Delineating the bidirectional association between pyoderma gangrenosum and immune-mediated rheumatic diseases: A population-based study

Pyoderma gangrenosum (PG) is a rare chronic ulcerating skin disorder with an immunological pathomemchanistic basis.^{1, 2} As with other neutrophilic dermatoses, PG usually has an associated disorder,¹ mainly Inflammatory bowel disease, arthritis and haematological malignancies.³ Immune-mediated rheumatic diseases (IMRD) are defined as a group of acquired diseases resulting from persistent immune-mediated inflammation.^{4, 5} These autoantibodies or autoreactive T cells can attack any organ of the body, leading to a wide array of signs and symptoms.⁴ This disease group consists of several potentially devastating conditions such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), psoriatic arthritis (PsA),⁴ Sjögren syndrome and dermatomyositis.⁴

Several case reports have pointed to the coexistence of PG and IMRD in individual patients.⁶ While the association of PG with RA is robust,^{3, 7} our knowledge about the potential of SLE, SSc and PsA to trigger PG is very sparse. The current study sought to investigate the bidirectional association between PG and IMRD. To outline the risk of developing IMRD after PG, we adopted a retrospective cohort study design, in which patients with PG were followed over time to estimate the incidence of IMRD. Additionally, to examine the likelihood of developing PG in individuals with a history of IMRD, we employed a case–control study design exploring the prevalence of preexisting IMRD (as the exposure) among patients who subsequently developed PG (as the outcome).⁸ The Appendix S1 further details information about the study population and the statistical analyses utilized in the current study.

The current study consisted of 302 with PG and 1497 matched control individuals. Characteristics of the study population are delineated in Table 1. A case–control study was conducted to clarify whether a history of IMRD places patients at increased odds of developing PG (Table 2). The likelihood of developing PG after being diagnosed with IMRD was increased more than threefold (OR: 3.89; 95% CI: 2.16–7.05). In a granular analysis, the odds of PG were elevated following SLE, SSc and RA, but not PsA (Table 2). In a multivariate analysis, a history of IMRD independently conferred more than fourfold elevated odds of PG (adjusted OR: 4.28; 95% CI: 2.21–8.32; p < 0.001).

A retrospective cohort study followed patients with PG and controls longitudinally and estimated the incidence of new-onset IMRD (Table 3). Overall, four cases of new-onset IMRD occurred among patients with PG and seven cases among controls. The crude risk of developing IMRD was comparable between cases and controls (HR: 3.19; 95% CI: 0.93–10.90; p = 0.064). The aforementioned risk was of no statistical significance in both genders and following adjustment for demographic variables and comorbidities (adjusted HR: 2.20; 95% CI: 0.53–9.13; p = 0.279). In a granular analysis, PG did not confer an elevated risk of any of the investigated specific IMRD (Table 3).

We then addressed the epidemiological characteristics of patients with IMRD-associated PG (n = 24) as compared to the remaining patients with PG (n = 278). Patients with a dual diagnosis of PG and IMRD were significantly older at the onset of PG (62.2 [15.0] vs. 53.4 [20.9] years, respectively; p = 0.033) and had a higher prevalence of hypertension (OR: 2.71; 95% CI: 1.12–6.55; p = 0.022; Table S1). In survival analysis, patients with IMRD-associated PG experienced a comparable risk of all-cause mortality, both in univariate (HR: 1.92; 95% CI: 0.91–4.05; p = 0.087) and multivariate (adjusted HR, 1.72; 95% CI: 0.70–4.23; p = 0.240) analysis (Figure S1).

The current study illuminates an important topic that has not been sufficiently investigated in the past. Other strengths of the research include utilizing a large-scale study population and investigating five different outcomes. The study's population-based nature argues against considerable selection bias as both inpatients and outpatients were subject to inclusion. The primary limitation, however, is the restriction of IMRD definition to four diseases (RA, SLE, SSc and PsA) and not including all diagnoses that pertain to the category of IMRD (such as Sjogren syndrome, dermatomyositis and mixed connective tissue diseases). Additionally, the low number of patients diagnosed with both PG and IMRD embodies another potential limitation.

In conclusion, this novel population-based study reveals that a history of IMRD, particularly RA, SLE and SSc, confers a high probability of PG. This association is unidirectional since patients with PG have no elevated risk of subsequent IMRD. Patients with IMRD-associated PG are typified by older age, higher frequency of hypertension and comparable risk of all-cause mortality. The study underscores the importance of awareness for PG in patients with IMRD, particularly RA, as early detection and treatment can improve outcomes.

None.

ADC served as an advisor, investigator or speaker for Abbvie, BI, Dexcel Pharma, Janssen, Novartis, Perrigo, Pfizer and Rafa. None of the other authors have any conflicts of interest to declare.

The current study was approved by the Institutional Review Board (IRB) of Ben-Gurion University in accordance with the principles outlined in the Declaration of Helsinki.