Exploring the hidden epidemic of infections in pemphigus vulgaris and foliaceus, examining why patients are vulnerable, common pathogens, and emerging research on the gut-skin axis.
Imagine living with painful blisters that cover your skin and mucous membranes, making every movement and meal a challenge. Now, imagine facing this while your body becomes increasingly vulnerable to severe and unusual infections. This is the reality for many patients with pemphigus, a group of rare autoimmune blistering diseases where the body's immune system mistakenly attacks healthy skin and mucosal cells.
While pemphigus itself presents with visible blisters and erosions, a less visible but equally dangerous threat lurks: opportunistic and nosocomial infections. These infections represent a critical frontier in understanding and managing this complex condition, as they often determine patient outcomes more than the disease itself.
The very treatments that control the autoimmune attack—powerful immunosuppressive medications—can simultaneously dismantle the body's defenses against pathogens, creating a precarious balancing act for clinicians and patients alike.
This article explores the hidden epidemic of infections in pemphigus vulgaris and foliaceus, examining why these patients are so vulnerable, which pathogens commonly threaten them, and how emerging research on the gut-skin axis might revolutionize our approach to their care.
Pemphigus patients face a multifaceted assault on their immune defenses from disease process, treatments, and associated complications.
Widespread blistering physically compromises the body's first line of defense, creating easy entry points for pathogens.
Pemphigus patients face a multifaceted assault on their immune defenses, creating what clinicians describe as a "perfect storm" for infections. This vulnerability stems from three primary sources: the disease process itself, its treatments, and associated complications.
The autoimmune process in pemphigus causes widespread blistering and erosions on the skin and mucous membranes, physically compromising the body's first line of defense against pathogens. These open wounds serve as easy entry points for bacteria, viruses, and fungi, allowing them to invade deeper tissues and potentially reach the bloodstream 4 . This breach in barrier function is particularly dangerous in pemphigus vulgaris, which almost always involves oral mucosal lesions that can extend throughout the gastrointestinal tract .
The second major factor is iatrogenic—resulting from medical treatment. Corticosteroids and other immunosuppressive agents (such as azathioprine, mycophenolate mofetil, and rituximab) form the cornerstone of pemphigus treatment by designingly suppressing the overactive immune system 9 . However, this same mechanism simultaneously weakens the body's ability to fight infections. A revealing study found that patients typically develop opportunistic infections while taking a mean dose of 0.8 mg/kg/day of prednisone, often in combination with other immunosuppressants 5 .
Research has identified several specific factors that significantly increase infection risk:
Disease Severity: Patients with moderate to severe pemphigus have significantly higher infection rates compared to those with mild disease 4 . The more extensive the blistering, the larger the compromised barrier area.
Multiple Hospital Admissions: Patients with repeated hospitalizations have dramatically higher infection rates (45.1%) compared to first-admission patients (18.27%) 4 . This reflects both disease severity and increased exposure to nosocomial pathogens.
Diabetes Mellitus: Diabetic pemphigus patients have double the infection rate (50%) compared to non-diabetics (24.82%) 4 , as diabetes further impairs immune function and wound healing.
Advanced Age: Older patients face increased susceptibility to opportunistic infections, likely due to age-related immune decline 5 .
Treatment Combinations: Certain drug combinations, particularly corticosteroids with azathioprine or mycophenolate mofetil, create profound immunosuppression 4 .
The statistics surrounding infections in pemphigus patients are sobering. A comprehensive retrospective study of 155 hospitalized pemphigus vulgaris patients revealed that 94 cases of infection were recorded among these patients—meaning many experienced multiple infections 4 . Even more striking, when including common minor infections like oral candidiasis and herpes simplex, approximately 60.65% of all patients developed some form of infection during their hospitalization 4 .
The infection profile in pemphigus patients encompasses both common and opportunistic pathogens, as illustrated in the following breakdown of infection types and their frequencies:
| Infection Type | Number of Patients | Percentage of Patients |
|---|---|---|
| Oral Candidiasis | 37 | 23.87% |
| Herpes Simplex | 15 | 9.68% |
| Bacterial Skin Infections | 16 | 10.32% |
| Urinary Tract Infections | 13 | 8.39% |
| Pulmonary Infections | 13 | 8.39% |
The microbiological profile of these infections reveals important patterns for clinical management. Staphylococcus aureus dominates skin infections, accounting for 93.7% of cultured cases, while Escherichia coli is the predominant urinary pathogen (53.8% of cases) 4 . These findings emphasize the importance of barrier disruption in pemphigus-related infections.
Perhaps more concerning is the antibiotic resistance pattern observed in these pathogens. Among Staphylococcus aureus isolates, significant resistance has been documented to penicillin (60%), cefazolin (40%), and cephalexin (26.7%) 4 . This resistance profile complicates treatment decisions and underscores the need for culture-guided antibiotic therapy.
Beyond common pathogens, pemphigus patients face threats from unusual opportunistic organisms that rarely affect immunocompetent individuals. A prospective cohort study found that the risk of developing such infections in the first year after pemphigus diagnosis is 9.3%, dropping to nearly zero thereafter 5 . This timeline corresponds with the most intensive immunosuppressive treatment phase.
The opportunistic pathogens observed in pemphigus include Nocardia, cytomegalovirus, Legionella, and Listeria 5 . These infections are particularly concerning as they may present with atypical symptoms in immunocompromised patients, delaying diagnosis. The consequences can be devastating—in the same study, two patients died within two months of opportunistic infection diagnosis, and two others suffered permanent neurologic impairment 5 .
| Pathogen | Clinical Significance | Mortality/Morbidity |
|---|---|---|
| Nocardia | Causes pulmonary and systemic infections | High morbidity, requires prolonged treatment |
| Cytomegalovirus | Can affect multiple organ systems | Particularly dangerous in severely immunocompromised |
| Legionella | Causes severe pneumonia | High mortality if not promptly treated |
| Listeria | Causes meningitis and bacteremia | Associated with neurologic sequelae |
A 2024 study revealed significant differences in gut microbiome composition between pemphigus patients and healthy controls, supporting the novel gut-skin axis concept.
Recent scientific investigations have revealed a fascinating connection between the gut microbiome and pemphigus activity—a relationship known as the gut-skin axis. In a groundbreaking 2024 study, researchers set out to determine whether alterations in gut microbiome composition might contribute to pemphigus pathogenesis 2 .
The research team employed sophisticated molecular techniques to compare the gut microbiomes of three distinct groups: patients with active pemphigus (AP), patients in pemphigus remission (PR), and healthy control subjects (HCs). The study enrolled 20 AP patients, 11 PR patients, and 47 HCs, collecting fecal samples from all participants for analysis 2 .
Fresh fecal samples were collected using standardized kits and immediately frozen at -80°C to preserve microbial DNA 2 .
Bacterial DNA was extracted using the PowerSoil DNA Isolation Kit, followed by sequencing of the 16S rRNA gene's V3 and V4 regions using the Illumina MiSeq PE300 platform 2 .
The resulting sequences were processed using advanced computational tools including VSEARCH and USEARCH to identify Amplicon Sequence Variants (ASVs)—the most precise unit for measuring microbial diversity 2 .
Researchers analyzed the relationship between specific bacterial taxa and clinical parameters, including autoantibody levels 2 .
The results revealed significant differences in gut microbiome composition among the three groups. At the family level, the abundance of Prevotellaceae and Coriobacteriaceae positively correlated with pathogenic autoantibodies 2 . At the genus level, several bacteria showed significant relationships with disease activity: Klebsiella, Akkermansia, Bifidobacterium, Collinsella, Gemmiger, and Prevotella all positively correlated with pathogenic autoantibodies, while Veillonella and Clostridium_XlVa showed negative correlations 2 .
The functional implications of these compositional differences were equally important. The BugBase analysis revealed that the sum of potentially pathogenic bacteria was elevated in the active pemphigus group compared to the remission group 2 . This suggests that disease activity correlates not just with specific pathogens, but with an overall shift toward a more pathogenic gut microbiome profile.
These findings support the novel concept that gut dysbiosis—an imbalance in the microbial ecosystem—may contribute to pemphigus pathogenesis through immune system modulation. The correlation between specific bacterial taxa and autoantibody levels provides compelling evidence for the gut-skin axis in pemphigus, potentially opening new avenues for adjuvant therapies targeting the microbiome 2 7 .
| Research Tool | Function | Application in Pemphigus Research |
|---|---|---|
| PowerSoil DNA Isolation Kit | Extracts microbial DNA from complex samples | Isolates bacterial DNA from fecal samples for sequencing 2 |
| 16S rRNA Gene Sequencing | Identifies and classifies bacterial species | Profiles gut microbiome composition in patients vs. controls 2 |
| Illumina MiSeq PE300 Platform | High-throughput DNA sequencing | Generates massive sequence data for microbiome analysis 2 |
| RDP Training Set (Version 16) | Reference database for bacterial classification | Assigns taxonomic identities to sequenced bacterial DNA 2 |
| EasyAmplicon Pipeline | Streamlines amplicon data analysis | Processes and normalizes sequencing data for statistical analysis 2 |
Given the high incidence and serious consequences of infections in pemphigus patients, a proactive preventive approach is essential. Key strategies include:
The introduction of biologic therapies has begun to transform pemphigus treatment, potentially offering more targeted immunosuppression with different infection risk profiles. Rituximab, a monoclonal antibody targeting CD20 on B cells, has emerged as a first-line treatment for moderate to severe pemphigus vulgaris 1 9 .
While rituximab effectively controls disease activity, it still carries significant infection risks. A systematic review of pemphigus foliaceus patients treated with rituximab reported an infection rate of 19.7% 9 . Interestingly, intravenous immunoglobulin (IVIg) demonstrated excellent efficacy with no reported infections in the same review, suggesting it may be a valuable option for infection-prone patients 9 .
The timing of infections follows a predictable pattern, with the highest risk occurring during the first year after diagnosis when immunosuppression is most intense 5 . This knowledge allows clinicians to focus preventive efforts when they are most needed.
The highest infection risk occurs during the first year after diagnosis when immunosuppression is most intense, allowing clinicians to focus preventive efforts when they are most needed.
The management of pemphigus has evolved significantly from focusing solely on controlling autoimmune activity to embracing a more holistic approach that prioritizes infection prevention and management. The sobering reality is that infections—not the primary autoimmune process—now represent the leading cause of mortality in pemphigus, accounting for many of the deaths in this patient population 8 .
Future research directions are increasingly focused on personalized treatment approaches that balance autoimmune control with infection risk. The exploration of the gut-skin axis offers promising avenues for novel therapies that might modulate the immune system through microbiome manipulation rather than broad immunosuppression 2 7 . Additionally, the development of more targeted biologic therapies continues to advance, with several late-stage pipeline drugs showing promise 1 .
For patients living with pemphigus, these advances offer hope for better outcomes with fewer infectious complications. As one research team concluded, "The differences in GM composition among the three groups, and the correlation between certain bacterial taxa and pathogenic autoantibodies of pemphigus, support a linkage between the GM and pemphigus" 2 . This growing understanding of the complex interplay between immunity, microbiome, and infection may ultimately lead to safer, more effective strategies for managing this challenging autoimmune disorder.
The battle against infections in pemphigus represents a critical aspect of comprehensive care—one that requires continued research, clinical vigilance, and a multidisciplinary approach to protect patients from these hidden threats while effectively managing their underlying autoimmune disease.