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Treating COVID-19 vaccine-related nodules with methotrexate
Patrick Treacy unveils the results of a study investigating the use of the immunosuppressant methotrexate to treat twenty-three patients unresponsive to any established treatment protocols
ABSTRACT During the COVID-19 pandemic, it was reported that patients who had cosmetic fillers experienced side effects after receiving the vaccines. The exact mechanism was thought to be due to Type IV hypersensitivity causing foreign body granulomas. These problems were initially treated with antihistamines, 5-fluorouracil, hyaluronidase and intralesional steroids. However, a cohort of patients remained unresponsive to any established treatment protocols. The objective was to evaluate the efficacy of using the immunosuppressant methotrexate to treat Covid vaccinerelated delayed onset nodules in twenty-three patients with moderate facial disfigurement unresponsive to established treatment protocols. All patients successfully responded to 10mgs of methotrexate for a three-month period and all their nodules dissipated
DURING THE COVID-19 PANDEMIC, dermal fillers made world headlines as it was reported that patients who had cosmetic fillers experienced side effects after receiving vaccines that utilised both viral vector and mRNA technology. Initially, the Moderna mRNA-1273 vaccine trial reported an incidence rate of facial swelling of 0.02% after receiving the vaccine, and later similar effects were noted from both the AstraZeneca and the Pfizer/BioNTech COVID-19 vaccine1,2. The exact mechanism was thought to be due to Type IV hypersensitivity causing foreign body granulomas. These problems appeared globally and were initially treated with antihistamines, 5-fluorouracil, hyaluronidase and intralesional steroids. However, the medical world also experienced a cohort of patients unresponsive to any established treatment protocols and we proceeded to solve the problem.
KEYWORDS Covid-19, vaccines, Injectables, nodules
Objective
The objective of this study was to evaluate the efficacy of using the immunosuppressant methotrexate to treat COVID-19 vaccine-related delayed onset nodules in
twenty-three patients with moderate facial disfigurement unresponsive to established treatment protocols, including intralesional steroids and hyaluronidase.
Implementation, tactics and strategy
We identified a cohort of 23 international patients injected with dermal filler or collagen stimulators who presented with delayed onset nodules after receiving the COVID-19 vaccine. Eighteen of these patients were from Ireland, three from the United Kingdom, and one each from France, the United States, and Dubai. All of the patients were unresponsive to established treatment protocols, including antihistamines, 5-fluorouracil (5-FU), 5-FU and lidocaine, and intralesional steroids. Some presented with as many as thirty to forty nodules in the case of poly-L-lactic acid (PLLA; Sculptra®, Galderma, Zug, Switzerland), and excision of implanted material was considered only as a last resort.
Eighteen of these complications related to both cross-linked and non-cross-linked hyaluronic acid fillers; fourteen to monophasic HA products (Juvederm®, Allergan, Irvine, CA, USA), (Teosyal®, TEOXANE Laboratories, Genève, Switzerland) (Stylage M, Vivacy, Paris, France); two to the biphasic filler, Restylane®, (Q-MED, Uppsala, Sweden), and two were an unknown product. Five were related to poly-L-lactic acid (PLLA; Sculptra®) and two of these patients had been injected nearly two years previously. All of the hyaluronic acid patients were injected intradermally or supraperiosteally. Two patients received Teosyal® HA filler (0.2 ml on each side) to their tear trough areas with microcannula, and both had received previous hyaluronidase with little effect.
None of the patients developed swelling, erythema, or nodules directly after dermal filler injection but presented with hard nodules about two weeks after vaccination. The patients received various vaccines, including the AstraZeneca COVID-19 vaccine, Pfizer/ BioNTech COVID-19 vaccine, and the Moderna vaccine. The Moderna and Pfizer/BioNTech vaccines are forms of mRNA vaccine. These vaccines work by teaching immune cells to make a harmless piece of ‘spike protein’. Unlike the Pfizer/BioNTech and Moderna coronavirus vaccines, the Oxford/AstraZeneca vaccine is not an mRNA vaccine. Instead, the AstraZeneca vaccine is a viral vector vaccine made from a weakened form of a common cold virus from chimpanzees.
Methods and material
Methotrexate is a chemotherapy agent and immunesystem suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. It is particularly used to reduce the activity of the immune system when it mistakenly attacks parts of the body, such as skin and joints, causing illness. Methotrexate is used to treat rheumatoid arthritis, psoriatic arthritis, vasculitis, systemic sclerosis, and severe psoriasis. It initially
PATRICK TREACY, MD, PHD, Medical Director, Ailesbury Clinics Ltd and Ailesbury Hair Clinics Ltd, Dublin, Cork, London, and Middle East
email: ptreacy@gmail.com
Table 1 Methotrexate monitoring recommendations
Table 2 Management of methotrexate toxicity
LABORATORY FREQUENCY MONITORING WHAT TO DO IF OUTSIDE LIMITS
Full blood count Baseline
Discuss with specialist team
(FBC)
Every two to four weeks immediately. initially, then every month to three months if results have been normal on a stable dose.
Liver function Baseline Withhold until discussed tests (LFTs) Every two to four weeks with specialist team. initially, then every month to Other factors to consider: three months if results have been normal on a stable • Check alcohol intake. dose. • Review medicines which may cause liver dysfunction (eg, NSAIDs).
Serum creatinine Baseline
Often performed at same time as LFTs and FBC monitoring during dosing changes. Every three months for patients on stable treatment. Reduce dose.
Chest X-ray Baseline
Repeat if respiratory symptoms occur (see below).
SYMPTOMS WHAT TO DO
Rash or oral ulceration Withhold methotrexate until discussed with specialist team. Folic acid mouth wash may help with mucositis.
Nausea and vomiting, Dividing the dose over the day or giving methotrexate diarrhoea
by subcutaneous injection is often a good way of avoiding nausea.
New or increasing Withhold and discuss URGENTLY with specialist team. dyspnoea or dry cough Arrange chest x-ray and respiratory function tests. (pneumonitis)
Severe sore throat, Request immediate FBC and withhold until results abnormal bruising available. Discuss any unusual results with specialist team.
needs to be closely monitored, requiring blood tests every two weeks until stable and then every three months.
Dosing
When methotrexate is used for Covid-19 vaccine nodules, it may be taken once a week (or in certain circumstances as three divided doses over 36 hours once a week). Folic acid is normally prescribed to be taken on a different day to methotrexate. Treatment of psoriasis with methotrexate is also prescribed intermittently over a week.
These are unusual dose regimens that may confuse some patients. It is important to clearly explain the dosing schedule to each patient and make sure they have understood the information. Specify on every prescription and on the dispensed medicine label the day of the week (written in full) the dose is to be taken.
Healthcare professionals should also check that the patient is taking methotrexate correctly. Serious and sometimes life-threatening or fatal adverse effects can be caused by incorrect methotrexate dosing.
Monitoring
It is imperative that monitoring of renal and liver function tests, full blood count and chest radiography occur before and during treatment. The Best Practice Advocacy Centre (BPAC) recommendations for monitoring methotrexate and management of methotrexate toxicity are outlined in Tables 1 and 23. Please note that local guidelines may vary3 .
Adverse effects
The risk of serious adverse effects is greater with higher doses and with prolonged methotrexate treatment. Hepatotoxicity may occur without previous signs of gastrointestinal or haematological toxicity. Pulmonary toxicity, including pneumonitis and pulmonary fibrosis,
Figure 1 Evidence of nodules at the site of poly-L-lactic acid (PLLA) injection following COVID-19 vaccination
Figure 2 Evidence of nodules at the site of poly-L-lactic acid (PLLA) injection following COVID-19 vaccination
can also occur at any time during therapy. Methotrexate is usually contraindicated in patients with impaired renal function.
Discussion
These problems appeared centred on hyaluronic acid dermal fillers and poly-L-lactic acid collagen stimulators, which usually rarely cause persistent side effects4. Dermal fillers and collagen stimulators are essentially foreign bodies, and some patients may develop a Type I hypersensitivity reaction after initial or repeated exposure to these injected products when exposed to the immune response to both viral and bacterial infection. This is related to immunoglobulin E (IgE)-mediated immune hypersensitivity. It is known that IgE stimulates mast cells to degranulate, releasing proteases, heparin, histamine, cytokines, prostaglandins, leukotrienes, and platelet-activating factor, which result in oedema, erythema, pain, and itching characteristic of an allergic response5. Reactions can be severe and can last for several weeks6 .
Delayed hypersensitivity reactions also occur, mediated by T-lymphocytes rather than antibodies. They typically occur 1 day after injection but may be seen as late as several weeks after injection and may persist for many months. These are characterised by induration, erythema, and oedema7,8 .
The different HAs have varying degrees of hardness (G’), which will influence their suitability for a particular procedure. In general, the greater the G’ of the product, the deeper it should be injected. It should be noted that while more concentrated products with a greater degree of cross-linking have a longer duration of effect, they also increase reactivity in the body and, thus, the risk of inflammation and granuloma formation. Fillers with biodegradable particles that stimulate the body to produce its own collagen have a longer duration of effect; such products include calcium hydroxylapatite (CaHA; Radiesse®; Merz Pharmaceuticals GmbH, Frankfurt, Germany) and poly-L-lactic acid (PLLA; Sculptra®). CaHA consists of synthetic CaHA microspheres suspended in a carrier gel. Injection provides immediate visual improvement with long-term deposition of new collagen surrounding the microspheres, which contributes to an average duration of effect of around 15 months.
Cases of dermal filler swelling resulting from SARS-CoV-2 vaccination with the Moderna-type vaccine had been successfully treated with lisinopril, an angiotensin-
converting enzyme inhibitor (ACE-1) in the United States. ACE-1 treatment has previously been used in the treatment of hypertrophic scars, keloids, and other inflammatory skin disorders and can assist in downregulating CD44 by inhibiting the pro-inflammatory Angiotensin II. Other cases were successfully treated in the United Kingdom and Germany with 0.5 mL of 50 mg/mL 5-FU, 0.3 mL of 10 mg/mL triamcinolone (or 40 mg/mL triamcinolone, depending on localisation and degree of inflammation), and 0.2 mL 2% lidocaine with adrenalin5 .
Outcomes
All patients successfully responded to 10 mg of methotrexate for a three-month period and all their nodules dissipated. One patient had to stop the treatment in week ten due to moderately severe anergia. The treatment protocol above was submitted and accepted by peer review at both the AIDA Dermatology Conference in Abu Dhabi (May 2022) and the IMCAS World Conference in Paris (June 2022). It has changed the lives of many patients by reducing the distress caused by this condition.
Declaration of interest None
Figures 1–4 © Patrick Treacy Tables 1–2 © Patrick Treacy
Key points
We identified a cohort of 23 international patients injected with dermal filler or collagen stimulators who presented with delayed onset nodules after receiving the Covid booster vaccine
Methotrexate is a chemotherapy agent and immune-system suppressant.
Healthcare professionals should also check that the patient is taking methotrexate correctly. Serious and sometimes lifethreatening or fatal adverse effects can be caused by incorrect methotrexate dosing
The risk of serious adverse effects is greater with higher doses and with prolonged methotrexate treatment.
All patients successfully responded to 10mgs of methotrexate for a three-month period and all their nodules dissipated
Figure 3 Evidence of nodules at the site of poly-L-lactic acid (PLLA) injection following COVID-19 vaccination
Figure 4 Evidence of nodules at the site of hyaluronic acid filler injection following COVID-19 vaccination
References
1. Savva D, Battineni G, Amenta F, Nittari G. Hypersensitivity reaction to hyaluronic acid dermal filler after the Pfizer vaccination against SARS-CoV-2. Int J Infect Dis. 2021 Dec; 113:233-235. doi: 10.1016/j.ijid.2021.09.066. Epub 2021 Sep 29 2. Michon A. Hyaluronic acid soft tissue filler delayed inflammatory reaction following COVID-19 vaccinatin- A case report. J Cosmet Dermatol. 2021; 20:2684-2690. 3. Methotrexate DBL Data Sheet 25 August 2017. URL: medsafe.govt.nz/ profs/Datasheet/d/ dblMethotrexateinjmayne.pdf 4. Sclafani AP, Fagien S. Treatment of injectable soft tissue filler complications. Dermatol Surg. 2009;35(Suppl 2):1672–1680. 5. Rowland Warmann MJ. Hypersensitivity reaction to hyaluronic acid dermal filler following novel coronavirus infection- a case report. J Cosmet Dermatol. 2021; 20:1557-1562. 6. Arron ST, Neuhaus IM. Persistent delayed-type hypersensitivity reaction to injectable non-animal-stabilized hyaluronic acid. J Cosmet Dermatol. 2007;6(3):167–171. 7. Turkmani MG, De Boulle K, Philipp-Dormston WG. Delayed hypersensitivity reaction to hyaluronic acid dermal filler following influenza-like illness. Clin Cosmet Investig Dermatol. 2019; 12:277-283 8. Van Dyke S, Hays GP, Caglia AE, Caglia M. Severe Acute Local Reactions to a Hyaluronic Acid-derived Dermal Filler. J Clin Aesthet Dermatol. 2010;3(5):32–35
