Disseminated cryptococcosis presenting with generalized cutaneous involvement in a rheumatoid arthritis patient receiving tofacitinib: A case report

Dear Editor, A 64-year-old woman with a 10-year history of rheumatoid arthritis, who was on maintenance immunosuppressive treatment with corticosteroids, developed progressive erythematous swelling of the left upper arm and left thigh for 1 month with irregular fever for 3 days. The patient had been on oral tofacitinib for treatment for 2 months. Chest computed tomography (CT) revealed scattered with inflammation in both lungs. We were unable to perform bronchoscopy with bronchoalveolar lavage due to the patient's shortness of breath, and lung tissue or secretions could not be obtained for further culture. The inflammatory markers (white blood cell count, percentage of neutrophils, and C-reactive protein) were also elevated. Galactomannan, β-D-glucan tests and cerebrospinal fluid examinations were negative. Cryptococcus was identified in the culture of her skin secretion and tissue. Susceptibility testing showed sensitivity to voriconazole, itraconazole, and amphotericin with minimum inhibitory concentrations (MICs) of 0.06, 0.06, and 0.5 μg/mL, respectively. Some cells in the immunopathological sections of the skin contained gray-blue spherical sporoid structures (Figure 1a,b). Periodic acid–Schiff -positive yeast-like cells were manifested in the subcutaneous tissue, also suggesting a Cryptococcus spp. infection (Figure 1c). Fungal spores were observed in the silver hexamine staining of skin biopsy tissue (Figure 1d). At the species level, C. neoformans var. grubbii was identified by Sanger sequencing and metagenomic next-generation sequencing (mNGS). Considering the patient's denial of a history of trauma or exposure to pigeon excrement, based on previous literature and the fact that lung inflammation worsened after multiple antibiotic treatments, the lung may have been the main source of Cryptococcus. The final diagnosis was disseminated cryptococcosis, after which the patient was treated with itraconazole (40 mg/day), fluconazole (20 mg/day), and voriconazole (40 mg/day). Eventually, the skin lesions of cryptococcal infection were basically cured. After discharge, the patient underwent chest CT again at the local hospital, which showed improvement of the chest inflammation. In comparison to asymptomatic pulmonary cryptococcosis, secondary cutaneous cryptococcosis can be the first clinical manifestation of disseminated infection, but it is difficult to diagnose clinically.1 Cryptococcus, Mucor and Aspergillus are opportunistic fungi that should be considered in patients with cellulitis-like skin lesions who take immunosuppressive agents. Tofacitinib, a Janus Kinases inhibitor, was the first to be approved for the treatment of rheumatoid arthritis, which selectively inhibits JAK1 and JAK3. There are some clinical cases of disseminated cryptococcal disease with the application of JAK inhibitors. Chen et al. showed that, Janus kinase-signal transducer and activator of transcription (JAK–STAT) activated in human monocytes is the active pathway in response to Cryptococcus neoformans infection.2 Some small molecule JAK inhibitors target the essential pathways of antifungal innate immunity, including JAK–STAT signaling.3 Traditional fungal identification methods have limited sensitivity, and pathogens are difficult to identify at the species level.4 mNGS can be utilized as an auxiliary method for the diagnosis of pulmonary cryptococcosis and can directly distinguish C. gattii from C. neoformans in clinical specimens without the need for culture.5 However, the sensitivity of mNGS still remains to be determined. The authors thank the patient for allowing us to report this case. The authors have no conflict of interest to declare. This retrospective study was approved by the ethics committee of the First Affiliated Hospital of Soochow University. The need for informed consent was waived by the Clinical Research Ethics Committee.