Metronidazole For Vulval Crohn’s Disease Treatment
Overview
Cutaneous vulval Crohn’s disease (VCD), an often overlooked extra-intestinal manifestation of Crohn’s disease (CD), poses diagnostic and therapeutic challenges due to its potential for significant edema, painful fissures, and lasting disfigurement of the vulval anatomy. The lack of consensus on optimal management adds to the complexity of addressing VCD. This systematic review explores the efficacy of metronidazole in treating VCD among women and children.
The study, registered under PROSPERO CRD420212-85033, systematically reviewed 49 records (comprising 40 case reports and 9 case series) meeting inclusion criteria. These records encompassed 57 patients aged 5–61 years. Common presenting features of VCD included edema, erythema, ulcers/fissures, and induration/thickening. Approximately 58% of patients also had concurrent gastrointestinal CD. Vulval biopsies were conducted in 83% of cases. Metronidazole was administered at daily doses ranging from 250 to 1500 mg, with treatment durations spanning 8 days to 18 months. Clinical improvement, observed in 70% of cases, indicated the potential efficacy of metronidazole in managing VCD. However, relapse occurred in 19% of cases, and 30% showed no response or worsening. Adverse side effects were noted in two persons.
The review concludes that metronidazole shows promise as a therapeutic option for VCD, either as a primary treatment or adjunctive therapy. Nonetheless, the current evidence remains insufficient to draw definitive conclusions. The authors recommend further research, emphasizing randomized controlled trials, to enhance understanding and establish more robust treatment guidelines for VCD.
Introduction
Crohn’s disease (CD), a chronic inflammatory disorder primarily affecting the gastrointestinal tract, presents extra-intestinal cutaneous manifestations in about 10% of cases. Among these, cutaneous vulval Crohn’s disease (VCD), a less common subtype termed “metastatic” CD, exhibits non-contiguous involvement with the gastrointestinal tract. The pathogenesis of VCD remains unclear, with proposed causes including immune complex deposition and type IV hypersensitivity reactions.
VCD’s characteristic features encompass “knife cut” ulcers, lesions, and edema affecting various vulval regions, making diagnosis challenging due to similarities with other conditions like hidradenitis suppurativa (HS). Diagnosis typically relies on clinicopathological correlation, with non-caseating, giant cell granulomas on histology providing strong support.
Treatment of VCD is intricate, involving corticosteroids, antibiotics, immunomodulators, biologics, and surgical interventions. Given the limited literature on VCD, therapeutic guidelines are lacking, and treatments are often adapted from those used for gastrointestinal CD. Metronidazole has been reported as a potentially beneficial treatment due to its cost-effectiveness and overall safety profile, although peripheral neuropathy may arise with prolonged or intensive use.
This systematic review aims to assess the evidence supporting metronidazole’s efficacy as a treatment for VCD in patients with a clinical or histological diagnosis. The review encompasses less than 200 reported cases of VCD, emphasizing the need for a comprehensive understanding of treatment options for this challenging manifestation of CD.
Method
This systematic review, registered with PROSPERO under the number CRD42021285033, adhered to PRISMA guidelines. The search, conducted in August 2022 on PubMed, MEDLINE, and Embase from inception, utilized keywords related to the vulva, Crohn’s disease, and metronidazole. Grey literature sources and non-English articles were excluded. Two authors independently extracted data, resolving discrepancies through discussion with two additional authors. The extracted information encompassed publication details, study type, conflicts of interest, and participant numbers. Variables such as patient age, symptoms, diagnosis method, gastrointestinal involvement, disease duration, treatments, follow-up duration, metronidazole regimen, patient response, relapse, and adverse events were recorded. Methodological quality, assessed using the Joanna Briggs Institute checklist, categorized case series and case reports as low-quality evidence. Studies meeting <50% of checklist criteria were graded as ‘very low’ quality.
Inclusion Criteria
The inclusion criteria for this comprehensive review encompassed all types of studies. To be considered, studies needed a well-defined study population consisting of adult and pediatric females diagnosed with cutaneous vulval Crohn’s disease (VCD), either clinically or histologically. Additionally, the studies were required to provide documented information regarding the utilization of metronidazole as a treatment and the subsequent outcomes related to this intervention. This rigorous inclusion framework aimed to ensure the reliability and relevance of the evidence reviewed, facilitating a comprehensive analysis of the efficacy and outcomes associated with metronidazole in the context of VCD.
Exclusion Criteria
Studies involving males, particularly those where data specific to females couldn’t be extracted separately, were excluded from consideration. Additionally, research focusing on fistulating Crohn’s disease (CD) was excluded from the review. The exclusion criteria also encompassed studies lacking original research data and articles not in the English language. These criteria were implemented to refine the scope of the review, ensuring a targeted analysis of relevant and gender-specific evidence related to cutaneous vulval Crohn’s disease and its treatment with metronidazole.
Result
The initial search yielded 650 records, of which 49 met inclusion criteria, including 40 case reports and 9 case series, involving 57 patients treated with metronidazole for Vulval Crohn Disease (VCD). Due to the absence of randomized controlled trials, a meta-analysis was not feasible, and results are presented descriptively.
Most commonly reported VCD features included swelling/oedema and redness/erythema. Patient ages ranged from 5 to 61 years, with a mean of 25 and a median of 23 years. Vulval biopsies were conducted in 47 out of 57 cases. Metronidazole, administered orally (n = 30) or topically (n = 4), showed daily doses from 250 to 1500 mg, with treatment durations ranging from 8 days to 18 months.
Metronidazole was often coupled with concomitant treatments, such as oral and topical steroids, immunomodulators, anti-TNF treatments, and anti-inflammatory medications. Positive responses, indicating clinical improvement, were observed in 70% of cases, with 13 describing ‘complete’ healing. Adverse events were infrequently reported, with two cases of peripheral neuropathy and elevated liver enzymes noted.
Follow-up duration and disease relapse varied widely, with reported durations ranging from 2 weeks to 10 years. Relapse occurred in 28% of cases, often following the reduction or cessation of medication. Methodological quality assessment categorized 45% of studies as ‘Low’ and 55% as ‘Very low’ using the Joanna Briggs Institute checklist for case series and case reports.
Conclusion
This systematic review assesses the treatment of Vulval Crohn Disease (VCD) with metronidazole, emphasizing the impact of vulval diseases on patients’ emotional well-being. The overreliance on histopathological data, specifically non-caseating granulomas, may lead to underreporting of VCD, especially as these granulomas are absent in a significant portion of gastrointestinal CD cases. The review suggests exercising vigilance for VCD in patients with gastrointestinal CD and vice versa.
Diagnosis of VCD can be challenging, as it may clinically resemble Hidradenitis suppurativa. The authors propose a diagnostic flow diagram to aid in identifying VCD, considering various factors. The primary goal in treating inflammatory disorders like VCD is remission induction and maintenance. Metronidazole, with unclear mechanisms of action but believed to possess anti-inflammatory and anti-infectious properties, showed symptom alleviation, even at doses as low as 250 mg daily.
While metronidazole’s efficacy alone remains unclear due to patients often receiving it as part of combination therapy, potential side effects, such as peripheral neuropathy, should be considered. Adverse events were infrequently reported in the reviewed studies. Peripheral neuropathy resulting from metronidazole has been documented, and rigorous reporting of adverse events is crucial for future dermatology studies.
The limitation of this review lies in the scarcity of high-level evidence, consisting mainly of case reports and series. Therefore, while positive responses to metronidazole treatment suggest its potential usefulness in managing VCD, more rigorous studies, ideally randomized controlled trials, are needed for a conclusive evaluation of VCD treatment methodologies. The authors emphasize the necessity for better safety reporting and advocate for a multidisciplinary approach in managing VCD to optimize outcomes.
Oncology Related Tools
Other
Latest Research
