JAKi: Can it be used to treat SAPHO syndrome?

Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare autoinflammatory disease characterized by skin and skeletal manifestations with a recurrent-relapsing pattern.1 Skeletal involvement in SAPHO syndrome presents as aseptic osteomyelitis, while skin involvement is marked by local infiltration of neutrophils. During disease flares, inflammatory markers which mediate inflammation in SAPHO are elevated. As an important intracellular transduction mediator, Janus kinase (JAK) can transmit signals and transport them to the nucleus to activate gene transcription. Blocking the downstream intracellular JAKs can block the upstream action of a range of cytokines. It has been shown that interleukin (IL)-1 mediates sterile bone inflammation.2 Th17 cells are present in the peripheral blood of SAPHO patients. IL-17 can promote osteogenesis.3 Study observed marked upregulation of IL-8 and tumor necrosis factor (TNF)-α production in the SAPHO patients, which might relate to causing polymorphonuclear neutrophil (PMN) priming.4 IL-23 stimulates amplification and maintenance of Th17 cells.5 Besides, the single-nucleotide polymorphisms of IL-23R are closely correlated with the occurrence of SAPHO syndrome.6 The anti-inflammatory effect of JAK inhibitors (JAKi) was demonstrated by blocking a variety of cytokines, such as IL-1, IL-8, IL-17, IL-23, and TNF-α.7 Therefore, JAKi might demonstrate greater anti-inflammatory activity than biologics that block only one kind of cytokine. As a novel class of drugs, JAKi have shown promising results in the treatment of various inflammatory arthropathies and skin diseases such as ankylosing spondylitis (AS), rheumatoid arthritis (RA),8 and psoriatic arthritis (PsA).9 Research on JAKi for treating SAPHO syndrome is currently mainly based on case reports, and more information needs to be gathered to validate their efficacy. Tofacitinib, baricitinib, and upadacitinib are all JAKi that are available for use in China and have been used in the treatment of SAPHO syndrome patients in clinical practice. These medications have shown promising results in managing the symptoms of SAPHO syndrome. This editorial aims to summarize the relevant content in this piece, which provides a potential treatment for SAPHO syndrome. To date, we have reported multiple cases of SAPHO syndrome patients treated with JAKi. In 2018, we first reported a case of refractory SAPHO syndrome with coexisting RA treated with tofacitinib and methotrexate, which not only relieved joint and anterior chest wall pain but also remitted pustules and lowered inflammatory markers to near-normal levels. For example, erythrocyte sedimentation rate (ESR), hypersensitivity C-reactive protein (CRP), and TNF-α were 45 mm/h, 22.3mg/L, and 66.0 pg/mL before, with decreased to 10 mm/h, 0.36 mg/L, and 8.8 pg/mL after treatment. Magnetic resonance imaging (MRI) showed improvement in synovial thickening and joint effusion.10 In 2020, our study found significant improvement in bone marrow inflammation with tofacitinib in a study involving 12 female patients. After 3 months, most patients showed improvement in bone marrow edema on MRI, with six showing moderate and three showing mild responses. Besides, there are seven of the eight patients with skin lesions alleviated.11 In the same year, we discovered that tofacitinib was not only effective in improving joint symptoms but also highly effective in treating pustulosis and nail changes.12 Similarly, in a report by Li et al., a woman who had shown no response to conventional treatment (including NSAIDs, DMARDs, TG, and BPs) experienced rapid improvement in her joint pain upon adding tofacitinib, subsequently leading to relief of skin and vertebral lesions.13 Successful cases of baricitinib treating SAPHO syndrome have also been reported, demonstrating its ability to improve hip joint involvement, relieve back pain and limping, and alleviate bone marrow edema. Recently, our team treated five patients with SAPHO syndrome who had no response to NSAIDs, TNFi, BPs, or other DMARDs. After 12 weeks of monotherapy with baricitinib, all patients showed varying degrees of improvement in clinical scores and laboratory indicators, with no reported adverse reactions during follow-up.14 It was also found that baricitinib treatment resulted in remission of osteomyelitis visible on MRI. Upadacitinib has recently been introduced for use in China. We first report the successful use of the upadacitinib for the treatment of SAPHO syndrome indicated the good short-term clinical efficacy.15 After 3 months of upadacitinib treatment, bone marrow edema and skin damage in patients with SAPHO syndrome were both effectively relieved. These cases demonstrate the potential of JAKi in alleviating skeletal and cutaneous symptoms of SAPHO syndrome. JAKi can also be effective in treating comorbidities caused by other factors while treating SAPHO syndrome. Tofacitinib not only treats SAPHO syndrome but also provides dual benefits for patients with coexisting lymphangioleiomyomatosis (LAM). A report in 2019 showed a case of a patient with both SAPHO syndrome and LAM, where tofacitinib improved symptoms and stabilized lung function. After treatment with tofacitinib, inflammatory markers decreased to near-normal levels, and MRI showed significant improvement in bone marrow edema.16 There are also reports indicating that tofacitinib can improve skin symptoms in patients with AS coexisting with SAPHO syndrome and prevent worsening of thoracolumbar pain after discontinuation of adalimumab.17 We also have a case report of a patient with coexisting SAPHO syndrome and Takayasu arteritis (TAK), where tofacitinib improved vascular thickness.18 Recently, a case of a patient who developed recurrent-relapsing polychondritis (RP) 10 years after being diagnosed with SAPHO syndrome has been reported. The patient experienced relief of auricular chondritis with successful treatment with tofacitinib.19 We are surprised to find that tofacitinib successfully treated SAPHO with Henoch–Schönlein purpura (HSP). The result shows that the ulcer was healed without further joint inflammation and new skin lesions.20 Furthermore, we found that SAPHO syndrome patients with ongoing bone marrow inflammation after mandibular surgery experienced symptom relief within 3 months of tofacitinib treatment, with no significant relapses during follow-up.21 Tofacitinib also rapidly improved IL-17 inhibitor-induced cutaneous reactions.3 Relevant summaries are listed in Table 1. Currently, we have achieved good results using three types of JAKi for treating SAPHO syndrome. Moreover, JAKi have also shown efficacy in SAPHO syndrome with coexisting LAM, TAK, HSP, and RP. This also provides a new research direction for the treatment of other rare diseases. However, there is currently a lack of research on optimal management of tapering or discontinuation of JAKi. Most patients experience relapses during dose reduction, and there are cases of JAKi resistance and treatment failure. The safety of JAKi in treating SAPHO patients also requires confirmation through large-scale clinical studies. We look forward to further research to confirm the efficacy of JAKi in treating SAPHO syndrome. In conclusion, JAKi have demonstrated good efficacy in treating SAPHO syndrome, and current research suggests that tofacitinib, baricitinib, and upadacitinib all hold the potential for treating SAPHO syndrome. Following large-scale clinical trials, JAKi may become a reliable treatment option for SAPHO syndrome. QY organized and wrote articles, MM and SL assisted in collecting data and polishing articles, YW and CL supervised the manuscripts. Not applicable. The authors declare no conflicts of interest. The data that support the findings will be available in PubMed at https://pubmed.ncbi.nlm.nih.gov/ following an embargo from the date of publication to allow for commercialization of research findings.