Update on Etiopathogenesis and Disease Associations
Towards a Closer Understanding of Granuloma Annulare (GA) Pathogenesis
Elucidating the pathogenesis of GA has been challenging and our understanding has evolved over the years. Recently, two published studies have advanced our understanding of GA pathogenesis by further uncovering its molecular basis and cytokine signature. Min et al. reported the upregulation of both T-helper (Th) 1 and Th2 pathways in GA lesions compared with healthy skin (of note, previously only the Th1 pathway was implicated in GA pathogenesis). Increased messenger RNA (mRNA) expression of cytokines corresponding to both T-cell axes were also noted: tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, and IL-12/23p4 (corresponding to Th1 pathway activation) and IL-4 and IL-31 (corresponding to Th2 pathway activation). The upregulation of IL-4 mRNA expression was particularly pronounced, with a 15,600-fold increase in GA lesional skin versus control skin. Furthermore, Th17 and Th22 axes and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway were also upregulated.
A 2021 study by Wang et al. also found activation of the Th1 and JAK-STAT pathways in GA. In particular, the investigators described the elevation of mRNA of key molecular mediators involved in the JAK-STAT pathway, such as IFN-γ, oncostatin M, and, to a lesser extent, IL-15 and IL-21. Interestingly, Wang et al. described upregulation of 'M1' macrophage polarization as well as 'M2' macrophage polarization. While contradictory, such a finding may be reconciled by ascribing a biphasic mechanism to GA pathogenesis. First, collagen degradation, mediated by a 'M1' macrophage response, is followed by tissue remodeling and mucin deposition mediated by a 'M2' macrophage response.
Neither the study by Min et al. nor Wang et al. identified targeting of CD8+ T cells to be of therapeutic potential. While Wang et al. did report an increased abundance of CD8+ T cells, the expansion of CD4+ T cells was more pronounced, a finding consistent with previous studies by Modlin et al..[37,38]
An important inconsistency between the work by Min et al. and Wang et al. is that Wang et al. did not find upregulation of the Th2 pathway that was reported by Min et al. However, plasma levels of IL-4 were elevated in two of the five patients studied by Wang et al. While larger studies evaluating the molecular markers of GA are needed to clarify this discrepancy, the current studies by Min et al. and Wang et al. pave the way for targeted therapies blocking the Th1 and JAK-STAT pathways.
New Evidence on GA Disease Associations
GA and Chronic Comorbidities. GA has been reported to be associated with a host of comorbidities. The link between diabetes mellitus (DM) and GA has been the most discussed and most debated, with smaller cohort studies reporting conflicting findings. A 2021 retrospective cohort study of 51,169 patients with GA is the largest and most rigorous study to date that investigates the link of GA with DM. The study investigators report that 21.1% of patients with GA had DM, while only 13.3% of matched controls had DM. The same study also found GA to be significantly associated with hyperlipidemia, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). The study suggests that DM and hyperlipidemia may instigate GA through a common pathway of T-cell dysregulation. Additionally, the association between GA and autoimmune disorders (RA and SLE) lends support to the idea that autoimmunity may be a driver of GA.
A recent nested case-control study of 177 GA patients (matched to 708 controls) in the All of Us database also found that GA was significantly associated with autoimmune disease, DM, and hyperlipidemia. The study also found hypothyroidism and ischemic heart disease to be significantly associated with GA.
GA and Malignancy
Notably, however, the study of 51,169 GA patients did not find a significant link between hematologic malignant neoplasms and GA. Another study of 5137 GA patients failed to establish a link between GA and solid organ cancers. A 2019 case-control study from Spain of 60 patients matched to 300 controls also did not find an association between GA and malignancy.
Nonetheless, the above studies are subject to a number of limitations. Both the 51,169 patient and 5137 patient studies include patients with all subtypes of GA; additionally, the studies include patients of all ages. It is possible then that an association between malignancy and generalized GA in older patients is hidden by cases of localized GA that may not be associated with malignancy. Additionally, the studies do not exclude drug-induced cases of GA, further occulting a possible association between frank GA and malignancy.
The 2019 Spanish study, although limited to cases of generalized GA, neither stratifies patients by age nor excludes cases of iatrogenic GA. Considering that malignancies are less frequent occurrences to begin with (compared with DM and hyperlipidemia), the lack of a stringent inclusion and exclusion criteria in studies investigating an association between GA and malignancy leaves this putative link to be still subject to dispute. A study limited to older (i.e. >60 years) patients with frank generalized GA may provide more rigorous results to settle this debate.
GA and Infectious Triggers. Unfortunately, there is a paucity of large-scale studies that investigate the role of infectious agents in triggering GA, although previously both viral and bacterial triggers have been suggested. A 2018 study of 73 biopsies of skin lesions from GA patients discovered Borrelia DNA to be present in 9.6% of biopsies and Chlamydiales DNA to be present in 72.6% of biopsies. However, eight of the patients positive for Chlamydiales DNA were treated with doxycycline for 9 months, but none responded, and only 28.6% of patients positive for Borrelia DNA responded to appropriate antibiotic therapy. Thus, the study authors assert that Borrelia and Chlamydiales do not unilaterally induce GA; rather, they suggest that Borrelia and Chlamydiales are triggers, which, together with other factors, set-up GA pathogenesis.
GA in the setting of viral infections has also been noted, with Epstein–Barr virus, human immunodeficiency virus, and varicella zoster virus (VZV)[45,46] being recently reported. Two cases of GA triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have also been described.[47,48]
In January 2021, Shah et al. reviewed granulomatous cutaneous drug eruptions and identified a number of iatrogenic causes of GA: allopurinol, amlodipine, anti-TNFα agents (infliximab, adalimumab, etanercept, and thalidomide), botulinum toxin, dabrafenib, desensitization injections, immune checkpoint inhibitors, intranasal calcitonin, gold, immunizations (hepatitis B and anti-tetanus vaccination), levetiracetam, paroxetine, pegylated IFNα, secukinumab, tocilizumab, topiramate, and vemurafenib. More recently, acetazolamide, apremilast, ixekizumab, mesotherapy, phototherapy, and measles, mumps, and rubella (MMR), pneumococcal, and VZV immunizations have also been implicated in instigating GA. The pathogenesis of drug-induced GA is not easily understood, and the induction of GA by anti-TNFα agents and apremilast in particular is paradoxical, as both TNFα inhibitors and apremilast have also been reported as effective therapies for GA. Instigation of GA by IL-17 inhibitors (ixekizumab and secukinumab) is also intriguing, as Min et al. reported hyperactivation of the Th17 axis in GA. We attempt to explain these paradoxical observations in Sect. 8 of the manuscript. We summarize the recent updates on GA epidemiology and etiopathogenesis in Table 2.
Am J Clin Dermatol. 2022;23(1):37-50. © 2022 Adis Springer International Publishing AG