FD and autoimmune diseases share complex inflammatory mechanisms that contribute to both tissue damage and clinical manifestations. The accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3) in lysosomes triggers an inflammatory cascade that progresses through three main phases. In the initial phase, the buildup of Gb3 affects tissues early, generating nonspecific and subclinical symptoms. In the clinical phase, chronic inflammation mediated by pathways such as NF-κB manifests as multisystemic damage, including endothelial dysfunction, oxidative stress, and progressive fibrosis. Finally, in the advanced phase, the accumulated damage leads to failure of key organs, such as the heart, kidneys, and nervous system.11–13At the molecular level, the onset of this dysregulated immune response is rooted in alterations to the innate immune response, triggering an inflammatory cascade mediated by toll-like receptors (TLRs), particularly TLR4, leading to increased production of inflammatory cytokines such as IFN-alpha and TNF-alpha. While the adaptive immune system is thought to play a less prominent role in FD-related inflammation, some hypotheses suggest that NK cells may contribute to antigen presentation to lymphocytes, acting as a bridge between innate and adaptive immunity in the autoimmune/autoinflammatory response in FD.13 A notable link identified in recent years is the complement system. Although its primary role is as an innate immune mechanism, the complement system also plays a fundamental role in adaptive immunity through processes such as opsonization, phagocytosis, and antigen presentation.13,14 We must consider that there is also an increase in autoantibodies in FD, stemming from the complex interaction between innate and adaptive immunity, with a component of autoreactivity driven by the exposure of autoantigens derived from acute and chronic tissue damage in FD, as well as the potential immunogenicity of Gb3 and Lyso-Gb3 accumulation.11–14 This chronic inflammatory process parallels autoimmune diseases, where immune dysregulation perpetuates inflammation, exacerbating tissue damage. Furthermore, inflammation in FD not only amplifies direct damage caused by Gb3 accumulation but also impairs the body's ability to resolve inflammatory processes, potentially worsening coexisting autoimmune conditions. Consequently, some authors, such as Rozenfeld et al., hypothesize that FD may be classified as an autoinflammatory disease.13,15

Several studies have explored the relationship between FD and autoimmune/autoinflammatory phenomena at both molecular and clinical levels. Fabry disease has been linked to systemic lupus erythematosus, IgA vasculitis, polyarteritis nodosa (PAN), systemic sclerosis, autoimmune thyroiditis, and classic rheumatologic conditions such as juvenile idiopathic arthritis and rheumatoid arthritis.16–23 In a case of PAN,18,19 a patient presented with acute intestinal ischemia, and histopathological analysis revealed intestinal vasculitis characterized by neutrophilic infiltrates, fibrinoid necrosis in medium-sized vessels (“pauci-immune”), and glycosphingolipid accumulation in most blood vessels. Positive staining for C3 and IgM was noted, suggesting immune complex involvement. Similarly, lesions consistent with cutaneous PAN have demonstrated C3 and IgM deposits in medium-sized vessels, with both cases exhibiting fibrolamellar structures typical of FD. These findings suggest that FD-induced vascular damage may expose endothelial antigens, promoting autoimmune responses and facilitating immune complex formation through mechanisms such as the immunogenicity of galactocerebroside or modifications of immunoglobulins by Gb3. Regarding systemic lupus erythematosus (SLE) and renal involvement,16 biopsies have shown mesangial proliferation, immunoglobulin and complement deposits, subendothelial and mesangial deposits on electron microscopy, and the characteristic cytoplasmic granules of FD. These overlapping features underscore a potential shared immunopathogenic pathway. Additionally, in IgA vasculitis associated with FD,17 six cases have been reported where aberrant glycosylation of IgA1 is hypothesized to predispose patients to both autoimmune and vasculitic processes with renal involvement, suggesting a broader role of glycosylation abnormalities in the disease's immunological context. Together, these findings highlight the intricate relationship between FD, autoimmune phenomena, and vasculitis.

ERT and oral chaperone therapy (such as migalastat) are currently used in FD to prevent the accumulation of metabolites and tissue damage. However, it is unclear whether ERT modulates the inflammatory response. Some studies report elevated levels of proinflammatory cytokines following ERT, while others describe a reduction, leading to a lack of consensus.13,24 There are no studies yet on chaperone therapies and their interaction with the immune system. It has been established that the efficacy of ERT is linked to the development of anti-drug antibodies (ADA). Patients lacking endogenous enzyme activity are at higher risk of developing ADA, which has also been associated with the use of agalsidase beta compared to agalsidase alpha (notably, our patient was on agalsidase beta). ADA levels are correlated with decreased ERT efficacy, exacerbating systemic tissue damage caused by FD and potentially further increasing this damage.13,14,24

This hypothesis is supported by findings showing that despite a significant reduction in Lyso-Gb3 levels with ERT, there is marked complement activation, as evidenced by elevated levels of C3a and C5a, particularly in patients with nonsense mutations who developed ADA. These findings suggest that complement activation, mediated by both classical and alternative pathways, persists independently of glucolipid reduction and may contribute to multiorgan damage. Additionally, elevated levels of proinflammatory cytokines such as IL-6 and TGF-β1 have been identified, which may drive renal inflammation and fibrosis, even under ERT. These findings open the possibility of utilizing therapies targeting other molecular pathways, such as complement inhibitors, in subgroups of patients with ADA and lack of treatment response due to ADA.13 It is important to differentiate this type of hypersensitivity reaction from type 1, which is associated with infusion-related reactions that can be extremely severe, potentially leading to anaphylactic shock.13,14,24

Attempting to establish a relationship between ERT and autoimmunity on the reviewed published cases linking FD to autoimmune disorders, we observed a wide variability in treatments and dosages, ranging from 0.2mg/kg of weekly ERT to the 1mg/kg administered to our patient. Alpha-galactosidase A activity also varied significantly, from undetectable levels (<10%) to as high as 76.1%, as reported by Shimazu et al.7 Consequently, we cannot propose any hypothesis regarding the relationship between treatment or dosage and the development of autoimmune complications, nor with alpha-galactosidase A activity. In fact, in a reported case of cutaneous PAN,19 a potential link between treatment and the development of PAN was suggested but later dismissed, as the complication arose despite the patient having discontinued treatment weeks prior. Any of the published articles have measured levels of ADA. In our case, these ADA were negative. This highlights that the relationship between FD and autoimmunity extends beyond the treatment itself or the development of ADA against ERT.

The association of FD and vasculitis is extremely rare, with only five cases of similar characteristics found in the literature, of which only one was associated with AAV. FD and AAVs (granulomatosis with polyangiitis – GPA, eosinophilic granulomatosis with polyangiitis – EGPA, and microscopic polyangiitis – MPA) can affect the kidneys, heart, central or peripheral nervous system, and lungs, with the most significant manifestations being renal involvement.5,6 Beyond the academic classification of AAVs, the genetic component and characterization of ANCA are crucial, as it has been documented that patients with anti-MPO and anti-PR3 have different genotypes that correlate better with the specificity of the ANCA antibody than with the histological classification of vasculitis itself. Another important aspect in this clinical scenario of coexisting FD and AAV is to discern whether the organ involvement, especially at the renal level, is compatible with one entity or another, posing a significant diagnostic and therapeutic challenge.6 The renal manifestations of AAV include necrotizing glomerulonephritis without glomerular immune deposits (also referred to as “pauci-immune”), crescents in more than 50% of glomeruli, and often a rapidly progressive course. In our patient's case, not only was the vasculitic component present at the renal level, but it also manifested at the pulmonary level with findings such as pulmonary nodules with the reverse halo sign and a tree-in-bud pattern affecting the small airways (Fig. 1).6–11 Delving into the pathophysiological aspects of the condition, it has been established that vasculitis can be preceded by multiple triggers, ranging from various infectious agents to their relationship with different drugs. All of this can determine the development of immunological mechanisms that initiate a systemic inflammation mediated by autoantibodies.6 The most significant immunological mechanisms involved are molecular mimicry, autoantigen complementarity, and epitope conformation, although, specifically, vasculitis with PR-3 specificity responds to humoral and cellular components. In the same vein, the role of extracellular traps from neutrophils (NETs) containing MPO (or PR-3) and DNA in a network of histones/chromatin is being investigated. While their primary function is beneficial for combating infections by providing a crucial innate immune mechanism, excessive NET release has been associated with numerous diseases through their effector action of neutrophil-mediated damage, allowing them to circulate, present antigens to the immune system, promote hypercoagulability, and activate the alternative pathway of complement.10 NETs are also being investigated as a pathogenic determinant in FD, playing an important role in the context of ischemic cerebrovascular involvement in these patients. The neutrophil participates in innate immunity processes and plays a fundamental role in the pathophysiology of AAV, specifically in GPA. The accumulation of glycosphingolipids may increase neutrophil survival, exacerbating its pathogenic power at the level of blood vessels and favoring the process of immune-mediated vascular damage. This has been evidenced in our patient with a sluggish renal evolution despite the establishment of appropriate treatment and the occurrence of deep vein thrombosis precipitated by an endovascular catheter, favored by a pro-coagulant inflammatory environment.5,10

In the last 20 years, a total of five cases5–11 of FD associated with rapidly progressive necrotizing glomerulonephritis have been published, although only one of them met the classification criteria for GPA with positive ANCA and PR-3 specificity. The case we present would be the second in which positivity for PR-3 ANCA with a significant titer is demonstrated, unlike the one published by Hanaoka et al.,8 in which the titer is not specified but was low. Regarding proteinuria levels, our patient presented higher values than those published, reaching almost nephrotic range. Although our case has a follow-up time of less than six months and there is a possibility of improvement in glomerular filtration afterwards, all cases were left with chronic kidney disease of varying degrees. Regarding the histopathological findings, in three of the four published cases, there was pauci-immune necrotizing involvement, similar to ours. Immunofluorescence did not yield results for any antibody; however, as in the cases by Singh et al.6 and Hanaoka et al.,8 there is positivity at the level of the arteriolar walls for C3.

Regarding therapeutic aspects, all cases utilized induction with steroids and cyclophosphamide, except for Shimazu et al.7 In our case, we opted to use, in addition to the aforementioned, rituximab and plasmapheresis with an optimal response both analytically (decrease of PR-3 titers to 13UI/ml, normalization of C-reactive protein, improvement of renal function and proteinuria) and clinically (defervescence, improvement of asthenia, absence of respiratory symptoms, and disappearance of skin lesions). A biopsy of the lung tissue was not performed due to the greater prognostic and therapeutic yield of obtaining a renal sample. None of the published cases resulted in death (including the present one).

Another aspect to highlight is the difficulty of making a differential diagnosis between FD and other systemic autoimmune diseases, as there may be patients mistakenly labeled as having small-vessel vasculitis when they actually have FD, and vice versa. Our case illustrates that both entities are not incompatible, emphasizing the possibility that AAVs may be underdiagnosed when their clinical presentation is interpreted as part of FD, especially in those with isolated, rapidly progressive renal involvement leading to dialysis, where the latter is held solely responsible for the deterioration of renal function.4,6–11