PD-1阻断剂所致皮肤不良反应分析及文献回顾

抗程序细胞死亡蛋白1及配体阻断剂为代表的免疫治疗在肿瘤治疗中取得了突破性的进展,皮肤不良反应是最常见的免疫相关不良反应(irAEs)。本文报道临床中诊治的一组免疫相关不良反应,共4例,分别为湿疹、多形红斑、TEN、嗜酸细胞增多性皮炎,并回顾分析在Pubmed数据库检索2015年至今发表的PD-1/PD-L1免疫治疗导致皮肤不良反应的病例报道,包括患者年龄、性别、致皮肤irAEs的药物、皮肤irAEs类型等。以期提高对肿瘤免疫治疗过程中皮肤不良反应的关注,及时救治危及生命的皮肤不良反应,帮助改善肿瘤患者生存质量和预后。     

Sarcoid-like granulomatous periocular dermatitis treated with tetracycline

Two cases of periocular micropapular dermatitis with sarcoid-like granulomatous histology are reported. After 8-12 weeks treatment with tetracycline the cutaneous eruptions of both patients cleared. The condition is equivalent to perioral dermatitis.     

PD-1/PD-L1抑制剂的皮肤不良反应

程序性细胞死亡受体-1（programmed cell death-1, PD-1）/程序性细胞死亡受体-配体1（programmed cell death-ligand 1, PD-L1）抑制剂治疗恶性肿瘤效果显著，但可引起斑丘疹样皮疹、瘙痒症和白癜风等皮肤不良反应,。本文对PD-1/PD-L1抑制剂的皮肤不良反应表现进行综述。     

淋巴瘤伴发皮肤肉芽肿的现象及其意义

淋巴瘤可伴发皮肤肉芽肿,其模式主要有两种:一种是淋巴瘤的特异性皮损中出现肉芽肿反应,例如肉芽肿性蕈样肉芽肿和肉芽肿性皮肤松弛症;另一种是淋巴瘤出现非特异的肉芽肿性皮损,主要见于一些系统性淋巴瘤.其组织病理学类型可为结节病样、环状肉芽肿样、结核样等.其机制及其与预后的关系尚不明确.肉芽肿形成可能是造成某些淋巴瘤特殊临床表现的原因,也容易掩盖淋巴瘤的真实面目,在临床和组织学诊断上需谨慎.     

免疫检测点抑制剂皮肤相关不良反应

免疫检测点抑制剂(immune-checkpoint inhibitors, ICIs)是近10年癌症治疗领域最重要的进展,包括抗细胞毒性T淋巴细胞抗原4(CTL A-4)、抗程序性细胞死亡1(PD-1)和抗程序性细胞死亡1配体1(PD-L1)抗体。ICIs的使用也导致了一系列新的免疫相关不良反应,其中皮肤相关不良反应较为常见。本文综述了ICIs皮肤相关不良反应及其管理。     

The spectrum of cutaneous granulomatous vasculitis: histopathologic report of eight cases with clinical correlation

Cutaneous granulomatous vasculitis is an uncommon histopathologic finding that has been associated with lymphoproliferative disorders, systemic vasculitis, autoimmune inflammatory diseases, and infection. To define further the concept of cutaneous granulomatous vasculitis and to emphasize its clinical importance, we reviewed biopsy material from 8 patients seen from 1985 through 1992. All biopsies showed evidence of blood vessel damage with fibrinoid change or hemorrhage (or both) and granulomatous inflammation in and around vessel walls. Special stains for microorganisms were negative in all cases. Associated medical disorders included neuropathy (2 patients), sarcoid-like disease (2), systemic vasculitis (1), lymphoma and suspected lymphoma (1 each), and associated herpes simplex virus (1). T-cell gene-rearrangement studies were negative in a patient with suspected lymphoma. Granulomatous cutaneous vasculitis is most commonly associated with lymphoma and systemic vasculitis. In selected cases, infection should be considered as an underlying cause.     

英夫利西单抗治疗重度斑块状银屑病的疗效和安全性及其对PD-1、PD-L1表达的影响

目的:探讨英夫利西单抗治疗重度斑块状银屑病的疗效和安全性及其对银屑病皮损组织中程序性死亡蛋白1（PD-1）及程序性死亡蛋白配体1（PD-L1）表达的影响。方法:2019年2-4月收集就诊于上海市皮肤病医院的17例重度斑块状银屑病患者,在第0、2、6、14、22、30、38、46周给予5 mg/kg英夫利西单抗静脉滴注治...     

Interstitial granulomatous dermatitis and granulomatous arteritis in the setting of PD-1 inhibitor therapy for metastatic melanoma

Checkpoint inhibition has become an important target in the management of malignant melanoma. As anti-CTLA4 inhibitors and anti-PD1 antibodies are increasingly utilized, reports of immune-related adverse events (IRAEs) are becoming more frequent. Common noted cutaneous IRAEs are morbilliform, lichenoid, bullous, granulomatous, psoriasiform, and eczematous eruptions. We report a case of interstitial granulomatous dermatitis and granulomatous arteritis in the setting of nivolumab (anti-PD1) monotherapy for metastatic melanoma. There are many different causes for granulomatous vasculitis, such as herpes virus infection, lymphoproliferative disorders, systemic vasculitis, and inflammatory bowel disease. This report adds to the growing literature on granulomatous IRAEs due to checkpoint inhibition.     

Pityriasis lichenoides in a girl with the granulomatous form of common variable immunodeficiency

Pityriasis lichenoides (PL) is a cutaneous disease of unknown origin. In our 8-year-old female patient with the granulomatous form of common variable immunodeficiency (CVID), PL occurred together with massive splenomegaly and intra-abdominal lymphadenopathy. Prednisone was efficient for treatment of her splenomegaly and autoimmune cytopenias. However, PL was resistant to both topical and systemic steroid treatment. Healing of PL was achieved with the use of a super-potent topical steroid, clobetasol propionate. A defect of T-cell function in CVID may contribute to development of PL. In the granulomatous form of CVID, sarcoid-like granulomas are the most commonly reported cutaneous lesions. PL has not been previously reported.     

Rechallenge of programmed cell death 1 inhibitor after an interval with dacarbazine treatment may be effective for advanced malignant melanoma

Immune checkpoint inhibitors (ICI) have been administrated as a standard medication in many cases of malignant melanoma (MM). They may be effective even for MM in advanced stages. However, it is still challenging to reduce the burden of MM, which were or became refractory to ICI, especially those without BRAF gene mutation. Re-administration of ICI after other modalities of treatment may be an option of treatment, but the efficacy and safety of retreatment with ICI have not been well established. We experienced four patients with advanced MM retreated with programmed cell death 1 (PD-1) inhibitor. All cases were refractory to the first PD-1 inhibitor, nivolumab, and then treated with dacarbazine (DTIC), followed by pembrolizumab. Two of the four cases achieved a partial response by switching to pembrolizumab as the second PD-1 inhibitor, and the other two cases resulted in progressive disease. In all cases, no new severe adverse events developed upon PD-1 inhibitor retreatment. Even if the first PD-1 inhibitor proves to be ineffective, it is worth re-administrating PD-1 inhibitor following a bridging therapy with DTIC.     

Interstitial granulomatous lesions as part of the spectrum of presenting cutaneous signs in pediatric sarcoidosis

Abstract:  Skin findings in childhood sarcoidosis vary greatly, but only a few occurrences have been published in which the histopathology has been characterized well. We describe a child with sarcoidosis in whom the cutaneous findings were atypical, resembling granuloma annulare. Histologic examination of these cutaneous lesions, however, revealed areas of sarcoid-like epithelioid cell granulomas, a palisading granulomatous process with features of granuloma annulare, as well as palisading neutrophilic and granulomatous dermatitis and interstitial granulomatous dermatitis. This underscores the variability of skin findings in childhood sarcoidosis—even within the same patient—and suggests that sarcoidosis should be considered in the differential diagnosis of children initially diagnosed with granulomatous skin lesions, such as granuloma annulare, palisading neutrophilic, and granulomatous dermatitis or interstitial granulomatous dermatitis, who demonstrate associated signs of systemic disease.     

免疫检查点抑制剂的皮肤并发症及治疗进展

免疫检查点抑制剂包括细胞毒性T淋巴细胞抗原4抑制剂,如易普利姆玛以及程序性死亡受体1/程序性死亡受体-配体1抑制剂nivolumab、派姆单抗和atezolizumab.随着免疫检查点抑制剂在肿瘤治疗领域应用的逐渐增加,免疫疗法相关不良反应已引起重视,其中最常见是皮肤并发症,主要包括以斑丘疹为代表的皮疹以及瘙痒症等疾病.临床上,对不同皮肤并发症早期诊断和制定正确的治疗方案十分重要,对常出现的以斑丘疹为代表的皮疹、瘙痒症等皮肤并发症应根据皮损的严重程度和临床分级进行监控和管理.     

Granulomas in common variable immunodeficiency: a diagnostic dilemma

A 60-year-old man with common variable immunodeficiency presented with a 7-year history of violaceous plaques and papules on the thighs, arms and trunk. In the preceding 2 years he had developed new lesions on both hands. He had been previously diagnosed with sarcoidosis on the basis of skin and visceral histology, but subsequent opinion was that these were sarcoid-like granulomas rather than being representative of true sarcoidosis. Biopsy of the hand lesions showed necrotizing granulomas, and a single acid-fast bacillus (AFB) was identified on Wade-Fite stain. Subsequent repeat tissue biopsies for histology, culture and polymerase chain reaction testing failed to confirm the presence of mycobacterial organisms and it was felt that the organism was a contaminant introduced during tissue processing. The hand lesions responded well to intralesional injections of triamcinolone acetonide 10 mg/mL and oral tetracycline 500 mg b.d. was later introduced with a good clinical response. The diagnostic dilemma of finding granulomatous inflammation in a patient with common variable immunodeficiency, and the significance of a single AFB on histology are discussed. The treatment of sarcoid-like granulomas with tetracycline therapy is also commented on.     

Familial juvenile systemic granulomatosis (Blau's syndrome)

Blau's syndrome refers to the rare familial presentation of a sarcoid-like granulomatous disease classically involving the skin, uveal tract and joints, in the absence of pulmonary manifestations.¹ The onset is in childhood, and the mode of inheritance is thought to he autusomal dominant. We report a 15-year-old female and her 22-month-old daughter who presented with clinical features similar to those of Blau's syndrome. In addition to the skin, eye and joint disease, the mother also developed neurological involvement. In both patients long-term systemic corticosteroids were required to control the disease.     

Etanercept-induced cutaneous and pulmonary sarcoid-like granulomas resolving with adalimumab

A 59-year-old female with rheumatoid arthritis on etanercept therapy presented with a 7-cm-large subcutaneous forearm mass. Multiple smaller nodules subsequently developed on the upper and lower extremities. Except for a new cough, the patient was systemically well. Biopsy of the mass showed sarcoidal type granulomatous inflammation with nodular aggregations of non-necrotizing epithelioid histiocytes in the subcutis. A chest computed tomography (CT) scan showed mediastinal adenopathy consistent with pulmonary sarcoidosis. Etanercept was discontinued, and the patient was started on adalimumab for rheumatoid arthritis control. The cutaneous nodules fully resolved in 6 months with no additional treatment. A 4-month follow-up CT scan showed significant regression of mediastinal adenopathy. The patient has since been maintained on adalimumab therapy for 2 years with no recurrence of sarcoid-like manifestations. Biologic response modifiers targeting tumor necrosis factor alpha (TNFα) are effective treatments of chronic inflammatory conditions such as rheumatoid arthritis and psoriasis. TNFα represents a major cytokine in granuloma formation, and TNFα inhibitors are sometimes efficacious in the treatment of sarcoidosis. Paradoxically, there is a small volume of literature implicating TNFα inhibitors in the development of sarcoid-like disease. We present this case to promote the recognition of TNFα inhibitor-induced sarcoidosis and to illustrate the wide clinicopathologic differential of sarcoidal type granulomas.     

Cutaneous immune-related adverse events to checkpoint inhibitors

The development of immunotherapy has led to a paradigm shift in the treatment of both solid and hematologic malignancies. As immunomodulatory therapies are employed with increasing frequency, a greater number of immune-related adverse reactions are being reported, and the majority of these involve the skin. As a result, dermatologists are increasingly becoming involved in the management of these cutaneous adverse reactions—often providing critical recommendations regarding ongoing cancer treatment.Cutaneous immune-related adverse reactions can vary significantly from patient to patient, making early recognition and timely intervention imperative to mitigate associated morbidity and potential treatment interruption. Although there is considerable overlap in the cutaneous adverse events caused by these immune checkpoint inhibitors, specific eruptions are characteristically associated with particular checkpoint inhibitors. In addition, a patient’s comorbidities or immune status can play a significant role in the presentation and management of such adverse reactions. This review characterizes and provides management guidelines for the various cutaneous toxicities associated with checkpoint inhibitor therapy, including CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. © 2020 Elsevier Inc. All rights reserved.     

A Granulomatous Drug Eruption Induced by Entecavir

Entecavir (Baraclude®, Bristol-Myers Squibb) is a potent and selective antiviral agent that has demonstrated efficacy in patients with chronic hepatitis B. The most frequent adverse events attributed to entecavir include increased alanine aminotransferase, upper respiratory tract infection, headache, abdominal pain, cough, pyrexia, fatigue, and diarrhea. Although quite a few randomized double-blind studies including ones investigating adverse events along with these general symptoms have been reported, few cases of cutaneous adverse events have been described in detail. We demonstrate a case of granulomatous drug eruption as a cutaneous adverse event induced by entecavir.     

Granulomatous reaction to Belotero Balance: A case study

Objective: The most commonly used dermal fillers are hyaluronic acids (HAs), and in general, are well tolerated with mild to moderate risk of adverse events. The most frequently reported side effects are injection site erythema and bruising. We present the first case of a patient who developed a severe granulomatous foreign body reaction to the HA filler, Belotero Balance. In our review of the literature, a granulomatous reaction has never before been reported as a side effect of this particular HA filler (1). Case: On exam, the patient had firm erythematous, granulomatous plaques on her bilateral cheeks, with a tender, fluctuant nodule on her right cheek. Complete resolution of this delayed reaction was achieved after several injections of intralesional Kenalog (IL-K) 2.5 mg/cc, and further fine-tuning was achieved through laser resurfacing. Conclusion: Granulomatous reactions can occur with any HAs, though such incidents are not commonly reported. These delayed reactions are generally localized immunological reactions, though biofilm infections should be excluded where appropriate. It is only with long-term (5-year) longitudinal studies that accurate numbers of such reactions will be known.     

The life-threatening eruptions of immune checkpoint inhibitor therapy

Immune checkpoint inhibitors (ICPi) have emerged as a new frontier of cancer therapy. Although monoclonal antibodies to cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have revolutionized oncologic management, these agents may result in a spectrum of immune-related adverse events (irAE) of which dermatologic toxicities are among the most frequent. Prompt recognition and management of irAE is essential for dermatologists caring for the expanding population of cancer patients exposed to these drugs. Cutaneous toxicities range from mild cases to severe and life-threatening presentations that may cause significant morbidity and mortality. This review provides an overview of severe cutaneous adverse reactions (SCARs) that may develop during ICPi therapy, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). In addition, immunobullous disorders, erythroderma, neutrophilic dermatoses, and cutaneous eruptions associated with systemic manifestations are discussed.     

Progressive supravenous granulomatous nodular eruption in a human immunodeficiency virus-positive intravenous drug user treated with highly active antiretroviral therapy

We describe a 41-year-old human immunodeficiency virus-infected woman with a previous history of intravenous drug abuse, who developed multiple linear nodules following the superficial veins on both arms. Histopathological examination disclosed a dermal histiocytic inflammatory reaction with sarcoid-like granuloma formation occasionally showing an intracytoplasmic refractile material in the histiocytic cells. Nodular lesions developed progressively after starting on highly active antiretroviral therapy (HAART) which increased her CD4 cell count and suppressed her viral load. The appearance of latent inflammatory or autoimmune disease following HAART is a well-recognized phenomenon. We consider that this peculiar 'progressive supravenous granulomatous nodular eruption' should be included within the spectrum of the so-called immune reconstitution inflammatory syndrome.