The management of PG remains a challenge as therapeutic decisions need to be personalized, focused on the presence of concomitant diseases, and the specific quantity, location, diameter, and depth of lesions. The topical therapy of PG often does not allow proper control of disease activity. Therefore, the additional use of systemic therapeutic agents is necessary in more severe PG cases.

For the purposes of this article, a detailed search of the PubMed database was carried out, using the following search terms: “pyoderma gangrenosum”, “hemophagocytic lymphohistiocytosis”, “HLH”, “double negative T lymphocytes”, “treatment of pyoderma gangrenosum”, “topical treatment of pyoderma gangrenosum”, and “systemic treatment of pyoderma gangrenosum”. Articles published till January 2021 were selected on the basis of their relevance. The list of suitable articles was amended by manual search of references of identified papers. All studies published in languages other than English were excluded. The most relevant papers on PG treatment involving more than 15 patients are listed in Table 2.

The most common topical treatments for PG include calcineurin inhibitors and potent or ultra-potent corticosteroids. According to Marzano et al., monotherapy with tacrolimus could be the first-line treatment of idiopathic, early, localized PG [29]. In a case series of five patients treated with 0.1% tacrolimus ointment, complete clinical remission was achieved within a mean time of 6 weeks [37]. Moreover, in another clinical trial conducted by Lyon et al., 11 patients with peristomal PG were treated with topical tacrolimus 0.3%, whereas 17 patients received topical clobetasol propionate 0.05% [30]. This study suggested that 0.3% tacrolimus might be more effective than clobetasol in managing PG lesions larger than 2 cm in diameter. Importantly, in most case reports, topical tacrolimus was used together with other systemic therapies.

Systemic corticosteroids and cyclosporin, either in monotherapy or combined, are considered first-line agents for PG. The results from a randomized controlled trial comparing oral cyclosporin (4 mg/kg per day) with prednisolone (0.75 mg/kg per day) showed no significant difference between these two regimens [26]. Despite similar adverse reactions, infections were more common in the prednisolone group, while renal impairment and hypertension were frequent in the cohort receiving cyclosporin. Hence, the specific side effect profiles of both drugs should be crucial in making treatment decisions.

In cases of refractory PG, intravenous immunoglobulin therapy (IVIG) can be used simultaneously with systemic steroids [36, 38,39,40]. In a systematic review of 49 patients, 43 (87.8%) achieved a complete or partial response, whereas complete response was observed in 26 (53.1%) of cases. Most patients received a dose of 2 g/kg and the average time to initial response was 3–5 weeks. These findings suggest that clinicians may consider IVIG as adjuvant therapy or a good alternative to cyclosporin and corticosteroids.

The use of other immunosuppressive agents, such as azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, or thalidomide have been described in the literature; however, more data are required to evaluate their effectiveness in the management of PG, as currently only individual case series are available [41,42,43,44].

In recent years, many new treatment approaches have been introduced for a subset of patients who only partially respond to conventional immunosuppressive therapy [45]. Although the role of cytokines in pathogenesis of PG is not fully understood, overexpression of tumor necrosis factor alpha (TNFα) is associated with the neutrophil infiltration characteristic of PG; therefore, this group of drugs may be useful. A multicenter study evaluated the efficacy and safety of adalimumab in active ulcers of PG [46]. In this clinical trial, 22 enrolled patients received adalimumab 160 mg at week 0, followed by 80 mg at week 2, and then 40 mg every week starting at week 4. Of this group, seven patients (32%) who achieved Physician Global Assessment (PGA) 0 (all ulcers completely healed) completed the study at week 26, while nine patients (41%) who reached improvement of ulcers with a PGA score of 1–3 at week 26 entered the extension period to receive adalimumab 40 mg every week until week 52. Eighteen patients experienced adverse events, most commonly infections (n = 11), whereas serious adverse events, such as anemia, cataract, bacterial arthritis, and pain due to PG, were reported by four patients. Nevertheless, the results of this study suggest that adalimumab is an effective and generally well-tolerated treatment for patients with PG.

The efficacy of infliximab for the treatment of PG was evaluated in a randomized, double-blind, placebo-controlled trial conducted by Brooklyn et al. [27]. In this study, 30 patients were randomized to receive an infusion of infliximab at 5 mg/kg or placebo at week 0. Thereafter, 13 patients received infliximab, and 17 patients received a placebo. At week 2, the infliximab group achieved better improvement (46%; 6/13) compared to placebo group (6%; 1/17). Subsequently, patients were reassessed, and those who did not respond were offered open-label infliximab at the same dose. At the end of the study, of the 29 patients who received infliximab, 69% (20/29) demonstrated a favorable clinical response.

Although data for the effectiveness of etanercept are limited to case reports and small case series, it appears to be useful in the treatment of recalcitrant and widespread PG [47,48,49,50,51,52,53]. The majority of studies showed clinical improvement or complete resolution with no serious adverse reactions. However, compared to infliximab, etanercept was less effective in the treatment of PG coexisting with active Crohn’s disease. Another novel TNFα inhibitor golimumab could be an interesting treatment option, especially for patients who did not respond to infliximab and adalimumab therapies [54]. In one case report, 24 weeks after the start of the treatment with golimumab, the patient showed complete remission of PG. It is worth noting, that TNFα inhibitors, especially adalimumab and etanercept, may elicit potential paradoxical effects and induce PG lesions. In such cases, the IL-12/23 inhibitor ustekinumab has proved to be beneficial [55], as several reports have demonstrated the complete resolution of resistant PG lesions with this drug. However, further research is required to confirm these results.

In some genetic syndromes such as PAPA (pyogenic arthritis, PG, and acne) mutation in the PSTPIP1 gene is common. In these cases, increased IL-1 production was noted. Therefore, IL-1 inhibitors could be the treatment of choice for this group of patients. Several studies have described the rapid and lasting response to anakinra in patients with PAPA syndrome [20]. Nevertheless, data suggesting its superiority over other biological drugs are still limited. Another monoclonal antibody targeting IL-1β canakinumab was found to be effective in the case of steroid-refractory PG [56]. In this prospective open-label study, five patients received canakinumab subcutaneously in a single dose of 150 mg at weeks 0 and 2, and a dose of 150–300 mg at week 4. Four out of five patients achieved reduction in wound size, as well as improvement of PGA score and the Dermatology Life Quality Index (DLQI). In addition, three out of five patients showed complete remission at week 16.

Among possible therapeutic options for PG, some molecules, such as corticosteroids, cyclosporin, and IVIG, may also be used in treatment of HLH. Simultaneously, the pathogenesis of these diseases is still not fully understood, which makes choosing the optimal treatment modality difficult. Moreover, both PG and HLH can coexist with various systemic disorders, and the requirement for successful therapy is to treat these comorbidities effectively, as well. Here, we demonstrate a case of the concomitance of these two rare diseases, where, despite intensive cooperative treatment, no successful outcome was obtained. A long thorough analysis of the interview and medical documentation also did not lead us to determine which of these conditions developed primarily and which was secondary.

The detection and further research of abnormalities within cell populations will possibly help us to understand mechanisms responsible for occurrence of these two conditions and their symptoms. In our patient we observed an increased NK cell population, constituting approximately 45% of all lymphocytes, while normally in adults they only represent about 10–15% of the total peripheral blood lymphocytes. In HLH, cytotoxic T lymphocytes and NK cells are dysfunctional, which leads to pathological immune stimulation resulting in a significant increase in proinflammatory cytokine concentrations and in reduced or absent NK cell activity. The functioning of T lymphocytes and NK cells may be affected also by genetic disorders, which results in abnormal synthesis of their intracellular cytotoxic granules [57, 58].

Additionally, an increased CD4−/CD8− (TCRγ/δ) DNT population was also revealed, constituting approximately 50% of all peripheral blood T lymphocytes, instead of the normally observed less than 5% [59]. The exact role and function of DNTs within the immune system remains still unclear. A high percentage of these cells is described in infections (both bacterial and viral), inflammatory diseases, post-splenectomy, cellular immunity deficiencies, autoimmune disorders, or lymphoproliferative malignancy [60,61,62]. Reports on immunophenotypic changes accompanying HLH focus mainly on the population of cytotoxic T lymphocytes, while reports on the presence of DNTs in the course of HLH are rare [9]. An increased, similarly to our observation, number of DNTs was reported by Dalal et al. [63], who studied various immunophenotypic abnormalities in adults with HLH. Splenic infiltration of atypical CD4−/CD8− α/β T cells in a 14-year-old boy diagnosed with HLH was reported by Hossny et al. [64].

PG and HLH appear to be disorders of the immune system and share common mechanisms consisting of increased production of cytokines, among others the IL-1 family. It is already well recognized that blocking of IL-1-mediated inflammation by anakinra (human IL-1 receptor antagonist) reduces consequences of tissue damage and organ failure. Anakinra is registered for treatment of rheumatoid arthritis, Still disease, and cryopyrin-associated periodic syndromes; however, it is also frequently used off-label. There are reports about successful anakinra therapy of PG in the context of PAPA syndrome [20], PG in association with hidradenitis suppurativa and acne (PASH syndrome) [21], and PG in association with rheumatoid and psoriatic arthritis [22, 23]. Anakinra was also reported as a useful therapeutic for patients suffering from severe HLH [24, 25]. Therefore, in the absence of standard therapy options, we decided to use anakinra in our patient. However, the ineffectiveness of this treatment may suggest the need to look for another common immunological checkpoint in patients with co-morbid HLH and PG. So far, there are no descriptions of such clinical cases; thus the aim of this case report is to draw attention to the need to search for new therapeutic options for these patients. Recently, monoclonal antibodies (such as emapalumab, a human IgG1 monoclonal antibody against interferon-gamma) and JAK pathway inhibitors (such as ruxolitinib) have been approved and reported to be effective in the treatment of HLH [65,66,67,68,69]. Further clinical trials are ongoing to confirm the effectiveness and safety of these and other biological and small molecule therapies in different groups of patients suffering from HLH. Currently, it seems that the use of biological drugs may be considered in the treatment of HLH patients, especially in patients refractory or intolerant to conventional HLH therapy. However, further controlled trials are warranted.