An update on recent randomized clinical trials in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disorder characterized by a remarkable clinical heterogeneity and variable disease course. In this multifactorial condition, the interaction of several pathogenic pathways related to inflammation, vasculopathy and fibrosis promote organ damage. The understanding of the pathogenesis of SSc has improved in recent years leading to the identification of relevant therapeutic targets. Over the last few years, insightful clinical trials have been published and great progress has been made in developing effective therapeutic options. The positive results of the Safety and Efficacy of Nintedanib in Systemic SClerosIS (SENSCIS) trial have led to the approval by drug agencies of the first drug for SSc-related interstitial lung disease. However, the majority of clinical trials have focused on immunosuppressive therapy. Although benefit trends have been observed, outstanding results have not been achieved and to date no immunosuppressant has been approved in SSc. Clinical trial design has evolved regarding inclusion criteria with the aim to enrich for progressive patients. Endpoints have also been revised to better cover the fields of patients’ feelings and functioning. Finally, background synthetic immunosuppressants have been allowed in some trials evaluating targeted therapies opening the door to combination therapies. Herewith, we provide an overview of the most significant clinical trials developed in recent years for the management of SSc.     

Videothoracoscopic lung biopsy in the diagnosis of interstitial lung disease

Objective: Interstitial lung diseases (ILD) require lung biopsy for the diagnosis in more than 30% of patients. Open lung biopsy (OLB) was generally considered the most reliable method of biopsy and tissue diagnosis. This study tests the diagnostic accuracy and safety of the videothoracoscopic lung biopsy (VTLB) in the diagnosis of ILD. Methods: During the last 5 years, 58 patients were submitted to VTLB under general anesthesia. The mean age was 49.6±12.0 years (range 21–69). All the biopsies were performed by an endostapler EndoPath 30 or 45. Conversion to minithoracotomy was necessary in only one patient because of extensive pleural sinfisis. All the specimens were sent to the microbiology and pathology department for microbiological and histopathological diagnosis. One chest-tube (28F) was positioned and connected to a drainage-system and placed on suction. Results: The histopathological diagnosis was obtained for all patients and therefore the diagnostic accuracy of the procedure was 100%. No postoperative haemothorax occurred and only two patients experienced a prolonged air-leakage (3.4%). The median duration of the chest-drain was 3 days (range 1–7) and the median hospital stay was 4 days (range 2–7). Conclusion: VTLB provides adequate specimen volume for histopathologic diagnosis and achieves a very high diagnostic accuracy (100% in our series). The postoperative morbidity and mortality rates are lower than those related to OLB. We conclude that VTLB is an effective and safe procedure in the diagnosis of ILD.     

系统性硬化症的肾脏损害

目的了解系统性硬化症肾脏损害的临床特点及病理特点。方法对我院９３例确诊的系统性硬化症（ＳＳｃ）患者进行回顾性临床分析，并对５例患者进行了肾组织病理学检查。结果有１９４％（１８例）患者有临床肾脏损害，肾功能衰竭发生率为５４％，本组病死率为１２９％，其中死于肾衰者占４１７％。４例患者和１例尸检的肾组织学显示ＳＳｃ的肾脏血管改变为多样性；４例显示有不同程度的小叶间动脉和弓动脉、入球动脉的受累，表现为血管内膜增厚，纤维组织呈“洋葱皮”样同心圆状排列，其中２例并无肾脏损害临床表现。另１例病程长达２２年的患者的肾脏病理表现主要为慢性肾小球肾炎。结论ＳＳｃ患者肾脏损害是一严重并发症，是其主要死亡原因。肾脏病理改变主要为肾脏血管病变，可发生在出现肾脏损害临床表现之前。对ＳＳｃ患者应密切加强随访。     

The first reported case of trastuzumab induced interstitial lung disease associated with anti-neutrophil cytoplasmic antibody vasculitis – A case report and a prospective cohort study on the usefulness of neutrophil derived biomarkers in monitoring vasculitis disease activity during follow-up

Targeted therapies against human epidermal growth factor receptor 2 (HER2) are associated with increased interstitial lung disease (ILD). Trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine have markedly extended HER2 breast cancer survival but current knowledge on how these HER2-targeted agents induce interstitial lung disease is still poorly defined due to limited cases in the literature. Physicians mostly managed this complication by dose interruption, dose de-escalation, or discontinuation with success. In 2019, the FDA had granted accelerated approval on trastuzumab deruxtecan (T-Dxd) in HER2 breast cancer in the late line setting. Severe ILD incidence rate was over ten percent and led to fatal outcomes in 2.2% of patients in the T-Dxd trial. Searching for biomarkers to detect ILD incidence before it becomes clinically fulminant or for treatment response monitoring is of high clinical value.A Case of life-threatening trastuzumab-induced ILD was encountered in our facility. The ILD was confirmed to be antineutrophil cytoplasmic antibody (ANCA) pulmonary capillaritis. The biomarker of neutrophil extracellular traps (NETs), serum MPO-DNA complex, showed a good correlation with the clinical severity. Soon after B cell depleting agent rituximab usage, the serum MPO-DNA outperformed ANCA autoantibody and maintained its correlation with clinical severity. In addition to the trastuzumab-induced ILD case, a prospective cohort in our facility also confirmed the usefulness of MPO-DNA in monitoring vasculitis activity. We postulated that upfront testing with biomarkers of vasculitis during HER2 targeted treatment with high ILD incidence may be beneficial in the future.     

Risk factors for acute exacerbation of interstitial lung disease following lung cancer resection: a systematic review and meta-analysis

Open in a separate window OBJECTIVESThe aim of this study was to investigate the risk factors for acute exacerbation (AE) of interstitial lung disease (ILD) following lung cancer resection. METHODSWe performed a literature screening on the databases including PubMed, Embase, Ovid MEDLINE^® and the Web of Science for related studies published up to January 2021. Eligible studies were included and data on risk factors related to postoperative AE were extracted. All analyses were performed with random-effect model.RESULTSA total of 12 studies of 2655 lung cancer patients with ILD were included in this article. The meta-analysis indicated that male [odds ratios (ORs) = 1.78, 95% confidence interval (CI): 1.02–3.11, P = 0.041], usually interstitial pneumonia pattern on CT (OR = 1.52, 95% CI: 1.06–2.17, P = 0.021), Krebs von den Lungen-6 [standardized mean difference (SMD) = 0.50, 95% CI: 0.06–0.94, P = 0.027], white blood cell (SMD = 0.53, 95% CI: 0.12–0.93, P = 0.010), lactate dehydrogenase (SMD = 0.47, 95% CI: 0.04–0.90, P = 0.032), partial pressure of oxygen (weighted mean difference = −3.09, 95% CI: −5.99 to −0.19, P = 0.037), surgery procedure (OR = 2.31, 95% CI: 1.42–3.77, P < 0.001) and operation time (weighted mean difference = 28.26, 95% CI: 1.13–55.39, P = 0.041) were risk factors for AE of ILD following lung cancer resection.CONCLUSIONSWe found that males, usually interstitial pneumonia pattern on CT, higher levels of Krebs von den Lungen-6, lactate dehydrogenase, white blood cell, lower partial pressure of oxygen, greater scope of operation and longer operation time were risk factors for AE of ILD following lung cancer resection. Patients with these risk factors should be more prudently selected for surgical treatment and be monitored more carefully after surgery.     

Interstitial lung disease (ILD) in systemic sclerosis (SSc)

Intersitial lung disease is a frequent complication of systemic sclerosis that often has a poor pognosis and together with pulmonary arterial hypertension are the most common cause of death in scleroderma patients. For detection and evaluation of interstitial lung disease, high-resolution CT and pulmorary functional tests are pivotal. The decision about whether to start treatment is often the most difficult challenge. Patients with short duration of systemic disease with recent deterioration in DCO are the candidates for immunosupressive therapy. Best current initial treatment is intravenous monthly cyclophosphamide together with low-dose oral glucocorticoids although azathioprine and mycophenolate mofetil are also widely used.     

结节性硬化症相关肾透明细胞癌一例报告并文献复习

目的 探讨结节性硬化症(tuberous sclerosis complex,TSC)相关肾细胞癌(renal cell carcinoma,RCC)的临床诊治特点.方法 回顾性分析1例TSC相关TCC患者的资料.男,22岁.自幼智障伴癫痫.发现双肾肿瘤5年,间断肉眼血尿2年,曾于1年内2次行超选择性左肾动脉栓塞术,但分别于术后6、10个月再次出现肉眼血尿.查体:智障表现,肥胖,头颈部血管纤维瘤及非创伤性趾甲沟纤维瘤.CT平扫检查左肾有一不规则实性占位,最大截面14.2 cm×9.0 cm,CT值45～54HU,增强扫描病变呈不均匀强化,CT值60～78 HU,左肾静脉内有充盈缺损;右肾见多发脂肪密度占位,CT值-38～-25 HU,最大截面7.2 cm × 5.7 cm.检索Pubmed和CBM数据库进行相关文献复习.结果 患者行经腹开放性左肾根治性切除术,病理诊断肾透明细胞癌,肾静脉内见瘤栓.随访4个月未发现肿瘤复发及转移.结论 TSC相关RCC临床罕见,诊断后可行肾部分切除术或根治性肾切除术.

Abstract：

Objective To explore the diagnosis and treatment features of tuberous sclerosis complex associated renal cell carcinoma.Methods A 22-year-old boy with a childhood history of epilepsy and mental retardation presented with a complaint of intermittent painless gross hematuria for the past 2 years.After superselective left renal artery embolization was done twice in the past year, painless gross hematuria was still repeated with 6- 10 months intervals.Physical examination showed retarded face, obesity, visible facial angiofibroma and a ditch fibroma.CT scan showed irregular lesions.The largest cross-section 14.2 cm × 9.0 cm in the left kidney was inhomogeneous enhanced from 45 - 54 HU in the plain phase to 60 - 78 HU in the contrast phase.Filling defect in the left renal vein and multiple fat-density lesions (CT value of -25 - -38 HU) with the largest cross-section 7.2 cm× 5.7 cm in the right kidney were also found in contrast CT scan.The PUBMED and CBM database were reviewed.Results Open retroperitoneal radical left nephrectomy was performed.Pathology showed renal clear cell carcinoma and renal vein thrombosis.There was no tumor recurrence or distant metastasis at 4-month follow-up.Conclusions Tuberous sclerosis complex associated renal cell carcinoma is rarely reported.Timely nephron-sparing surgery is necessary when the diagnosis is established, or radical nephrectomy is also necessary if nephron-sparing surgery is impossible.     

Nutrition‐related factors associated with waiting list mortality in patients with interstitial lung disease: A retrospective cohort study

Japanese patients with interstitial lung disease (ILD) sometimes die waiting for lung transplantation (LTx) because it takes about 2 years to receive it in Japan. We evaluated nutrition‐related factors associated with waiting list mortality. Seventy‐six ILD patients were hospitalized in Kyoto University Hospital at registration for LTx from 2013 to 2015. Among them, 40 patients were included and analyzed. Patient background was as follows: female, 30%; age, 50.3 ± 6.9 years; body mass index, 21.1 ± 4.0 kg/m²; 6‐minute walk distance (6MWD), 356 ± 172 m; serum albumin, 3.8 ± 0.4 g/dL; serum transthyretin (TTR), 25.3 ± 7.5 mg/dL; and C‐reactive protein, 0.5 ± 0.5 mg/dL. Median observational period was 497 (range 97‐1015) days, and median survival time was 550 (95% CI 414‐686) days. Survival rate was 47.5%, and mortality rate was 38.7/100 person‐years. Cox analyses showed that TTR (HR 0.791, 95% CI 0.633‐0.988) and 6MWD (HR 0.795, 95% CI 0.674‐0.938) were independently correlated with mortality and were influenced by body fat mass and leg skeletal muscle mass, respectively. It is suggested that nutritional markers and exercise capacity are important prognostic markers in waitlisted patients, but further study is needed to determine whether nutritional intervention or exercise can change outcomes.     

Ocular manifestations in patients with systemic sclerosis

Systemic sclerosis (SSc) is a rare, chronic autoimmune disease with unknown etiology. Its prominent features are fibrosis, vasculopathy and impaired immune response. Disease can also affect eyes leading to various findings in ophthalmological examination.The objective of this study was to determine the prevalence and type of ocular involvement in patients with SSc. A systematic literature review was conducted using electronic databases. A combination of following keywords was used: “systemic sclerosis” and ophthalmology-related search terms, including the keywords “eye”, “ocular” and “ophthalmic”.In conclusion, eyelid and conjunctival abnormalities and dry eye disease are among the most common ocular manifestations of SSc. Their diversity is connected to complexity of the disease.     

Ultrasound prevalence of wrist,hand, ankle and foot synovitis and tenosynovitis in systemic sclerosis,and relationship with disease features and hand disability

IntroductionIn systemic sclerosis, few studies have shown that hand and wrist ultrasound is more sensitive than clinical examination in the detection of synovitis and tenosynovitis. Even fewer studies have investigated ankle and foot involvement with ultrasound. Our objectives were to investigate ultrasound prevalence of wrist, hand, ankle and foot synovitis and tenosynovitis in patients with systemic sclerosis classified with ACR/EULAR 2013 criteria, and to study their relationship with disease features and hand disability.MethodsConsecutive patients with systemic sclerosis, classified with ACR/EULAR 2013 criteria, were included in a monocentric cross-sectional study. They underwent standardized musculoskeletal clinical examination and hand, wrist, ankle and foot ultrasound. Clinical, biological and imaging data were also collected.ResultsFifty-five patients were included. Ultrasound was more sensitive than clinical examination to detect at least one synovitis (respectively 52% versus 25%, P = 0.025) and at least one tenosynovitis (respectively 16% versus 4%, P = 0.009); 18% of patients had ankle tenosynovitis and 29% had ankle and/or foot synovitis, mostly located at metatarsophalangeal joints (25.5%). Having at least one ultrasound hand synovitis was associated with higher Cochin hand functional disability scale (mean 25 ± 3 versus 12 ± 2, P = 0.003) and diffuse cutaneous subset (P = 0.038).ConclusionOur study shows that ultrasound is more sensitive than clinical examination to detect synovitis and tenosynovitis in systemic sclerosis. The foot involvement is less frequent than hand involvement, mainly localized at metatarsophalangeal joint. Finally, having at least one synovitis of the hand is associated with diffuse cutaneous subset and higher hand disability.     

Interstitial cystitis in a woman with systemic mastocytosis

Studies have reported detrusor mastocytosis in patients with interstitial cystitis. The author describes a patient with systemic mastocytosis who was confirmed to have detrusor mastocytosis and interstitial cystitis. She responded to therapy with pentosanpolysulfate. The literature on systemic mastocytosis and the role of mast cells in the pathophysiology of interstitial cystitis are reviewed.     

A case of Mikulicz’s disease complicated with severe interstitial nephritis associated with IgG4

A 48-year-old woman who had bilateral swelling in the eyelids and submandibular region was admitted. Clinical findings suggested that her renal function had deteriorated. Laboratory data showed renal insufficiency (2.52 mg/dl), hypergammaglobulinemia (IgG 3,729 mg/dl, IgA 124 mg/dl, IgM 73 mg/dl). Gallium-67 scintigram indicated abnormal uptake in bilateral lacrimal glands, submandibular glands, and kidneys. A diagnosis of Mikulicz’s disease and interstitial nephritis was made, since biopsy specimens of her lacrimal gland and minor salivary gland showed diffuse infiltration of lymphocytes. In addition, renal biopsy specimens showed diffuse severe interstitial infiltration of IgG4-positive mononuclear cells. Symptoms and laboratory data normalized in response to methylprednisolone semi-pulse therapy and prednisolone 50 mg/day. Mikulicz’s disease was recently reported to be IgG4 associated disease. In our case, Mikulicz’s disease complicated with diffuse severe interstitial nephritis was successfully treated by corticosteroid. The present case supports the hypothesis that IgG4-related autoimmune disease could be causes of Mikulicz’s disease and interstitial nephritis.