Kaposi's sarcoma (KS) is a rare lympho-angioproliferative disorder associated with human herpesvirus 8, also known as KS-associated herpesvirus (KSHV).¹ The epidemiological classification describes five presentations of KS, namely: AIDS-associated KS, classic KS in older European men, endemic KS in younger men and children in sub-Saharan Africa, nonepidemic KS in men who have sex with men (MSM) with no identifiable immunodeficiency and iatrogenic KS.¹

Apart from well-described iatrogenic KS occurring among organ transplant recipients, an increasing incidence of KS has been observed in patients on long-term immunosuppression for other diseases.^{1, 2}

We report here a case of KS in a patient who had received ruxolitinib, a Janus kinase (JAK) inhibitor, for myelofibrosis (MF). We then conducted a literature review for ruxolitinib-induced KS, and second, reviewed spontaneous reports recorded in the French national pharmacovigilance database (FPVD) up to April 14, 2021. To identify articles reporting KS in patients receiving ruxolitinib, we searched the PubMed database using the equation “ruxolitinib” AND “Sarcoma, Kaposi” [MeSH].

A 71-year-old heterosexual Caucasian man, born in Italy, was hospitalized in April 2020 for deterioration of his general status. He had a history of MF that reported 7 years of biannual surveillance from diagnosis in 2009 to 2016, when the occurrence of splenomegaly justified introduction of ruxolitinib 10 mg twice a day, leading to improvement of splenomegaly over the subsequent year. In 2018, the dose of ruxolitinib was increased to 15 mg twice a day due to recurrence of splenomegaly.

Physical examination at admission revealed multiple purple papular cutaneous lesions on the left leg and no oral lesions. Thoracic computed tomography scan did not show KS lesions. KSHV serology was positive, with a KSHV viral load of 2799 copies/mL (3.45 log/mL). The KSHV-strain subtype was Subtype C, C3 variant. The skin biopsy confirmed the KS diagnosis. Lymphocyte and CD4 cell counts were 100/μL and 32/μL, respectively. HIV, Hepatitis B, and Hepatitis C serologies were negative. The ruxolitinib dose was reduced to 5 mg twice daily, but the KS lesions worsened on the skin and began to appear on the patient's palate. In August 2020, the KSHV viral load rose to 12 131 copies/mL (4.08 log/mL), while the CD4 cell count decreased to 21/μL. Ruxolitinib was stopped and doxorubicin chemotherapy was initiated. Unfortunately, the patient's condition continued to deteriorate due to the extent of KS, and the patient died 2 weeks after ruxolitinib discontinuation.

In addition to the case presented here, three other cases have been described in the literature since 2017 and one patient was reported in the FPVD in 2018.^2-4 The main characteristics of the five patients are presented in Table 1. All were male, with a median age of 71 years (range, 56–81 years). Four of them had MF and one had essential thrombocytopenia. The KS diagnosis was based on pathology exams of skin biopsies in all patients. In one patient, non-HIV endemic KS was diagnosed 1 month before ruxolitinib initiation and followed by rapid aggravation. In the other patients, the median time from ruxolitinib initiation to KS diagnosis was 2.2 years (range, 9 months to 7 years). Three patients had a cutaneous presentation of KS, whereas two had a muco-cutaneous form at diagnosis. The CD4 cell count was only known for two patients, one at 412/μL at diagnosis and the other at 32/μL. Therapeutic management of KS led to initial ruxolitinib dose reduction before discontinuation in one case, with no improvement of KS progression, and discontinuation for all patients. The time from KS diagnosis to ruxolitinib discontinuation was available for four out of five patients (median 2.2 months; range, 2 weeks to 18 months). The two patients who had early ruxolitinib discontinuation after KS diagnosis (2 and 6 weeks) had favorable outcomes, with disappearance of the KS lesions; one with almost total regression of the lesions 10 months after ruxolitinib discontinuation and the other with complete remission 4 months after discontinuation, associated with surgical resection and intralesional vincristine.^{3, 4} KS-related death was observed in two patients; in one case, at 1 month after ruxolitinib discontinuation, and in the other, at 5 months after discontinuation, despite specific treatment with radiotherapy and paclitaxel. One patient died 4 months after ruxolitinib discontinuation due to cytopenia and kidney damage; no improvement in the KS lesions was observed in that patient.² No ruxolitinib discontinuation syndrome was reported in any patient.

Ruxolitinib is a potent and selective JAK1 and 2 inhibitor indicated for the treatment of myeloproliferative neoplasms such as MF.² The JAK signal transducer and activator of transcription (JAK–STAT) pathway have a central role in intracellular signaling of cytokines by regulating cell proliferation. It is critical to blood formation and immune response.² JAK2 is associated with hematopoiesis and its activation leads to myeloproliferative syndromes, while JAK1 plays a role in proinflammatory cytokines and type I interferon production.⁵ Ruxolitinib is predominantly selective for JAK2, whereas other JAK inhibitors used in inflammatory diseases (e.g. filgotinib, tofacitinib, baricitinib, and upadacitinib) are preferentially selective for JAK1.⁵

To the best of our knowledge, this is the first review of iatrogenic KS in patients treated with ruxolitinib. Several other opportunistic infections, such as HBV reactivation, EBV-associated lymphoproliferative disorders, VZV meningo-encephalitis, CMV retinitis, multifocal progressive leukoencephalopathy, pneumocystis, and tuberculosis have previously been reported.^2-4

Salivary and sexual transmissions are the major modes of KSHV transmission.¹ However, KSHV could also be transmitted through transplantation of infected organs and blood transfusion, although systematic leucocyte-depletion of red blood cell units reduces the risk of transmission.¹ KSHV establishes a lifelong latency in B-lymphocytes and endothelial cells.¹ The occurrence of KS during ruxolitinib treatment may be due to reactivation of latent KSHV or through acquisition. Apart from one patient with a diagnosis of non-HIV endemic KS established before ruxolitinib introduction, KSHV serology status was unknown before ruxolitinib onset in the other patients. However, all patients were from regions with an intermediate to high frequency of KSHV carriers, such as Italy, North Africa, and the Okinawa region of Japan.^{1, 2}

Among HIV patients, although KSHV diseases can occur at any CD4 cell count, the risk increases when CD4 cell count decreases.¹ Treatment with ruxolitinib may also cause absolute reduced CD4 and/or CD8 cell counts.⁵ In this series of cases, only two patients had CD4 assessment at KS diagnosis; one had a very low CD4 cell count (32/μL), and the other had a CD4 cell count at 412/μL.³ The median time from ruxolitinib initiation to KS diagnosis was 2.2 years (range 9 months to 7 years). The impairment of natural killer (NK) cell function by ruxolitinib could also explain the increasing risk of viral infections.⁴ Indeed, CMV retinitis and progressive multifocal leukoencephalopathy have been described in patients treated with ruxolitinib, despite normal CD4 cell count.⁴ Furthermore, substantial alterations in the NK cell receptor repertoire in healthy KSHV carriers, and impaired NK-cell lytic capacity in patients with active KS have been reported.⁴ In addition, KSHV deploys several mechanisms to inhibit interferon synthesis, which could explain the efficacy of interferon-alpha in the treatment of AIDS-associated KS.¹

Reduction or withdrawal of immunosuppressants is the first-line therapy in iatrogenic KS.¹ Despite reducing the ruxolitinib dose, KS lesions progressed rapidly in one patient. Early interruption of ruxolitinib after KS diagnosis (at 2 and 6 weeks) enabled remission in two patients. In contrast, KS worsened in the other patients who had a longer time between KS diagnosis and ruxolitinib withdrawal.

KS has not been described in patients treated JAK inhibitors that are preferentially selective for JAK-1, suggesting the major role of JAK2 inhibition in KS occurrence. This is consistent with in vitro studies showing that JAK2/STAT3 pathway inhibition enhances KSHV replication through reductions in pro-inflammatory cytokines IL-6 and TNF.⁶

Because ruxolitinib is a recent treatment that is increasingly being used for its efficiency in myeloproliferative disorders, detecting and preventing potentially harmful infectious side effects of this drug is essential. KSHV serology screening for all patients initiating ruxolitinib treatment could help to identify patients at risk of KS. In patients with positive KSHV serology, close follow-up should be performed with regular cutaneous examination, CD4 cell count, and KSHV viral load assessment. In patients with negative KSHV serology, follow-up of KSHV serology could be useful, particularly in patients with iterative blood transfusions, those living in regions with intermediate/high prevalence of KSHV, and those at higher risk of acquisition. Early interruption of ruxolitinib after KS diagnosis may facilitate spontaneous disease regression.

卡波西肉瘤 (KS) 是一种罕见的淋巴血管增生性疾病，与人类疱疹病毒 8 相关，也称为 KS 相关疱疹病毒 (KSHV)。¹流行病学分类描述了 KS 的五种表现，即：艾滋病相关 KS、欧洲老年男性的典型 KS、撒哈拉以南非洲年轻男性和儿童的地方性 KS、男男性行为者 (MSM) 的非流行性 KS没有可识别的免疫缺陷和医源性KS。¹

除了在器官移植受者中发生的医源性 KS 外，在因其他疾病长期免疫抑制的患者中观察到 KS 的发病率不断增加。^{1, 2}

我们在此报告一例 KS 病例，该患者因骨髓纤维化 (MF) 接受了一种 Janus 激酶 (JAK) 抑制剂鲁索替尼 (ruxolitinib)。然后，我们对鲁索替尼诱导的 KS 进行了文献综述，其次，回顾了截至 2021 年 4 月 14 日在法国国家药物警戒数据库 (FPVD) 中记录的自发报告。为了确定报告接受鲁索替尼患者 KS 的文章，我们搜索了 PubMed 数据库使用等式“鲁索替尼”和“卡波西肉瘤”[MeSH]。

一名出生于意大利的 71 岁异性恋高加索男子因身体状况恶化于 2020 年 4 月住院。他有 MF 病史，报告从 2009 年到 2016 年诊断为 7 年两年一次的监测，当时脾肿大的发生证明每天两次 10 mg 鲁索替尼的引入，导致随后一年脾肿大得到改善。2018年，由于脾肿大复发，鲁索替尼的剂量增加到每天两次，每次15毫克。

入院时体格检查发现左腿多处紫色丘疹性皮损，口腔无皮损。胸部计算机断层扫描未显示 KS 病变。KSHV 血清学呈阳性，KSHV 病毒载量为 2799 拷贝/mL (3.45 log/mL)。KSHV 毒株亚型为 C 亚型，C3 变体。皮肤活检证实了 KS 诊断。淋巴细胞和 CD4 细胞计数分别为 100/μL 和 32/μL。HIV、乙型肝炎和丙型肝炎血清学均为阴性。鲁索替尼剂量减至每天两次，每次 5 mg，但 KS 病变在皮肤上恶化并开始出现在患者的上颚。2020 年 8 月，KSHV 病毒载量上升至 12 131 拷贝/mL（4.08 log/mL），而 CD4 细胞计数下降至 21/μL。停用鲁索替尼并开始多柔比星化疗。不幸的是，病人'

除了这里介绍的病例外，自 2017 年以来，文献中还描述了另外 3 例病例，2018 年 FPVD 报告了 1 例患者。^2-4五名患者的主要特征见表 1。均为男性，中位年龄为 71 岁（范围 56-81 岁）。其中 4 人患有 MF，1 人患有原发性血小板减少症。KS 诊断基于所有患者的皮肤活检病理检查。在一名患者中，非 HIV 地方性 KS 在 ruxolitinib 开始前 1 个月被诊断出来，随后迅速恶化。在其他患者中，从开始使用鲁索替尼到诊断 KS 的中位时间为 2.2 年（范围为 9 个月至 7 年）。3 名患者有 KS 皮肤表现，而 2 名患者在诊断时有粘膜皮肤表现。只有两名患者的 CD4 细胞计数已知，一名诊断时为 412/μL，另一名为 32/μL。KS 的治疗管理导致在 1 例中停药前减少初始鲁索替尼剂量，KS 进展没有改善，所有患者均停药。从 KS 诊断到停用鲁索替尼的时间可用于五分之四的患者（中位 2.2 个月；范围为 2 周至 18 个月）。KS 诊断后（2 周和 6 周）早期停用鲁索替尼的 2 例患者预后良好，KS 病灶消失；一种在鲁索替尼停药后 10 个月病灶几乎完全消退，另一种在停药后 4 个月完全缓解，与手术切除和病灶内长春新碱有关。KS 诊断后（2 周和 6 周）早期停用鲁索替尼的 2 例患者预后良好，KS 病灶消失；一种在鲁索替尼停药后 10 个月病灶几乎完全消退，另一种在停药后 4 个月完全缓解，与手术切除和病灶内长春新碱有关。KS 诊断后（2 周和 6 周）早期停用鲁索替尼的 2 例患者预后良好，KS 病灶消失；一种在鲁索替尼停药后 10 个月病灶几乎完全消退，另一种在停药后 4 个月完全缓解，与手术切除和病灶内长春新碱有关。^3、2名患者观察到4例KS相关死亡；在一种情况下，在鲁索替尼停药后 1 个月，在另一种情况下，在停药后 5 个月，尽管接受了放疗和紫杉醇的特殊治疗。一名患者在鲁索替尼停药后 4 个月因血细胞减少和肾损伤而死亡；在该患者中未观察到 KS 病变的改善。²没有任何患者报告鲁索替尼停药综合征。

Ruxolitinib 是一种有效的选择性 JAK1 和 2 抑制剂，适用于治疗骨髓增生性肿瘤，如 MF。² JAK 信号转导和转录激活因子 (JAK-STAT) 通路通过调节细胞增殖在细胞因子的细胞内信号传导中发挥核心作用。它对血液形成和免疫反应至关重要。² JAK2 与造血相关，其激活导致骨髓增生综合征，而 JAK1 在促炎细胞因子和 I 型干扰素产生中起作用。⁵ Ruxolitinib 主要对 JAK2 具有选择性，而用于炎症性疾病的其他 JAK 抑制剂（例如丝氨酸替尼、托法替尼、巴瑞替尼和 upadacitinib）优先对 JAK1 具有选择性。⁵

据我们所知，这是对接受鲁索替尼治疗的患者的医源性 KS 的首次回顾。其他几种机会性感染，如 HBV 再激活、EBV 相关淋巴组织增生性疾病、VZV 脑膜脑炎、CMV 视网膜炎、多灶性进行性白质脑病、肺孢子菌病和结核病之前已有报道。^2-4

唾液和性传播是 KSHV 传播的主要方式。¹然而，KSHV 也可以通过受感染器官的移植和输血传播，尽管红细胞单位的系统性白细胞消耗降低了传播的风险。¹ KSHV 在 B 淋巴细胞和内皮细胞中建立了终生潜伏期。¹鲁索替尼治疗期间KS的发生可能是由于潜在KSHV的重新激活或通过获得。除了在引入鲁索替尼之前诊断为非 HIV 地方性 KS 的患者外，其他患者在使用鲁索替尼之前 KSHV 血清学状态未知。然而，所有患者均来自KSHV携带者的中高频率地区，如意大利、北非和日本冲绳地区。^{1, 2}

在 HIV 患者中，尽管任何 CD4 细胞计数都可能发生 KSHV 疾病，但当 CD4 细胞计数减少时风险会增加。¹使用鲁索替尼治疗也可能导致 CD4 和/或 CD8 细胞计数绝对减少。⁵在这一系列病例中，只有两名患者在 KS 诊断时进行了 CD4 评估；一个的 CD4 细胞计数非常低 (32/μL)，另一个的 CD4 细胞计数为 412/μL。³从开始使用鲁索替尼到诊断 KS 的中位时间为 2.2 年（范围为 9 个月至 7 年）。鲁索替尼对自然杀伤 (NK) 细胞功能的损害也可以解释病毒感染风险的增加。⁴事实上，尽管 CD4 细胞计数正常，但在接受鲁索替尼治疗的患者中已经描述了 CMV 视网膜炎和进行性多灶性白质脑病。⁴此外，据报道，健康 KSHV 携带者中 NK 细胞受体库的显着改变，以及活动性 KS 患者的 NK 细胞溶解能力受损。⁴此外，KSHV 采用多种机制来抑制干扰素合成，这可以解释干扰素-α 在治疗 AIDS 相关 KS 中的功效。¹

减少或停用免疫抑制剂是医源性 KS 的一线治疗。¹尽管减少了鲁索替尼的剂量，一名患者的 KS 病变进展迅速。KS 诊断后（第 2 周和第 6 周）早期中断鲁索替尼可使两名患者得到缓解。相比之下，在 KS 诊断和鲁索替尼停药之间有较长时间的其他患者中，KS 恶化。

在接受 JAK-1 优先选择性的 JAK 抑制剂治疗的患者中尚未描述 KS，这表明 JAK2 抑制在 KS 发生中的主要作用。这与体外研究一致，表明 JAK2/STAT3 通路抑制通过减少促炎细胞因子 IL-6 和 TNF 来增强 KSHV 复制。⁶

由于鲁索替尼是一种最近的治疗方法，由于其在骨髓增殖性疾病中的有效性而越来越多地被使用，因此检测和预防这种药物的潜在有害感染性副作用至关重要。对所有开始鲁索替尼治疗的患者进行 KSHV 血清学筛查有助于识别有 KS 风险的患者。对于 KSHV 血清学阳性的患者，应进行密切随访，定期进行皮肤检查、CD4 细胞计数和 KSHV 病毒载量评估。在 KSHV 血清学阴性的患者中，KSHV 血清学随访可能是有用的，特别是对于反复输血的患者、居住在 KSHV 中/高患病率地区的患者以及获得较高风险的患者。KS 诊断后早期中断鲁索替尼可能有助于自发疾病消退。