remibrutinib.
- Type 3 (Non-IgE Receptor Mediated):
- Mechanistically unclear; complement or alternative receptors may drive disease.
- Often the mildest but least responsive group.
- Type 1 ("Auto-allergy"):
Quote:
“It’s not a homogeneous disease. This is a heterogeneous disease… mainly from a genotype perspective.” – Dr. Mark Sirota [03:50]
- Practical Pearl:
Streamlining initial therapy selection based on associated allergies/asthma and expected IgE levels.
2. Patient Stratification & Therapy Tailoring
[05:49 – 09:10]
- Type 1 CSU:
- Younger onset, atopic background, robust response to omalizumab or possibly dupilumab.
- Type 2B CSU:
- Older onset, autoimmune background, slower omalizumab response, consider remibrutinib.
- Type 3 CSU:
- Indeterminate pathway, generally less severe.
Quote:
“I’m going to use that [endotype approach] to sort of define which drug I’m likely to use first. No data to back that up, just makes sense to me though.” – Dr. Matt Zirwas [09:03]
3. Lab Testing: When, What, and Why?
[10:00 – 16:08]
- Routine lab work for CSU rarely changes management per Dr. Sirota.
- Only helpful in ruling out mimics (e.g., parasitic infection, urticarial vasculitis, bullous pemphigoid).
- Chronic urticaria index (histamine release assay) may have prognostic utility (“this is long term”).
- Skin biopsy for unclear cases.
Quote:
“I don’t routinely order lab testing for CSU patients… lab testing is very unhelpful.” – Dr. Mark Sirota [10:59]
- Testing only if:
- Patient is atypical or unresponsive to standard algorithm.
- Ruling out mimics is critical due to “diagnosis of exclusion” nature of CSU.
4. Algorithm of Care: Antihistamines and Beyond
[17:33 – 26:28]
Antihistamines:
- Start with non-sedating options (fexofenadine, loratadine, cetirizine, levocetirizine).
- Increase up to four times the standard dose if needed.
- Avoid sedating antihistamines due to regimen confusion and suboptimal safety.
Quote:
“I don’t personally recommend the sedating antihistamines even at night… There are much better options to treat people’s sleep.” – Dr. Mark Sirota [18:42]
What’s New & What’s Next:
- Omalizumab (Xolair): Longtime standard, rapid responders likely Type 1 CSU.
- Dupilumab (Dupixent): Now FDA-approved, especially for omalizumab failures.
- Remibrutinib and Other BTK Inhibitors: Not yet FDA-approved, but rapid onset and promising for “autoimmune” features.
- Barzolvolumab (anti-C-kit antibody): Under phase 3 trials, directly depletes mast cells; may cause hypopigmentation side effects.
- Mycophenolate (Cellcept): An “off-algorithm” but well-tolerated and rapid alternative, especially after other immunosuppressants fail.
5. Rapid-Onset vs. Maintenance Therapies
[26:28 – 29:01]
- Remibrutinib:
- Very fast-acting (“within the first two to four weeks”), selectively targets BTK, does NOT impair overall immunity.
Quote:
“Small molecule intracellular targets, they work really quickly… probably within the first two to four weeks…” – Dr. Mark Sirota [27:37] - Most ‘bleeding events’ are minor (petechiae/purpura), not true bleeding risks.
- Barzolvolumab (C-kit inhibition):
- Effectively depletes mast cells but not universally effective, suggesting possible major role of basophils in some CSU patients.
- Potential for hypopigmentation is a unique side effect.
6. Refining Diagnosis: Asking the Right Clinical Questions
[33:48 – 36:10]
- Always ask about recent infections and opioid use (both can trigger hives).
- Opioids (via direct mast cell degranulation) are a common but rarely volunteered cause.
- Complement activation after infection (C3a/C5a) can drive mast cell histamine release.
Quote:
“When you’re evaluating a hive patient, you want to ask them if they’ve had an infection… and if they’re taking opioid pain medications…” – Dr. Mark Sirota [35:19]
7. The TSH Debate: When Does it Matter?
[36:10 – 38:32]
- Dr. Zirwas argues for at least annual TSH testing in CSU patients due to their increased risk for developing hypothyroidism.
- Dr. Patton prefers history-driven, symptom-based labs rather than routine screening.
- Dr. Sirota: Treating hypothyroidism can improve hives in some patients (“autoimmunity begets autoimmunity”).
8. Meta-Analysis Insights: What’s Most Effective?
[22:13 – 25:43]
- Network meta-analysis (Chew et al): assessed efficacy/safety for systemic treatments in over 11,000 patients with CSU.
- Highest certainty and greatest mean decreases in UAS7: omalizumab, remibrutinib, barzolvolumab, legolizumab, dupilumab.
- Cyclosporine: effective, but with safety concerns.
- Mycophenolate: best number, but weaker studies.
Quote:
“Cyclosporine… maybe among the most effective… also the only drug listed as maybe among the most harmful.” – Dr. Tim Patton [22:56]
9. CSU Therapy Pearls
- Switch therapies if response is inadequate — likely some overlap in efficacy.
- Bridge with cyclosporine for severe, refractory cases, transition to safer long-term agents.
- Cellcept (mycophenolate): a reasonable, broad-spectrum, well-tolerated alternative after other agents have failed.
- Expect more biologic and small molecule options as studies progress.
10. Fun Moments & Notable Quotes
On Sedating Antihistamines:
"They're gonna mess it up and take it in the morning, then go drive a forklift or something… For that reason I just stick to one pill." – Dr. Mark Sirota [18:42]
On Lab Testing:
"If you walk in and they have psoriasis, you can diagnose psoriasis... But the physical exam finding for urticaria is unique in that it’s just simply a physical exam finding. It doesn’t tell you anything yet." – Dr. Mark Sirota [16:08]
Network Plots:
"Figure 2 is a network plot of the studies analyzed. These plots remind me of that video game from the 80s called Tempest. So they should call these Tempest plots." – Dr. Tim Patton [22:03]
On Drug Selection:
"I'm...CSU experts can go to hell, I'm using mycophenolate first." – Dr. Tim Patton [23:08]
On Mechanisms:
"If the Barzo got rid of...your mast cells, seems like Barzo should be like 100% effective… but it’s not." – Dr. Matt Zirwas [30:30]
Important Timestamps for Key Segments
- [01:21] – Overview of CSU mechanisms (Type 1/2/3)
- [05:30] – Importance of genotype over phenotype
- [09:10] – Linking endotype to therapy
- [10:00] – Lab testing: when and which tests
- [17:33] – Antihistamine selection debate
- [22:13] – Network meta-analysis findings
- [26:28] – Mechanism and rapid onset of remibrutinib
- [30:30] – Novel agents: Barzolvolumab efficacy and side effects
- [36:10] – TSH debate in CSU
- [41:33] – Trivia section
Memorable Trivia & Light Moments
[41:33 – end]
Three trivia questions close the episode, ranging from the first non-sedating antihistamine and its cardiac side effects, to the foods most associated with latex-fruit syndrome. Laughter ensues around mangos, leech therapy, and nostalgia for discontinued drugs.
"You guys worked together to get that. Everybody wins." – Dr. Tim Patton [44:54]
Conclusion
This episode offers a practical, entertaining, and up-to-date perspective on managing CSU, from refining your diagnostic workup to anticipating the next generation of targeted therapies. The lively interplay between experts deepens clinical understanding, sheds light on real-world management challenges, and delivers memorable pearls for daily practice.
For more fun, learning, and unfiltered clinical wisdom, tune in each week to Derms on Drugs!