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Indian J Dermatol
Indian J Dermatol
IJD
Indian J Dermatol
Indian Journal of Dermatology
0019-5154
1998-3611
Wolters Kluwer - Medknow India

IJD-69-328
10.4103/ijd.ijd_56_24
Therapeutic Round
Sarcoidosis and Polymethyl Methacrylate (PMMA) Granulomas following COVID-19 Vaccination (ChAdOx1): Successful Treatment with Tofacitinib
Ianhez Mayra 12
Miot Hélio A 3
Caetano Lívia VN 2
de Paula Henrique Moura 2
Freire Giselle GS 2
Torres Pedro PTS 4
1 From the Department of Dermatology, Cório Clínica, Goiânia – GO, Brazil
2 Department of Dermatology, Universidade Federal de Goiás, Goiânia GO, Brazil
3 Department of Dermatology, Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Botucatu SP, Brazil
4 Department of Radiology, Hospital Einstein, Goiânia GO, Brazil
Address for correspondence: Prof. Mayra Ianhez, Rua Piquiri, Quadra AH6, Lote 1, Alphaville Araguaia, Goiania-GO, Brazil. E-mail: ianhez@hotmail.com
Jul-Aug 2024
19 8 2024
69 4 328332
1 2024
5 2024
Copyright: © 2024 Indian Journal of Dermatology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Sarcoidosis and complications related to fillers have been reported following the COVID-19 vaccination. Additionally, cutaneous sarcoidosis has been observed around polymethyl methacrylate (PMMA) injection sites. Foreign-body reactions to PMMA can occur simultaneously with systemic sarcoidosis, suggesting a shared pathogenic mechanism between both conditions. To report a case of sarcoidosis and PMMA granulomas following COVID-19 vaccination (ChAdOx11), successfully treated with tofacitinib. We present a 59-year-old woman who developed systemic sarcoidosis and a granulomatous reaction to PMMA filler following the COVID-19 vaccination (ChAdOx11). Notably, both PMMA and the vaccine were potential triggers for sarcoidosis. Treatment with tofacitinib produced marked improvement in both the cutaneous and pulmonary involvement of sarcoidosis and the granulomatous reaction to PMMA. This successful outcome suggests tofacitinib, a pan-JAK inhibitor, an alternative treatment for cutaneous and systemic sarcoidosis, as well as a potential therapy for granulomatous complications of dermal fillers, such as PMMA.

KEY WORDS:

Aesthetic dermatology
COVID-19
granuloma
Janus kinase inhibitors
polymethyl methacrylate
sarcoidosis
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pmcIntroduction

Sarcoidosis is a multi-system granulomatous disease of unknown aetiology that can affect any organ. Its most prevalent manifestations include symmetrical bilateral hilar adenopathy, diffuse lung micronodules, or both. Skin involvement is observed in approximately one-third of patients and can emerge on scars, in injured areas, and around embedded foreign bodies.[1] Moreover, sarcoidosis can be triggered by different environmental factors, including aesthetic fillers and vaccines.[23]

Polymethyl methacrylate (PMMA) is a synthetic polymer used as a permanent aesthetic filler that has been associated with chronic granulomatous reactions characterised by the presence of giant cells encapsulating its molecules.[2] Additionally, there have been reports of cutaneous sarcoidosis developing around PMMA injection sites, as well as foreign-body reactions to PMMA occurring simultaneously with systemic sarcoidosis.[45]

During the COVID-19 pandemic, cases of systemic sarcoidosis[3] and complications related to fillers have been reported following COVID-19 vaccination.[36]

We present a patient who developed sarcoidosis and a granulomatous reaction to PMMA following COVID-19 vaccination (ChAdOx11). Both conditions successfully responded to oral tofacitinib.

Materials and Methods

A 59-year-old, otherwise healthy woman, presented with severe erythema and induration with telangiectasias [Figure 1a and b] on the nasolabial folds (NLF) 20 days after receiving a second dose of the COVID-19 vaccination (ChAdOx11-AstraZeneca). She reported a cosmetic PMMA filler injection on the same topography 3 years earlier. Simultaneously, previously subtle scars on her hands and knees became infiltrated and tender [Figure 1c]. Her family and psychosocial history were unremarkable. Dermoscopy revealed multiple telangiectasias and citrine pigmentation with an erythematous background, resembling an ‘apple-jelly’ pattern. However, no lymphadenopathy was observed in the cervical, occipital, axillary, or inguinal regions.

Figure 1 Clinical presentation: (a and b) Before treatment – nasolabial folds (c) Left hand (d and e) After treatment – nasolabial folds. (f) Left hand

Although the patient did not exhibit respiratory symptoms, chest tomography (CT) revealed confluent perilymphatic subpleural nodules in the upper lobes [Figure 2a, arrows], suggesting a diagnosis of systemic sarcoidosis. The spirometry test and electrocardiogram results were within normal limits.

Figure 2 Chest computed tomography: (a) Before treatment. (b) After treatment

Dermatological high-frequency ultrasound (HFUS) of the NLF revealed hyperechoic foci, resulting in posterior acoustic shadowing, as well as posterior reverberation in a ‘comet tail’ pattern, located in the superficial and deep hypodermis suggesting the presence of PMMA. There was increased echogenicity of the surrounding tissue, intralesional, and perilesional flow on power Doppler study, consistently with a local inflammatory reaction [Figure 3a].

Figure 3 High-frequency ultrasound of the nasolabial fold. (a) Before treatment. (b) After treatment (GE Logic P9 R3, high-frequency linear transducer, 18 MHz)

Histopathological examination of the facial skin revealed a lymphohistiocytic infiltrate, comprising epithelioid histiocytes and giant cells forming granulomas with phagocytosis of exogenous material, consistent with a PMMA foreign-body reaction. PMMA is found within the vacuoles (arrows) [Figure 4a and b]. The histopathological examination of the nodule on the hand (at the scar topography) revealed epithelioid histiocytes and multinucleated giant cells forming ‘naked’ granulomas, consistent with sarcoidosis [Figure 4c and d].

Figure 4 Cutaneous histopathology presentation: (a and b) Nasolabial fold (HE-10× and HE-20×, respectively). (c and d) Hand nodule (HE-10 × and HE-20×, respectively)

We also conducted laboratory investigations and cultures to rule out infectious granulomatous diseases (such as tuberculosis and other mycobacteria), with skin biopsy cultures, chest CT scans, tuberculosis purified protein derivative test (PPD), as well as rheumatological tests for granulomatous diseases of the lungs and systemic granulomatous conditions, which yielded negative results. Serum calcium levels were within the normal range; however, the angiotensin-converting enzyme level was elevated at 76 U/L (reference <63 U/L).

Results

The cutaneous nodules showed improvement after treatment with prednisone (1 mg/kg/d) and hydroxychloroquine (400 mg/d). However, they reappeared after the corticosteroid dosage was tapered. Oral corticosteroids and hydroxychloroquine were interrupted after 6 and 3 months of the onset of the nodular formations, respectively.

Treatment with tofacitinib 5 mg twice daily was initiated in February 2023 and lessened the patient’s pain in the NLF in the first month. In 3 months, there was complete clearance of cutaneous NLF induration and tenderness, with minimal residual erythema remaining [Figure 1d and e]. The cutaneous nodules at previous scar sites completely improved [Figure 1f]. A chest CT showed a substantial reduction in the number and size of the subpleural nodules and an improvement in the hilar infiltrate [Figure 2b]. The HFUS of the NLF showed an absence of flow on power Doppler study and preserved echogenicity of the surrounding tissue, despite the presence of PMMA [Figure 3b]. A laboratory workup revealed mild dyslipidemia and a slight increase in creatine phosphokinase levels. The patient was pleased with the prospect of avoiding surgical removal of the PMMA implants and the suspension of oral corticosteroids. She is in the 1-year follow-up, tapering tofacitinib to 5 mg once a week, without any nodulation, with mild erythema and residual telangiectasias. The treatment for the patient will be the discontinuation of tofacitinib and the use of ND: YAG laser for the residual telangiectasias. The patient provided special informed consent to publish their clinical data and images.

Discussion

COVID-19 infection and vaccination elicit a series of immune reactions in different tissues, including the skin.[78] Four cases of sarcoidosis or sarcoidosis-like reactions following COVID-19 vaccination have been reported.[3] Of these cases, two occurred after the AstraZeneca vaccine and two after the Pfizer vaccine.[3] Additionally, PMMA filler-related complications have been reported following COVID-19 vaccination.[6] Permanent fillers can induce localised granulomatous inflammatory reactions and sarcoidosis.[245] Therefore, our patient had two antigenic triggers that could have caused the onset of sarcoidosis.

The treatment for PMMA complications involves significant challenges. Its permanent nature necessitates continuous systemic and intralesional corticosteroid use, producing serious side effects. In most severe cases, surgical excision is necessary, creating indelible scars.[25] Currently, there is a need for treatment options for complications arising from permanent fillers, particularly due to the global increase in PMMA aesthetic procedures.

Do sarcoid granulomas exhibit immunological similarities with granulomatous reactions from filler complications? Sarcoid granulomas are characterised by the predominant role of macrophages and exhibit a Th1-driven immunological response. This response involves T-lymphocytes secreting interleukins IL-2, IL-6, IL-12, IL-15, and interferon gamma (IFN-γ), all of which are dependent on the JAK-STAT signaling pathway, in conjunction with tumour necrosis factor-alpha (TNFα).[9] In granulomatous immune reactions to dermal fillers, there is an upregulation of the Th1 pathway with an increase of macrophages in the surrounding area as well as an increase in TNFα, IFN-γ, and IL-12.[10] Both conditions appear to be Th-1-driven with the central role of macrophages and an increase in IFN gamma and TNF alpha.

Do sarcoid granulomas and dermal filler complications share similarities in their treatment? From a therapeutic perspective, sarcoidosis can be treated with corticosteroids, tetracycline antibiotics, antimalarial drugs, thalidomide, methotrexate, anti-TNFα, and, more recently, Janus kinase inhibitors (JAKi).[9] The therapeutic approach to delayed-onset nodules (DONs) to dermal fillers, which are histologically characterised as granulomatous reactions, is advancing. Treatment of DONs with systemic corticosteroids is described in several guidelines, along with various immunosuppressants.[11] Recently, methotrexate has become significant, with a study demonstrating successful treatment of 13 cases of delayed onset nodules from various fillers, with 10 cases treated successfully without recurrence.[12] The use of methotrexate can be justified as it inhibits the Th1 pathway, specifically TNFα, IFN-γ, and IL-14 and IL-13.[13]

Because JAKi can block granuloma formation not only in sarcoidosis but also in several patients with other inflammatory disorders with macrophage activation, such as Crohn’s disease, granuloma annulare, and necrobiosis lipoidica.[14] We hypothesise that tofacitinib could also improve the delayed granulomatous reaction from PMMA.

In our case, the use of tofacitinib served as a demonstrative paradigm, demonstrating that the granulomatous manifestations triggered by both sarcoidosis and complications of dermal filler are underpinned by a similar immunological schema. Given that tofacitinib is a pan JAK, impacting JAK1, JAK3, and, to a lesser extent, JAK2, it effectuates the suppression of IL-2, IL-4, IL-6, IL-7, IL-15, and IL-21, in addition to IFN-γ and TNF-α.[15] Nevertheless, it remains the possibility that the granuloma formation surrounding PMMA may be primarily caused by sarcoidosis itself, rather than a reactionary phenomenon to PMMA. Surprisingly, during this review, a study was published showing that an isolated filler complication (hyaluronic acid) was successfully treated with abrocitinib,[16] a new and selective JAK1 inhibitor that blocks IL-4, IL-13, IL-22, IL-31, TSLP, and IFN-γ[17] This suggests JAK inhibitors could represent a viable therapeutic alternative to control complications associated with dermal fillers.

Safety concerns involving tofacitinib include opportunistic infections, thrombosis, haematological alterations, increased creatine phosphokinase levels, and lipid profile changes.[1819]

Overall, these findings and the notable improvement in both clinical and ultrasonographic parameters, observed in this case, implied that tofacitinib might be a viable option for treating PMMA-induced granuloma. However, additional studies are necessary to confirm the efficacy of JAKi, in treating granulomatous complications due to PMMA and, maybe, in other types of permanent dermal fillers, such as silicon. Such findings could mitigate the risks associated with prolonged systemic steroid therapy and the adverse events linked to surgical excisions of these granulomas.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
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