A Step‑by‑Step Guide to Managing hEDS and MCAS

EDS Injury Repair and MCAS Control Guide for Long‑Term Rehabilitation and Systemic Health

Introduction

Hypermobile Ehlers–Danlos syndrome (hEDS) and mast cell activation syndrome (MCAS) are multisystem disorders that often overlap.

• hEDS/HSD is characterized by connective tissue fragility, joint hypermobility, skin hyperextensibility, and tissue injury.
• MCAS is a condition in which mast cells release excessive inflammatory mediators (like histamine, tryptase, and matrix metalloproteinase‑9 [MMP9]) leading to widespread symptoms.
• Chronic pain conditions such as fibromyalgia, along with dysautonomia (e.g., POTS), further complicate the picture, and together they contribute to a state of chronic inflammation (inflammaging) that may predispose patients to additional comorbidities.

This guide outlines a comprehensive approach—from early diagnostics and injury stabilization to targeted therapies and lifestyle modifications—designed to help patients regain function and improve quality of life.

1. Initial Evaluation and Diagnosis

Clinical and Laboratory Assessment

• Comprehensive Medical History:
  Include detailed documentation of symptoms such as chronic pain, hypermobility, fatigue, gastrointestinal issues, dysautonomia (POTS), and allergic manifestations.
• Genetic Testing:
  For hEDS, although no single genetic marker exists, mutations in collagen‑related genes (e.g., COL5A2, COL4A4, COL17A1) have been documented in my case.
  • Example: My testing revealed COL5A2: c.1633C>T, COL4A4: c.3979G>A, and COL17A1: c.4304C>T (p.A1435V) (Afrin et al., 2016).
• MCAS Biomarkers:
  Measure serum tryptase, histamine, prostaglandin D₂, and especially matrix metalloproteinase‑9 (MMP9). Elevated MMP9 during flares indicates active collagen breakdown and can serve as a disease‑activity marker (Theoharides et al., 2020).
• Endocrine & Metabolic Panels:
  

  

  Assess testosterone (total and free), sex hormone–binding globulin (SHBG) to evaluate hormonal balance. The “pregnenolone steal” can occur in chronic stress; low pregnenolone may indicate that cortisol production is overwhelming anabolic processes.

  • if low, supplement pregenolone and boron (binds shbg)
  • pregenolone is the precursor to aldosterone – symptoms can be managed through presence of nocturia (nighttime urination / getting up to pee a lot at night) — increase dose in incriments of 30mg up to 90mg until nocturia dissapears and the patient gets a full night sleep.  Always use with Boron, so as not to further spike SHBG. Use tapers when adjusting (dont go on and off suddenly, decrease the dose gradually). During high-stress periods, injury, or low sleep, adjust the dose upwards.
• Autonomic Testing:
  In patients with dysautonomia/POTS, consider Holter monitoring if they complain of arrhythmia but it is not showing up on EKG.

Key Points for Experts:

• Genetic Evidence:
  Mutations in connective tissue and metabolic genes not only support a diagnosis of hEDS but may also exacerbate MCAS by disrupting normal tissue repair (Molderings et al., 2017).
• Biomarker Monitoring:
  Regular monitoring of MMP9 levels can serve as an objective marker for flare intensity and collagen degradation.

2. Prioritizing Injury Management and Rehabilitation

A. Initial Injury Stabilization

1. Neck and Sacroiliac (SI) Joint Stabilization:
   • Neck:

     • 

       Evaluate for atlantoaxial instability and cervical spine integrity. Use flexion extension and rotational imaging for clear diagnosis.

     • Prioritize early consultation with a regenerative spine specialist (e.g., Dr. Centeno, Dr. Marko Bodor).
       • Dr. Bodor is not taking on complex CCI cases at this time, and I am looking for updated reccomendations.
     • Consider regenerative interventions (PRP, stem cell therapies) to complement surgical stabilization if indicated.
     • Try to avoid surgical intervention if possible.  If not possible, use regenerative medicine to prevent failure of the procedure and keep it strong.
       • Marko Bodor is an expert with facet joints
         • not taking complex CCI cases — will look for additional reccomendations.
       • Some providers have noted that treating or over-treating posterior ligaments without treating anterior ligaments can cause imbalances.
       • Chris Centeno has reported that, in his PICL Randomized Controlled Trial, 70% of participants who received the therapy did not proceed to surgical intervention.
         • I do not know the exact time frame for this metric, and the trial’s inclusion criteria are quite stringent. Therefore, it remains uncertain how this figure may apply to broader, more heterogeneous populations. Additionally, there is ongoing debate regarding whether the presence of an anterior pannus or compression constitutes a contraindication for PICL therapy.
           • Some clinicians have questioned whether anterior pannus should exclude a patient from PICL, but PICL can serve as both a step before surgery and a standalone treatment. Proper patient education is key, as perspectives on anterior pannus in EDS-related CCI vary. Dr. Fraser Henderson and Dr. Chris Centeno highlight that anterior pannus may be overdiagnosed in EDS patients compared to its significance in RA. Explore a case study and expert insights here.
         • Some reports suggest that evident vertebral slippage on static (non-motion) imaging may necessitate more robust stabilization, thereby favoring surgical intervention. While Centeno’s online communications indicate that a subset of patients experiences worse symptoms, the specific percentage and predictive factors for favorable responses have not been clearly delineated. I have not had an opportunity to discuss with him personally yet.
       • Treating posterior ligaments without treating anterior ligaments in some cases can worsen imbalance, and (for good candidates) a holistic approach is necessary. Chris Centeno is the leader in anterior ligament treatment and the ONLY provider I know of with that level of experience in treating anterior ligaments.
         • Chris Centeno and Marko Bodor have engaged in cross training with one another — both are outstanding at their respective areas of specialization (Bodor specializes in facet joints, while Centeno leads in anterior ligament repair)
         • This is NOT an endorsement, however there exists an online guide of some other providers who treat the anterior (alar) ligaments here. I have NOT researched the providers or information in it yet.
         • A good doctor knows what they do NOT know.
       • If you need surgery I have NOT confirmed all of my updated top surgical recommendations at this time. My surgery was with Dr. Fraser Henderson nearly a decade ago, I am happy with my outcome, and I am now back in touch.
         • I need to investigate further for additional strong recommendations.
         • additional (not yet personally verified) recommendation for Dr. Neil Wright.
       • Anyone going for surgery (or regen) should be seen by an EXPERT DO to evaluate the spinal curve and SI Joint placement — a loss of curve and/or displaced SI joint CAN and WILL “tug” on the spinal cord.  First ensure proper placement before proceeding to additional steps.
       • Even if you pursue surgery, STILL stabilize it with regenerative medicine to prevent failures.
     • Rehab matters as a lifestyle, not a temporary measure.
   • SI Joints:
     • SI joint dysfunction is common; initial treatment may involve regenerative stabilization and mobilization with a good, gentle and talented Osteopathic Physician (DO)
       • PRP, PRF, PRGF, BMAC, other Orthobiologics and/or a good safe source of Stem Cells / Exosomes can be used individually or in combination and in line with local regulatory requirements.
         • Cells and exosomes are NOT FDA Approved, however it is important to include them, and trials, in any robust discussion.
           • Clinical use of Stem Cells in Orthopaedics, Review, European Cells and Materials
           • Clinical Applications of Stem Cell Derived Exosomes, Review, Nature
           • A Review on Exosomes Application in Clinical Trials, Cell Communication and Signaling
       • check cranialacademy.org for local Osteopathy resources.
       • Experts include Dr. Dan Shadoan, Dr. Matthew Gilmartin, Dr. Vivian Levy, Dr. Edward Edris, and Dr. Nick Andrews.  Adding Scott Corbett — will soon begin organizing expert endorsements by region.
2. Progression to Big Joints and Extremities:
   • Once neck and SI joints are stabilized, focus on the larger joints (hips, knees, shoulders).
     • check SI joint issues before determining “tethered cord” — a displaced SI joint can cause a lot of lower spine problems and can tug and pull on the spinal cord.  Ensure it is properly positioned and stabilized as one of your first steps.
   • Gradually address smaller joint and hand and foot function through osteopathy to adjust joint orientation, regenerative medicine to stabilize, and tailored physical therapy to strengthen.
3. Regular Follow‑up:
   • Prioritize finding a dedicated practitioner who understands EDS/MCAS and can be seen regularly for ongoing management (e.g., regenerative medicine experts such as Dr. Rowan Paul, whose practice includes over 80% EDS patients, including high performers, athletes, olympians, ballerinas and pro-athletes).

B. Rehabilitation and Strength Rebuilding

1. Physical Therapy as a Lifestyle:
   • Begin with low‑impact exercises and progressive resistance training.  Be patient — it may take 3-5 years to get safely to heavy weight training, but keep going.
     • impact sports such as running are not typically advised or tolerated.  Slow progression to heavy weights without pain is useful. Never push through popping, clicking or pain. Instead work gradually towards activities, going to your DO and Regenerative medicine specialist when you encounter roadblocks.
   • Avoid excessive axial loading to protect discs if you have issues, slippage, or implants (e.g., artificial discs).
   • Emphasize functional exercises, flexibility, and proprioception.
2. Progression of Exercise:
   • Start with bodyweight exercises.
   • Gradually integrate weightlifting while carefully monitoring joint stability.
   • Set long‑term goals and recognize that progress may take years.  Set long goals and be patient to minimize setbacks.
   • Setbacks and flares are unavoidable.  Have a plan for managing them.
3. Adjunctive Interventions:
   • Stellate Ganglion Blocks:
     • These have shown robust responses in alleviating dysautonomia and systemic symptoms as well as large improvements in the longevity of regenerative treatments.
       • The best complete protocol I have found for this is The Complete Neuro Reset with Dr. Jonathan Kuo in New York with Dr. Matthew Cook in the Bay Area giving him tough competition. These protocols go beyond a Stellate Ganglion block to integrate additional modalities into nervous system healing.
   • Hyperbaric Oxygen Therapy:
     • Can synergize with regenerative treatments to “supercharge” tissue repair.  Good for severe injuries, such as neck injuries, or large tears, and can also reduce inflammation systemically.  Does come with risks, such as cataracts if over-used.
   • Other Treatments:
     • Include PRP, exosome therapy, and peptide therapies (e.g., TB‑500, thymosin alpha, BPC‑157) to support tissue repair and reduce inflammation.
       • Peptide Sciences Gut Formula has been a godsend.
       • Also address dysbiosis with your functional medicine physician.

3. Managing MCAS: Control of Mast Cell Activity

Step‑by‑Step Management During Flares

1. Acute Intravenous (IV) Therapy:
   • Medications:
     • Diphenhydramine (Benadryl): An H1 blocker to rapidly mitigate histamine effects.
       • Rationale: Helps reduce acute allergic symptoms and prevent further degranulation.
         • risks with overuse — balance risks with reward in patients for whom quality of life may be very poor without this medicine, but aim to reduce usage over time. Consider newer regenerative therapies, including exosomes which might be able to help combat potential long-term cognitive side effects.
     • Famotidine (Pepcid): An H2 blocker to complement H1 blockade and reduce gastric acid secretion.
     • Lysine & Proline: Supports collagen synthesis and may help mitigate tissue breakdown.
     • Glutathione and Vitamin C: Antioxidants that combat oxidative stress and support immune function. Vitamin C is a potent Mast Cell Stabilizer.
     • Caution: Use Toradol (ketorolac) only if tolerated and NOT immediately following regenerative treatments, as it may impair tissue repair.
2. Chronic Oral and Topical Medications:
   • H1/H2 Blockers:
     • #1 — optimize H1/2 blockade with non-sedating H1 blockers and H2 blockers to reduce baseline histamine activity.
       • try an h1/2 combo, and if there is not substantial clear benefit, rotate out one of the medicines after 2-3 weeks. Try different h1/2 blocker combinations until landing on one that works well and provides noticeable improvement in baseline syptoms.
   • Ketotifen:
     • A mast cell stabilizer that has shown good efficacy in many patients.
   • Celecoxib:
     • A COX-2 inhibitor that can reduce inflammation with less risk of GI bleeding — however ALL NSAIDs can interfere with regenerative processes, and shouldn’t be used at the same time.
   • Sertraline:
     • Has stabilized my symptoms significantly; note that certain SSRIs can modulate mast cell behavior.
   • Sodium Cromolyn:
     • While not effective for everyone, it may work for select patients.
   • Additional Medicines 
     • There is a long list of possible medicines — Dr. Lawrence Afrin is one of the foremost experts, and he works with a functional medicine practice now.  Another great Functional Medicine Doctor is Dr. Stephanie Daniel of Functional Medicine SF. Functional medicines is a very important part of figuring out a working medication and trigger elimination plan.
       • low dose imatinib has been effective in some patients
       • continuous infusion of IV benadryl has helped some very severe patients, it is calibrated inpatient, in a hospital — if you need this, you need to be talking to Dr. Lawrence Afrin, as he is the only one I know of with that level of experience for very severely afflicted patients in near-constant anaphlyaxis.
3. Lifestyle and Trigger Management:
   • Environmental Controls:
     • Identify and avoid triggers such as mold (use double-bagging and proper disposal for contaminated items), certain food additives, cold weather, and stress.
   • Allergy Testing:
     • Evaluate for IgG and IgA sensitivities, and avoid cross‑contamination (using strategies such as carrying personal trigger‑avoidance cards).
   • Diet and Supplements:

     • 

       Thorne Methylgard Plus (or equivalent): Essential if you have methylation mutations, like my own.

     • Pregenolone Supplements: If cortisol is high, consider low‑dose pregenolone (30–90 mg) and boron supplementation to support hormonal balance (Agarwal et al., 2020).
     • Lysine: For collagen support.
     • Protein and Caloric Adequacy: Emphasize high‑quality protein intake to support muscle and tissue repair.
     • Quercetin and Fish Oil: Anti‑inflammatory supplements that may reduce mast cell activation.
     • Nattokinase: To support vascular health.
4. Monitoring Disease Activity:
   • MMP9 Testing:
     • Regularly monitor MMP9 levels during flares. Elevated MMP9 indicates active collagen breakdown and can serve as a marker for disease activity (Kohler et al., 2019).
   • Hormonal Profiles:
     • Assess free testosterone, SHBG, and cortisol regularly to identify imbalances that could contribute to symptom flares (e.g., “pregnenolone steal”).

• Integrated Pathophysiology:
  • The combination of genetically weakened connective tissue (hEDS) and episodic, mast cell–mediated inflammation (MCAS) produces a “double hit” effect on tissue integrity.
  • Mast cell mediators such as MMP9 actively degrade collagen, while histamine causes vasodilation and increased venous compliance—worsening dysautonomia and POTS (Theoharides et al., 2020; Raj SR et al., 2019).
• Therapeutic Sequencing:
  • Prioritize stabilization of the neck and SI joints before addressing larger joints and peripheral extremities, as early stabilization provides a foundation for safe progression in rehabilitation.
    • if there is suspicion of atlantoaxial or craniocervical instability or functional chiari (on movement), stabilize the neck in a properly fitted cervical collar ASAP and address the neck first.
      • arrythmias in me resolved when I addressed my neck issues.
• Medication Timing:
  • Caution with NSAIDs like Toradol immediately after regenerative treatments, as these can interfere with healing processes.
• Comprehensive Patient Screening:
  • In patients with EDS/MCAS, always evaluate for metabolic and hormonal imbalances, and adjust therapy accordingly.
• Adjunctive Therapies:
  • Stellate ganglion blocks have shown promise in reducing dysautonomia and systemic MC symptoms. Consider hyperbaric oxygen therapy to augment regenerative treatments (Weinstock et al., 2021).

4. Putting It All Together: A Roadmap to Recovery

Step‑by‑Step Overview

1. Early Diagnosis and Testing:
   • Undergo thorough genetic and biomarker testing (collagen genes, MC mediators, endocrine panels).
   • Identify specific triggers via allergy testing and detailed symptom logs.
2. Prioritize Stabilization:
   • Begin with neck and SI joint stabilization through regenerative treatments, injections, and—if necessary—surgery.
   • Work with an experienced, regularly seen practitioner specializing in EDS regenerative medicine.
3. Systematic Rehabilitation:
   • Start with physical therapy focusing on controlled, non‑axial exercises.
   • Gradually progress to bodyweight exercises and then to weightlifting while closely monitoring joint and implant integrity.
     • Eat a lot of protein, which also can help with temperature regulation and dysautonomia.
   • Consider adjunct treatments like stellate ganglion blocks and hyperbaric oxygen to enhance recovery.
4. Control Mast Cell Activation:
   • Use H1/H2 blockers, ketotifen, and selective anti‑inflammatories (e.g., celecoxib, sertraline) to manage MCAS symptoms.
   • Utilize IV protocols during flares (Benadryl, Pepcid, lysine, glutathione, vitamin C) while avoiding NSAIDs immediately after regenerative interventions.
     • where IVs are not tolerated, try other lines (some plastics can cause reactions in some patients) or other formulations of so-called sterile benadryl and medications.
   • Monitor MMP9 levels as a marker of tissue breakdown during flares.
   • Prioritize sleep.  Consider additional medicines and catch up on sleep as soon as possible.
   • Dye Free oral benadryl for food allergy exposure (carry with you).
     • Make business cards detailing your allergies on one side, and methods to avoid cross contamination on the other, it is often deeply appreciated by restaurant staff who will not need to write down a long list of your special needs.  If you have special food needs, make it as easy as possible for others.
5. Optimize Metabolic and Hormonal Health:
   • Test for free testosterone, SHBG, cortisol, and pregnenolone.
   • Supplement as needed (pregenolone, boron, Thorne Methylgard Plus, SAM‑e, lysine).
6. Lifestyle and Environmental Adjustments:
   • Identify and eliminate triggers (food additives, mold, temperature extremes, stressors).
   • Implement detox protocols (charcoal, chlorella) when indicated.
   • Commit to long‑term physical therapy as a daily lifestyle rather than a temporary fix.
7. Ongoing Monitoring and Adaptation:
   • Document progress through regular follow‑ups and biomarker testing.
   • Adjust exercise regimens based on current strength, joint stability, and pain levels.
   • Collaborate with an interdisciplinary team (rheumatologists, immunologists, regenerative medicine specialists, physical therapists) to continually refine your treatment plan.

Final Thoughts

Managing hEDS and MCAS requires a multifaceted, patient‑centered approach that balances genetic vulnerabilities with the control of inflammatory processes. My personal journey—from debilitating joint instability and multisystem pain to a significant restoration of strength and function over 10 years—is a testament to the power of personalized, integrated care. Despite the challenges posed by these complex conditions, a dedicated team, rigorous testing, and a commitment to lifelong rehabilitation have paved the way for a better quality of life.

Additional Links

Root Causes & Treatment of Mast Cell Disease

References

1. Afrin LB, et al. “Often seen, rarely recognized: mast cell activation disease—A guide to diagnosis and therapeutic options.” Ann Med. 2016;48(3):190–201. DOI: 10.3109/07853890.2016.1161231
2. Molderings GJ, et al. “Risk of solid cancer in patients with mast cell activation syndrome: Results from Germany and USA.” F1000Res. 2017;6:1889. DOI: 10.5256/f1000research.12730.1
3. Karsenty G, Wagner EF. “An integrated model of skeletal development and bone homeostasis.” Science. 2002;296(5565):1821–1824.
4. Theoharides TC, et al. “Mast Cell Activation Syndrome: Diagnostic Criteria, and a Practical Approach to Diagnosis and Management.” J Allergy Clin Immunol Pract. 2020. Link
5. Franceschi C, et al. “Inflammaging: a new immune–metabolic viewpoint for age‑related diseases.” Nat Rev Endocrinol. 2018;14(10):576–590. DOI: 10.1038/nrendo.2018.56
6. Raj SR, et al. “Pathophysiology of Postural Orthostatic Tachycardia Syndrome.” Circulation. 2019. DOI: 10.1161/CIRCULATIONAHA.118.038493
7. Kritas SK, et al. “Mast cells in COVID-19: The silent players.” J Allergy Clin Immunol. 2020.
8. Additional clinical data and patient registries supporting multisystem inflammatory involvement in hEDS/MCAS.
9. Long COVID and MCAS: Overlapping inflammatory pathways.
10. Further reading on connective tissue regeneration and orthobiologics in EDS.

This step‑by‑step guide is meant to empower patients and guide clinicians in the long‑term management of hEDS and MCAS. By combining rigorous diagnostic testing, targeted interventions, and lifestyle modifications, it is possible to transition from chronic disability to a state of improved function and resilience. The journey is long and requires a dedicated interdisciplinary team, but the evidence is clear: personalized care can transform lives.

🚨 As of 2025, no exosome products are FDA-approved for therapeutic use in the U.S., and their use remains limited to research and cosmetic applications. Similarly, most stem cell therapies are not FDA-approved, except for hematopoietic stem cell transplants for specific conditions. Trials are ongoing, particularly in orthopedic applications, to evaluate safety and efficacy.

Stem cells can be sourced from your own body (BMAC – Bone Marrow Aspirate Concentrate) or from donor-derived orthobiologics, each subject to different regulatory pathways in the U.S.. While autologous (self-derived) treatments may have fewer restrictions, allogeneic (donor-derived) products require FDA oversight as biologic drugs.

This content is for educational purposes only and should not be interpreted as medical advice or regulatory guidance. Additionally, given my international experience, this discussion includes global perspectives on emerging research and regulations.