UNASSIGNED: To report clinical features and treatment outcome of three cases with isolated corneal intraepithelial neoplasia (CIN).
UNASSIGNED: This case series presents 3 patients with isolated CIN. Data collected included, presenting signs and symptoms including vision, anterior segment examination, medical and surgical outcomes and signs and symptoms at lost post-treatment visit.
UNASSIGNED: Case 1 was a 45-year-old male who presented with an isolated grayish amoeboid corneal lesion which was excised with alcohol assisted epitheliectomy, he also received 6 cycles of topical mitomycin C (MMC) 0.02% and one injection of interferon alfa-2b with no recurrence during the 10-year follow-up period. Case 2 was 78-year-old male referred for a suspicious white corneal lesion which was completely excised, the patient also received 6 subconjunctival injections of interferon alpha-2b. However, the lesion recurred at 2.5-years post-treatment. Case 3 was a 63-year-old male patient who presented with an isolated corneal lesion that was excised using alcohol-assisted epitheliectomy, patient received four cycles of topical 5-fluorouracil with no recurrence at last follow-up visit at 6 months.
UNASSIGNED: Isolated corneal intraepithelial neoplasia (CIN) is a rare entity with few reported cases in the literature. In this case series, we report long and short-term management outcomes of combined surgical and medical therapy for isolated CIN.

BACKGROUND: Thrombotic microangiopathy is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. The pathological features include vascular damage that is manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall. Thrombocytopenia is one of the common adverse effects of interferon therapy. However, a more serious but rare side effect is thrombotic microangiopathy.
METHODS: We report the case of a 36-year-old Asian male patient with clinical manifestations of hypertension, blurred vision, acute renal failure, thrombocytopenia, and thrombotic microangiopathy. Renal biopsy showed interstitial edema with fibrosis, arteriolar thickening with vitreous changes, and epithelial podocytes segmental fusion. Immunofluorescence microscopy showed C3(+), Ig A(+) deposition in the mesangial region, which was pathologically consistent with thrombotic microangiopathy renal injury and Ig A deposition. The patient had a history of hepatitis B virus infection for more than 5 years. Lamivudine was used in the past, but the injection of long-acting interferon combined with tenofovir alafenamide fumarate was used since 2018. The comprehensive clinical investigation and laboratory examination diagnosed the condition as thrombotic microangiopathy kidney injury caused by interferon. After stopping interferon in his treatment, the patient\'s renal function partially recovered after three consecutive therapeutic plasma exchange treatments and follow-up treatment without immunosuppressant. The renal function of the patient remained stable.
CONCLUSIONS: This report indicates that interferon can induce thrombotic microangiopathy with acute renal injury, which can progress to chronic renal insufficiency.

UNASSIGNED: Malignant atrophic papulosis (MAP) is a rare obliterative vasculopathy whose etiology and pathophysiological mechanisms remain unknown, and the treatment is still empirical. It can involve multiple systems, especially the gastrointestinal tract and central nervous system, and has a poor prognosis.
UNASSIGNED: A 20-year-old Chinese male appeared to have Widespread atrophic papules and plaques, intermittent abdominal pain, recurrent bowel perforation, and psoas abscess. The clinical diagnosis of MAP was supported by skin biopsy. He was then treated with anticoagulants, antiplatelets, glucocorticoids, and immunosuppressants and started on eculizumab and hirudin after the first surgical interventions. Despite the aggressive immunosuppression, anticoagulant, antiplatelet, humanized monoclonal antibodies, and surgery therapy, he died five months after presentation.
UNASSIGNED: MAP is an extremely rare obliterative vasculopathy manifesting as benign cutaneous involvement or potentially malignant systemic involvement. MAP patients who exhibit any abdominal symptoms should undergo laparoscopy and evaluation in time and start on eculizumab and treprostinil as soon as possible, as the combination of them is presently the most effective treatment option for gastrointestinal MAP and hopefully reduce mortality.

BACKGROUND: H Syndrome is a rare genetic condition caused by biallelic pathogenic variants in the SLC29A3 gene. It is characterized by a wide range of clinical manifestations, many of which are related to the immune-rheumatological field. These include scleroderma-like skin changes, deforming arthritis, and enlarged lymph nodes. The condition also features cardiac and endocrine defects, as well as hearing loss, for which the immune pathogenesis appears less clear. Immunomodulatory medications have been shown to improve many symptoms in recent experiences.
METHODS: A 21-year-old girl was referred to our institute after being diagnosed with H syndrome. Her medical history was characterized by the development of finger and toe deformities, which developed since the first years of life and progressively worsened with clinodactyly. At 6 years of age, she was diagnosed with diabetes mellitus without typical autoantibodies and with bilateral sensorineural hearing loss. She also complained of frequent episodes of lymphadenopathy, sometimes with colliquation and growth retardation due to pancreatic insufficiency. It wasn\'t until the genetic diagnosis of H syndrome that the continual increase in acute phase reactants was noticed, suggesting that an immunological pathogenesis may be the source of her problems. During her visit to our institute, she reported serious pain in both feet and hands and difficulty walking due to knee arthritis and muscle contractures. Conventional therapy with steroid injection in affected joints and methotrexate only led to partial improvement. After a thorough assessment of her inflammatory profile showing a high interferon score, the girl received treatment with baricitinib. Furthermore, based on recent data showing that SLC29A3 deficiency results in interferon production because of Toll-like Receptor 7 activation in lysosomes, hydroxychloroquine was also added. The combination of the two drugs resulted for the first time in a rapid and persistent normalization of inflammatory markers, paralleled by a dramatic improvement in symptoms.
CONCLUSIONS: We describe the results of inhibiting IFN inflammation in H syndrome and discuss how JAK inhibitors and antimalarials might represent a mechanistically based treatment for this orphan drug disorder.

BACKGROUND: Immunization against the Yellow fever virus (YFV) with the 17D live-attenuated vaccine is the most effective way to prevent the disease. However, unexpected severe adverse events can occur. They consist in a neurological impairment - neurological disease (YEL-AND), a YF-like illness - viscerotropic disease (YEL-AVD) or anaphylaxis. In this article, we describe the epidemiology, clinical and biological features of YEL-AND and YEL-AVD cases reported to the French National Reference Center for Arboviruses (NRCA) in the past 10 years.
METHODS: We conducted a national, retrospective study using the database of the NRCA from June 2012 to June 2022. All patients whose biological samples were sent to the NRCA for detection of YFV by serology and/or RT-qPCR for a suspected vaccine-associated adverse event were included. We collected data by reading medical records and conducted complementary neuro-immunological analysis, followed by a search for autoimmunity against type-1-interferon when samples were available at the NRCA.
RESULTS: There were 10 cases of YEL-AND and 2 cases of YEL-AVD reported to the NRCA in the past 10 years, which represented an overall incidence of 0.6 for 100 000 doses. A total of 6/12 cases were previously healthy patients (50%, mean age 31 years), and 4/12 cases had cardiovascular co-morbidities (42%, mean age 56 years). The majority of YEL-AND had a favourable outcome at 6 months of follow up. One YEL-AVD patient passed. In secondary analyses, we evidenced a significant blood cerebrospinal fluid (CSF) barrier dysfunction, without intrathecal synthesis of immunoglobulin and without argument for a neuron damage. We further detected a significant rate of anti-type-1alpha interferon antibodies in 3/10 tested patients (2 YEL-AND and 1 YEL-AVD).
CONCLUSIONS: YEL-AND and YEL-AVD are rare events that can underlie defect in the innate immunity of apparently healthy or mild co-morbid subjects. Outcome was generally favourable in the YEL-AND cases of our series, but still life-threatening or even fatal in the YEL-AVD cases.

ISG15 deficiency is a rare disease caused by autosomal recessive variants in the ISG15 gene, which encodes the ISG15 protein. The ISG15 protein plays a dual role in both the type I and II interferon (IFN) immune pathways. Extracellularly, the ISG15 protein is essential for IFN-γ-dependent anti-mycobacterial immunity, while intracellularly, ISG15 is necessary for USP18-mediated downregulation of IFN-α/β signalling. Due to this dual role, ISG15 deficiency can present with various clinical phenotypes, ranging from susceptibility to mycobacterial infection to autoinflammation characterised by necrotising skin lesions, intracerebral calcification, and pulmonary involvement. In this report, we describe novel variants found in two different families that result in complete ISG15 deficiency and severe skin ulceration. Whole exome sequencing identified a heterozygous missense p.Q16X ISG15 variant and a heterozygous multigene 1p36.33 deletion in the proband from the first family. In the second family, a homozygous total ISG15 gene deletion was detected in two siblings. We also conducted further analysis, including characterisation of cytokine dysregulation, interferon-stimulated gene expression, and p-STAT1 activation in lymphocytes and lesional tissue. Finally, we demonstrate the complete and rapid resolution of clinical symptoms associated with ISG15 deficiency in one sibling from the second family following treatment with the Janus kinase (JAK) inhibitor baricitinib.

Cutaneous lupus erythematosus (CLE), the main manifestation of systemic lupus erythematosus (SLE), is driven by type I interferons (IFNs) and often only partially responds to conventional therapies. Treatment of seven SLE patients with the monoclonal antibody anifrolumab induced fast and sustained remission of previously refractory CLE lesions, beginning within the first weeks of treatment. Decline in CLASI-A score was paralleled by a reduction in IFN score determined by mRNA expression of seven IFN-stimulated genes (ISGs) in blood. These data suggest that a subset of ISGs could be a valuable biomarker in CLE.

Multiple hemorrhagic brain lesions are mainly diagnosed based on clinico-radiological features integrated with histological data. Intravascular papillary endothelial hyperplasia (IPEH), or Masson\'s tumor, is a very rare entity, particularly when localized in the brain. In this study, we describe a case of multiple recurrent brain IPEHs and provide details on the diagnostic phase, therapeutic approaches, and related challenges. A 55-year-old woman presented with a relapsing neurological deficit. Brain magnetic resonance imaging (MRI) revealed a hemorrhagic right frontal-parietal lesion. When new neurological symptoms occurred, subsequent MRI scans detected more bleeding cerebral lesions. She underwent a series of single hemorrhagic lesion debulking. For any samples that underwent histopathological examination, the first results were not informative; the second and the third results revealed hemangioendothelioma (HE); and the fourth results led to the IPEH diagnosis. Interferon alpha (IFN-α) and subsequently sirolimus were prescribed. Both were well tolerated. Clinical and radiological features remained stable 43 months after starting sirolimus therapy and 132 months after the first diagnosis. To date, 45 cases of intracranial IPEH have been reported, mostly as single lesions without parenchymal location. They are usually treated by surgery and sometimes by radiotherapy upon recurrence. Our case is notable for two main reasons: because of the consecutive recurrent multifocal exclusively cerebral lesions and the therapeutic approach we used. Based on multifocal brain recurrence and good performance, we propose pharmacological therapy, including IFN-α and sirolimus, to stabilize IPEH.

Myeloproliferative neoplasms (MPN) such as essential thrombocythemia (ET) and polycythemia vera (PV) are rare during pregnancy. However, they are harmful because they are associated with an increased risk of thromboembolic, hemorrhagic, or microcirculatory disturbances or placental dysfunction leading to fetal growth restriction or loss. Low-dose aspirin and low-molecular-weight heparin (LMWH) are recommended to reduce pregnancy complications, and interferon (IFN) is the only treatment option for cytoreductive therapy based on the likelihood of live birth in pregnant women with MPN. Since ropeginterferon alfa-2b is the only available IFN in South Korea, we present a case report of ropeginterferon alfa-2b use during pregnancy in an MPN patient. A 40-year-old woman who had been diagnosed with low-risk PV in 2017 and had been maintained on phlebotomy, hydroxyurea (HU), and anagrelide (ANA) for 4 years was confirmed as 5 weeks pregnant on 9 December 2021. After stopping treatment with HU and ANA, the patient showed a rapid increase in platelet count (1113 × 109/L to 2074 × 109/L, normal range, 150-450 × 109/L) and white blood cell count (21.93 × 109/L to 35.55 × 109/L, normal range, 4.0-10.0 × 109/L). Considering the high risk of complications, aggressive cytoreductive treatment was required, for which we chose ropeginterferon alfa-2b, as it is the only available IFN agent in South Korea. The patient underwent 8 cycles of ropeginterferon alfa-2b over 6 months during pregnancy and delivered without any neonatal or maternal complications. This case report highlights the importance of considering treatment options for MPN patients who are pregnant or planning a pregnancy, as well as the need for further investigation into the safety and efficacy of ropeginterferon alfa-2b in this population.

Hepatic epithelioid hemangioendothelioma (HEH) is a very rare tumor originating from vascular endothelial cells, with unpredictable malignancy. At present, there is no standard treatment protocol yet established. Both surgical resection and liver transplantation have been reported to be effective treatments for HEH; however, multiple intrahepatic lesions or extrahepatic metastasis make these procedures unsuitable to most patients. Systematic therapy has also been investigated, but the results are undetermined due to the limited cases. Interferon-alpha 2b (IFN-a 2b) has also been used for the treatment of HEH. Based on our previous study, the rate of tumor regression with IFN-a 2b monotherapy was more than 50%. Here, we reported a patient with advanced HEH, who achieved a partial response with the combined therapy of anlotinib and IFN-a 2b. The tumor stayed stable for 2 years with anlotinib monotherapy and regressed 3 months after the combined therapy of anlotinib and IFN-a 2b. The synergistic effect of combined therapy with anlotinib and IFN-a 2b provided promising guidance for future clinical study.