Improvement of Lymphangioleiomyomatosis Following Successful Tofacitinib Treatment for Refractory Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis Syndrome
Lymphangioleiomyomatosis (LAM) is a rare, multi-systemic disease that predominantly affects women and is characterized by cystic lung destruction, chylous fluid accumulation, and abdominal tumors. The disease leads to a decline in lung function at a rate two to four times faster than the typical age-related decline. Although the mammalian target of rapamycin (mTOR) inhibitor has shown some benefits for LAM patients, treatment options remain limited. Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a heterogeneous disease spectrum characterized by osteoarticular and dermatological manifestations. Conventional treatments for SAPHO syndrome, including non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs, bisphosphonates, and intra-articular steroids, often fail to control disease progression. Biological agents have recently shown promise in refractory cases. Janus kinase (JAK) inhibitors, which target the JAK-STAT signaling pathway, have demonstrated efficacy in treating autoimmune diseases. Tofacitinib, a selective JAK inhibitor, has shown good efficacy in treating refractory SAPHO syndrome.
This report presents a case of a 29-year-old female patient with SAPHO syndrome complicated by LAM. The patient experienced significant improvement in both arthralgia and pulmonary function following tofacitinib treatment. The patient initially presented with progressive polyarthralgia and elevated serum inflammatory parameters in May 2016, leading to a diagnosis of SAPHO syndrome. Enhanced computed tomography (CT) revealed diffusely distributed round, regular, thin-walled cysts in the lung and cystic lesions along the lymphatic vessels in the posterior mediastinum and retroperitoneal region. The vascular endothelial growth factor D (VEGF-D) level was elevated at 1776 pg/mL (reference range: <800 pg/mL). Based on the 2017 American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline, the patient was diagnosed with LAM.
Despite sequential administration of NSAIDs, glucocorticoids, and interleukin (IL)-6 inhibitors, there was no substantial improvement in symptoms, laboratory parameters, or imaging findings. Given the observed efficacy of tofacitinib in other rheumatologic disorders and a previous SAPHO case, tofacitinib was considered for this patient. Tofacitinib, which acts upstream of the mTOR pathway, was hypothesized to have potential therapeutic effects for LAM. The patient was started on tofacitinib at a dose of 5 mg orally twice daily. Three weeks later, the patient reported marked symptom improvement, and inflammatory markers decreased to nearly normal ranges. The disease activity index also declined. After 16 weeks of treatment, magnetic resonance imaging (MRI) showed significant improvement in bone marrow edema in the sacroiliac and sternoclavicular regions. Pulmonary function tests, which initially showed an obstructive defect, demonstrated improvement in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO) following tofacitinib administration. The patient tolerated the medication well with no adverse effects, and her VEGF-D level remained stable at 1931 pg/mL.
The JAK-STAT pathway plays a crucial role in intracellular signaling of type I and type II cytokines. By inhibiting JAK, tofacitinib blocks the action of pathological cytokines. As downstream mediators, JAK inhibitors have the potential to exert greater anti-inflammatory activity than biologics that target only one cytokine. Tofacitinib selectively suppresses JAK1 and JAK3, blocking signals of several essential cytokines involved in the transcription of genes responsible for inflammation and immune regulation. Previous studies have reported crosstalk between the JAK and phosphoinositide 3-kinase/protein kinase B/mTOR signaling pathways, suggesting potential therapeutic benefits of targeting molecules in this pathway.
In the initial stages of the clinical course, the patient lacked respiratory symptoms but exhibited typical radiological changes and elevated VEGF-D levels. To avoid invasive techniques, histopathological confirmation was not performed. However, serial monitoring and the later reduction in pulmonary function supported the diagnosis of LAM. One limitation of this case is that lung function indicators might overestimate the therapeutic effect of JAK inhibitors. Early in the disease, lung function might be underestimated due to restricted thoracic mobility caused by thoracic pain associated with SAPHO syndrome. Nonetheless, the improvement in DLCO and stabilization of chest CT findings supported the benefit of JAK inhibitors for LAM. Common adverse effects of JAK inhibitors include an increased risk of infection and myelosuppression. In this case, no obvious toxicity was reported during the 16 weeks of tofacitinib treatment, though long-term safety requires further investigation.
This case highlights the clinical utility of tofacitinib in preventing LAM progression and controlling osteoarticular and cutaneous manifestations of SAPHO syndrome. Future clinical trials on a larger scale are needed to elucidate the efficacy of JAK inhibitors for LAM and SAPHO syndrome. The patient provided consent for her clinical information and images to be reported in the journal, with efforts made to ensure anonymity.
doi.org/10.1097/CM9.0000000000000441
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