**3. Discussion**

Immunosuppressive therapy—mostly corticosteroids in combination with CsA depending on the severity, the extent of the PG lesion, and previous conditions, is the cornerstone of the treatment in PG patients. In addition, proper local treatment, including adapted wound care to prevent secondary bacterial infection and slight compression, as well as administration of analgesics for pain relief, is important [16]. In the case of our patient, pain relief and reduction in wound size occurred after initiating the therapy with corticosteroids and CsA. At the time of treatment, the patient was not vaccinated yet, and as the patient contracted a COVID-19 infection, we needed to decide how to continue the immunosuppressive therapy.

Patients with severe COVID-19 infections may receive systemic corticosteroids in order to reduce the systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction [4]. The uncontrolled proinflammatory response with the release of cytokines known as the cytokine storm is not well defined. It has been reported to occur after unsuccessful viral clearance and it might involve less specific defense mechanisms such as monocyte and macrophage activation [19]. The exact pathophysiologic mechanisms are unclear. One study reported elevated IL-6 levels in severely ill COVID-19 patients [20]. Conversely, another study on 46 critically ill COVID-19 patients showed no difference in levels of IL-6/8 and tumor necrosis factor (TNF), compared with other critically ill patients, and even lower levels than in critically ill patients with a septic shock [21].

How to deal with immune suppressive medication during COVID-19 infection is not standardized yet. One study on 374 clinician-reported psoriasis patients from 25 countries showed that the hospitalization rate due to COVID-19 was more frequent in patients using nonbiologic systemic therapy than in those using biologics (OR = 2.84; 95% CI = 1.31–6.18). Other risk factors in this study were older age, male sex, nonwhite ethnicity, and comorbid chronic lung disease [22]. Some studies advise withholding immune-modulating medication, with the exception of corticosteroids [5]. Contrarily, a recent position statement on immunotherapeutics in patients with inflammatory skin disease pointed out that limited data suggested there is no additional risk for patients using CsA. However, no dose-dependent advice was given in this paper [23]. CsA has already been used as a treatment for patients with COVID-19, as reported in the World Health Organization (WHO) guidelines [4,24,25]. CsA bind to cyclophilin, which theoretically inhibits SARS-CoV-2 replication [26]. In agreement, in another review, it was concluded as well that "there is no evidence that [the] use of cyclosporine possesses an additional risk for severe COVID-19" [27]. Other studies on immunosuppressives during COVID-19 infection suggest that cyclosporine A can potentially prevent acute respiratory failure and hyperinflammationinduced lung injury [28,29]. On the other hand, an increased risk of several viral infections is seen in organ transplant patients treated with CsA [30]. As a causative factor, CsA suppresses helping T cells and precursors of cytotoxic T lymphocytes and depresses the innate immune system by inhibition of natural killer cells, which are the most important immune cells in this regard, along with antibody-dependent cellular cytotoxicity and certain cytokines (IL-6, IL-2), prominently interferons. NF-κB suppression inhibits mainly the production of proinflammatory cytokines. An animal study demonstrated an inability to mount an effective immune response to viral infections with the administration of CsA [31]. Even though a potential beneficial effect of cyclosporine has been discussed in several studies, the experts are not yet unified regarding this topic. In addition, most studies do not give dose-dependent advice for CsA. When administrating CsA we have to keep in mind that it will inhibit establishing immune memory following COVID-19 infection or vaccination [32].

In the presented case, methylprednisolone and cyclosporine were the main therapy of the patient. Their specific immunosuppressive mechanisms are described in Figure 2. Methylprednisolone is a synthetic glucocorticoid and displays the same features (immunosuppressive, anti-inflammatory, and antiallergic) as cortisol. Corticosteroids inhibit both T and B cells. It rapidly reduces circulating T cells due to enhanced circulatory emigration, induction of apoptosis, inhibition of T-cell growth factors, and impaired release of cells from lymphoid tissues. Effects on B-cell function and immunoglobulin production are more delayed [33]. Potent suppressive effects on the effector functions of monocytes and neutrophils, as well as the suppression of NF-κB and activator protein- 1 (AP-1), are of great importance because they inhibit many inflammatory and immune modulators as a result of modulation of the expression of pro-inflammatory cytokines such as IL-1b, TNFα, and IL-2 (Figure 4) [34]. As a result, the cellular and humoral immune reactions regress. In addition, suppression of NF-κB can suppress the synthesis of cyclooxygenase-2 (COX-2). α

κ

In conclusion, the glucocorticoid responsive genes encode a large array of effectors in the host antiviral defense system [35]. Synergistically, cyclosporine A binds to cyclophilin, which leads to an inhibition of calcineurin, leading additionally to inhibition of intracellular NF-κB (Figure 4) [3]. As a consequence, the transcription factor NF-AT cannot be dephosphorylated, and the cytokine IL-2 is produced in lower quantities. Consequently, T lymphocytes are activated less. Interestingly, a mutation in the NF-κB signaling pathway (critically important for regulation of the innate and adaptive immune responses) has been identified in a PG case report [36]. It has been postulated that observed effects of corticosteroids are dose dependent probably due to the variable dose-dependent affinity of target genomic sites for the glucocorticoid receptor and that some additional genes are affected as the concentration of glucocorticoid increases [34]. It has been proven that corticosteroids improve survival of critically ill COVID-19 patients; nevertheless, a recent study showed that a dose over 40 mg methylprednisolone equivalent dosing (MED) had a higher mortality rate [37]. In the aforementioned recent position statement, it was advised to continue corticosteroids at a lower dose < 10 mg prednisolone since it may suppress viral clearance [30]. α β

κ

κ

**Figure 4.** Effect of (**a**) prednisolone and (**b**) cyclosporine A.

Alternative treatment of pyoderma gangrenosum includes azathioprine, methotrexate, thalidomide, dapsone, mycophenolate mofetil, sulfasalazine, cyclophosphamides, colchicine, antitumor necrosis factor-alpha inhibitor (TNF-α), and intravenous immune globulin (IVIG). As our patient reacted well to the combinational therapy with cyclosporine and corticosteroids, alternative therapy was not taken into consideration. Additional therapeutic options include antibodies against IL-17, IL-12/IL-23, Il-6, IL-1β, IL-1 receptor I, as well as JAK1, 2, and 3 inhibitors [16,38–44]. For all the mentioned therapeutic options, and likewise for CsA, limited data demonstrated no risk for severe COVID-19 infection [30].

In conclusion, we cautiously advise the adaption of immune suppressive therapy in patients with pyoderma gangrenosum suffering from COVID-19. Adaptation should be performed according to the severity of the disease and the stage of treatment. In patients with symptomatic light to moderate infection, we suggest temporarily halving the CsA treatment in case of high dosage and lowering the corticosteroid dose.

**Author Contributions:** Conceptualization, M.L.; methodology, M.L., A.R., A.L., L.V. and M.R.M.; investigations, M.L., M.R.M. and A.L.; writing—original draft preparation, M.R.M. and M.L.; writing review and editing, M.L., M.R.M., A.R., A.L. and L.V.; visualization, M.R.M. and M.L.; supervision, M.L., A.R. and A.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki. Approval of the ethics committee was not needed considering the retrospective nature of the study and that the findings are a description of a single case report. This paper follows the rules of the Declaration of Helsinki. The patient involved in the research agreed to participate and agreed to provide case details and have the results of the research about them published.

**Informed Consent Statement:** Verbal and written informed consent was obtained from the subject involved in the study. Anyone involved in the research agreed to participate and agreed to provide case details and have the results of the research about them published.

**Data Availability Statement:** Most data are presented in the manuscript. Further details are available on request from the corresponding author. The data are not publicly available due to privacy restrictions.

**Acknowledgments:** We are grateful to Anne Piron for the histological analysis.

**Conflicts of Interest:** The authors declare no conflict of interest.
