What is causing this patient's vulvar ulcerations?

CASE A 37-year-old G2P2002 woman presented to an obstetrics/gynecology (OB/GYN) clinic with a 7-day history of vulvar and mouth ulcers and a fever. History The patient's medical history included major depressive disorder, generalized anxiety disorder, and insomnia, for which she was taking sertraline, hydroxyzine, and trazodone, respectively. She also reported that she was in the process of being evaluated by rheumatology for possible rheumatoid arthritis but had not yet received a diagnosis. She reported a family history of rheumatoid arthritis and psoriasis in her mother. Her social history included a monogamous relationship with a partner with a penis. Five days prior to her presentation to the OB/GYN clinic, she was evaluated for these symptoms at an urgent care and also described a recurrent history of mouth ulcers three to four times per year. During that visit, she was tested for herpes simplex virus (HSV) 1 and 2 using nucleic acid amplification tests via polymerase chain reaction. Results of these tests, which used swabs from both the tongue and the vulva, were pending at the time of the OB/GYN clinic visit; however, she received a prescription for valacyclovir for a presumed genital herpes outbreak. Additionally, records from the urgent care confirmed that the patient tested negative for gonorrhea, chlamydia, trichomoniasis, bacterial vaginosis (BV), vaginal candidiasis, SARS-CoV-2, influenza A and B, and respiratory syncytial virus. The following day (4 days prior to her visit to the OB/GYN clinic), the patient returned to urgent care with worsening symptoms, including a fever of 102.0 °F, chills, fatigue, myalgia, headache, and dysuria. She was tested for HIV 1/2 and syphilis, which were ultimately negative. She was again preliminarily diagnosed with a primary HSV outbreak but directed to the ED due to her fever, worsening symptoms, and mild hypotension (BP of 98/55 mm Hg). At the ED, the on-call gynecology provider confirmed the patient's likely diagnosis of primary HSV, and she was discharged with lidocaine gel for her vulvar lesions and hydrocodone-acetaminophen for analgesia. Two days later (2 days prior to her visit to the OB/GYN clinic), the patient presented to the ED again, as she learned that her HSV results were negative, her pain was uncontrolled, and she had a persistent fever over 100.0 °F. At the ED, her C-reactive protein was found to be elevated at 95 mg/dL. The patient was again swabbed for HSV at the site of her vulvar ulcerations, and she was again tested for respiratory viruses; all tests were negative. She was given IV pain medications and was again discharged home with the diagnosis of primary HSV. At the time of her visit to the OB/GYN clinic, 5 days had elapsed since the patient's initial urgent care visit, and she had noted no improvement in any of her symptoms. Physical examination On examination, the patient was pale and ill-appearing. She was hypotensive with a BP of 80/54 mm Hg, which improved to 90/58 mm Hg after she drank juice and ate crackers. The patient was afebrile, having taken over-the-counter acetaminophen prior to arrival at the clinic. Examination of the oral cavity revealed one ulceration on the inferior left buccal mucosa. The genital examination revealed multiple ulcerations around the vaginal introitus that were exquisitely tender to palpation. The speculum and bimanual examinations revealed cervical motion tenderness, and copious brown, watery discharge. DIFFERENTIAL DIAGNOSIS HSV Behçet disease Syphilis Epstein-Barr virus Cytomegalovirus Pyelonephritis Pelvic inflammatory disease OUTCOME The patient was directed to the ED due to hemodynamic instability and worsening pain where she was admitted to the hospitalist service. Initially, treatment was initiated for possible pyelonephritis, as her urinalysis was largely positive for leukocyte esterase; however, the patient's urine culture showed no growth at 24 hours. There was also an initial concern for possible pelvic inflammatory disease due to the cervical motion tenderness that was elicited during the pelvic examination at the OB/GYN clinic, thus ceftriaxone 1 g/day IV infusion and doxycycline 100 mg orally twice a day were initiated. Because of the team's concern for early sepsis, multiple laboratory tests and cultures were performed. The patient's lactate was normal; her blood cultures were negative; and repeat testing for HSV, chlamydia, gonorrhea, and syphilis was also negative. She tested negative for Mycoplasma and Ureaplasma from a vaginal swab but tested positive for BV. An abdominal and pelvic CT scan was unremarkable. OB/GYN was consulted on day 1 of admission due to the vulvar ulcerations. Given the patient's constellation of signs, they were concerned for nonmenstrual toxic shock syndrome, and ceftriaxone and doxycycline were discontinued, and vancomycin, clindamycin, and cefepime IV infusions were initiated. On hospital day 2, an infectious diseases specialist was consulted who expressed concern for possible Behçet disease and, despite multiple negative tests, added IV acyclovir 5 mg/kg every 8 hours to cover for possible HSV as a precaution. Because various viruses and bacteria can present, albeit rarely, with vulvar ulcerations, OB/GYN recommended testing for group A strep (GAS), cytomegalovirus (CMV), and Epstein-Barr virus (EBV).1 Testing for GAS and CMV was negative. Testing for EBV showed prior infection and convalescence with no current infection. After a 5-day hospitalization, the patient was prescribed a 7-day course of oral cefuroxime 250 mg twice daily for possible urinary tract infection and metronidazole 500 mg twice daily for BV, and was discharged home without a definitive diagnosis for her vulvar ulcerations. She was directed to follow up with rheumatology after discharge. As the patient was already established with rheumatology, she followed up with them within weeks of her discharge from the hospital. Rheumatology agreed with the diagnosis of Behçet disease that was suggested by infectious diseases and prescribed colchicine 0.6 mg/day to decrease the patient's risk for future exacerbations. Subsequently, the patient developed papulopustular lesions on her face within the following 2 months. She was evaluated by a dermatologist who confirmed the diagnosis via a pathergy test that yielded a positive result (Figure 1). Given that Behçet disease is a vasculitis, the patient was further evaluated for internal vasculitic lesions with computed tomography angiography (CTA) of her head, neck, abdomen, and pelvis. All CTA results were unremarkable. She continues to be followed by rheumatology and dermatology.FIGURE 1.: Pathergy test placement on right forearmDISCUSSION Behçet disease is a rare, systemic vasculitis of unknown etiology.2 It may present with recurrent mucous membrane ulcerations, uveitis, papulopustular dermatoses, arthritis, myalgia, thrombophlebitis, and/or aneurysm formation. Almost all patients who experience this disorder have a history of recurrent oral ulcers.3 Several possible genetic and environmental factors have been posited as contributing to the development of the disorder, but no clear etiology has been established.1 For example, the development of Behçet disease is strongly correlated with the presence of the HLA-B51 gene.1 Disease development may also be connected to high colonization rates by certain bacteria, such as Streptococcus sanguinis, in the oral microbiome.4 Prevalence is highest in Central Asia and the Mediterranean region, with approximately equal distribution among the sexes.5 At least 17 different diagnostic or classification criteria for Behçet disease have been proposed, each with varying levels of sensitivity and specificity.6 Consensus diagnostic criteria have not yet been established; however, two different international classification criteria are commonly used to identify patients for clinical trials: namely, the International Study Group (ISG) criteria and the revised 2014 International Criteria for Behçet Disease (ICBD) criteria.6 The ISG criteria were released in 1990. To meet these criteria, patients must exhibit recurrent oral ulceration at least three times in one 12-month period plus exhibit at least two minor symptoms (recurrent genital ulceration, eye lesions, skin lesions, and/or positive pathergy test).7 The revised 2014 ICBD criteria, on the other hand, assign a score of 1 or 2 to the following criteria: ocular lesions, oral aphthosis, genital aphthosis, skin lesions, neurologic manifestations, vascular manifestations, and positive pathergy test. A score of 4 or more signifies a positive screen for Behçet disease.8 The patient described in this case met both ISG and ICBD criteria for Behçet disease. Of note, the ISG criteria show lower sensitivity than the ICBD (90.0% vs 97.6%) but higher specificity (98.8% vs 90.8%); however, no consensus exists on the best diagnostic or classification criteria.9 As such, Behçet disease is typically a diagnosis of exclusion based on clinical signs and symptoms.3 As demonstrated in this case, the nonspecific skin pathergy reaction test is often used to aid in diagnosing Behçet disease. It is reasonably specific for Behçet disease but has an increasingly low sensitivity, where positive results are often attributed to other conditions such as Crohn disease and Sweet syndrome.10 To perform the test, several needles are inserted into the patient's forearm to create trauma to the skin. The test is interpreted at 24 to 48 hours and is considered positive if an erythematous papule greater than or equal to 2 mm or a pustule forms at the needle insertion site.10 Given its unknown etiology and relapsing and remitting course, Behçet disease treatment focuses on symptom management. The European Alliance of Associations for Rheumatology (EULAR) periodically publishes recommendations for Behçet disease management, most recently in 2018.11 Given the potential for permanent organ damage in patients with ocular, vascular, neurologic, and gastrointestinal involvement, this population is treated more aggressively when compared to patients who only experience dermatologic or joint involvement.11 Topical corticosteroids and colchicine are recommended for managing dermatologic involvement, whereas disease-modifying antirheumatic drugs, biologics, and immunosuppressants are generally reserved for other manifestations such as ocular or vascular.11 EULAR also reminds clinicians that prompt treatment, prevention of recurrence, and treatment individualized to each patient's specific manifestations should be the cornerstones of management.11 CONCLUSION Although Behçet disease is rare, clinicians should maintain a broad differential, considering the entire clinical picture when approaching a patient with mucous membrane ulcerations that are not responding to typical treatment. A prompt diagnosis and initiation of anti-inflammatory agents in this case may have alleviated the patient's pain more quickly and prevented multiple outpatient visits, a lengthy hospitalization, and a risk of sepsis.