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Background. ROSAH syndrome is a rare autoinflammatory disease with autosomal dominant inheritance caused by gain-of-function missense mutations in the ALPK1 gene on chromosome 4. This leads to hyperactivation of the NF-κB signaling pathway and chronic cytokine-mediated inflammation (IL-1, IL-6, and TNF-alpha). ROSAH is an acronym for the following clinical findings: retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache. Reports have documented approximately 70 cases since the first description in 2012.   Materials and Methods. We describe the case of a 22-year-old woman who presented in 2021 with bilateral progressive visual loss, dyschromatopsia, frontal headache, and severe fatigue. Ophthalmologic examination revealed bilateral papilledema, vitreous inflammation, macular edema, retinal dystrophy, retinal vascular inflammation, and neurodegeneration of outer retinal layers. Neuroimaging was unremarkable, but lumbar puncture showed elevated opening pressure (27 mmHg). Splenomegaly (13 cm) was detected on abdominal ultrasound. Laboratory tests are reported in the Table. An initial diagnosis of atypical systemic lupus erythematosus (SLE) was made, and high-dose corticosteroids were started (pulsed methylprednisolone followed by tapering oral prednisone). Additional treatments included low-dose aspirin (100 mg/day) and acetazolamide (1250 mg/day). The patient was treated subsequently with steroid-sparing drugs: azathioprine (2 mg/kg/day) and hydroxychloroquine (200 mg/day) later switched to mycophenolate mofetil (3 g/day), and then rituximab (1 g every two weeks, 2 doses). These treatments improved visual acuity and vitreous inflammation but had a limited effect on papilledema and retinal dystrophy. For these conditions, corticosteroids were the only effective treatment. In 2023, the patient was referred to our center: attempts to taper corticosteroids and acetazolamide resulted in the recurrence of headaches and ocular symptoms, along with worsening macular edema. Additionally, she exhibited hypohidrosis. Clinical reassessment revealed that her father had progressive blindness and severe papilledema secondary to hypertensive hydrocephalus.   Results. Given these findings, the patient underwent molecular genetic testing (next-generation sequencing (NGS) panel for autoinflammatory diseases). A heterozygous missense pathogenic variant in ALPK1 (c.710C>T; p.Thr237Met) was identified, confirming the diagnosis of ROSAH syndrome. In December 2024, treatment with tocilizumab (8 mg/kg every 4 weeks) was started. After 4 months, the patient showed significant improvement in papilledema and complete recovery of visual acuity along with resolution of systemic symptoms, despite continued tapering of prednisone (7.5 mg/day) and acetazolamide (750 mg/day).   Conclusions. ROSAH syndrome is an emerging autoinflammatory disorder with limited documented cases. This report highlights its diagnostic complexity and therapeutic challenges. Tocilizumab, an anti-IL-6 receptor antibody, appears to be a well-tolerated and effective treatment, especially for ocular manifestations. Further studies are needed to better understand the pathogenesis and to establish standardized treatment protocols.

The purpose of this case report was to demonstrate the efficacy of Tocilizumab in the treatment of severe coronavirus disease 2019 (COVID-19) in obese patients who presented with a week's history of fever and one day of shortness of breath (SOB). It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). COVID-19 has rapidly spread throughout the world, resulting in a global pandemic. Severe COVID-19 causes proinflammatory cytokine release and is associated with a high morbidity and mortality rate. Furthermore, obesity is an independent risk factor for developing severe COVID-19 complications with a high mortality. Stopping this cascade early in the disease's progression has resulted in a significant improvement in outcome. Tocilizumab in conjunction with systemic corticosteroids as part of the standard of care for halting pro-inflammatory cytokine cascades in early disease courses and prone positioning has been shown to improve respiratory parameters while also reducing the need for mechanical ventilation and Intensive Care Unit (ICU) stay (14 days as in our case).

Background. Mixed Connective Tissue Disease (MCTD) is a systemic autoimmune disorder characterized by the presence of anti-U1 ribonucleoprotein (U1-RNP) antibodies associated with clinical features commonly observed in systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis (RA), and polymyositis/dermatomyositis. The pediatric-onset form of the disease is among the rarest entities in pediatric rheumatology.   Case Report. We present the case of a 21-year-old Pakistani woman diagnosed with MCTD at the age of 11 (2015), with onset characterized by Raynaud’s phenomenon (scleroderma capillaroscopic pattern), polyarthritis, and recurrent parotitis. Laboratory findings showed ANA 1:640 speckled pattern, anti-U1-RNP 643 U/mL, rheumatoid factor (RF) 1750 IU/mL, and elevated ESR and CRP. She was treated in the pediatric setting with oral corticosteroids, hydroxychloroquine (HCQ) 300 mg/day, and methotrexate (MTX) up to 20 mg/week. In 2021, due to partial disease control, mycophenolate mofetil (MMF) 1.5 g/day was added, achieving a good response. At age 18 (2022), upon transfer to our care, she presented with active arthritis and elevated inflammatory markers. Instrumental assessment ruled out cardiac and pulmonary involvement. In December 2022, arthritis of the hands and wrists persisted, with ESR 120 mm/h and CRP 2.3 mg/dL (normal <1 mg/dL). Prednisone (PDN) was increased up to 12.5 mg/day and MMF to 2 g/day (in combination with MTX 20 mg/week and HCQ 300 mg/day). Throughout 2023, she experienced recurrent episodes of painful left parotid swelling without fever (ESR 120, CRP 4.5 mg/dL), which responded to tapered corticosteroid therapy (PDN 25 mg/day). In early 2024, she developed progressive fatigue, worsening arthritis of hands and feet, bilateral parotid swelling, and persistently elevated inflammatory markers. MTX was replaced with azathioprine for approximately four months, without clinical improvement (MMF 2 g + HCQ 200 mg + PDN 15 mg/day). In April 2024, azathioprine was discontinued and therapy with rituximab (1 g at T0 and T15) was initiated but suspended after the second infusion due to a mucocutaneous allergic reaction. In October 2024 (ESR 138, CRP 3.1 mg/dL), off-label use of subcutaneous tocilizumab 162 mg weekly was requested and approved (in combination with MTX 10 mg/week and HCQ 200 mg/day). After five months of treatment, the disease is well controlled. The patient no longer presents active arthritis or acute parotitis episodes, prednisone was tapered to 5 mg/day, and inflammatory markers improved (ESR 84 mm/h, CRP 0 mg/dL).   Conclusions. Tocilizumab is a humanized monoclonal antibody targeting the IL-6 receptor, approved for use in RA, juvenile idiopathic arthritis, and giant cell arteritis. Only a few reports in the literature describe tocilizumab use in MCTD, all in pediatric cases with articular involvement. Given its proven efficacy in juvenile idiopathic arthritis, we decided to usetocilizumab in this patient, obtaining a favorable response on arthritis, systemic disease activity, and parotitis. This therapy requires careful clinical and laboratory monitoring.  

After analyzing the immune characteristics of patients with severe coronavirus disease 2019 (COVID-19), we have identified that pathogenic T cells and inflammatory monocytes with large amount of interleukin 6 secreting may incite the inflammatory storm, which may potentially be curbed through monoclonal antibody that targets the IL-6 pathways. Here, we aimed to assess the efficacy of tocilizumab in severe patients with COVID-19 and seek a therapeutic strategy. The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People’s Hospital were given tocilizumab in addition to routine therapy between 5 and 14 February 2020. The changes of clinical manifestations, computerized tomography (CT) scan image, and laboratory examinations were retrospectively analyzed. Fever returned to normal on the first day, and other symptoms improved remarkably within a few days. Within 5 d after tocilizumab, 15 of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% of patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% of patients (16/19). No obvious adverse reactions were observed. All patients have been discharged on average 15.1 d after giving tocilizumab. Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.

Introduction: Tocilizumab (TCZ) is an anti-interleukin-6 antibody that has been used for the treatment of severe coronavirus disease 2019 (COVID-19). However, concrete evidence of its benefit in reducing mortality in severe COVID-19 is lacking. Therefore, we performed a systematic review and meta-analysis of relevant studies that compared the efficacy of TCZ in severe COVID-19 vs. standard of care (SOC) alone.Methods: A literature search for studies that compared “tocilizumab” and “standard of care” in the treatment of COVID-19 was done using major online databases from December 2019 to June 14, 2020. Search words “Tocilizumab,” “anti-interleukin-6 antibody,” and “COVID-19” or “coronavirus 2019” in various combinations were used. Articles in the form of abstracts, letters without original data, case reports, and reviews were excluded. Data were gathered on an Excel sheet, and statistical analysis was performed using Review Manager 5.3.Results: Sixteen studies were eligible from 693 initial studies, including 3,641 patients (64% males). There were 13 retrospective studies and three prospective studies. There were 2,488 patients in the SOC group (61.7%) and 1,153 patients (68.7%) in the TCZ group. The death rate in the TCZ group, 22.4% (258/1,153), was lower than in the SOC group, 26.21% (652/2,488) [pooled odds ratio 0.57 (95% CI 0.36–0.92), p = 0.02]. There was a significant heterogeneity (inconsistency index = 80%) among the included studies.Conclusion: The addition of TCZ to the SOC might reduce mortality in severe COVID-19. More extensive randomized clinical trials are needed to validate these findings.

A cytokine storm is a hyperinflammatory state secondary to the excessive production of cytokines by a deregulated immune system. It manifests clinically as an influenza-like syndrome, which can be complicated by multi-organ failure and coagulopathy, leading, in the most severe cases, even to death. The term cytokine storm was first used in 1993 to describe the graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. It was then reused to define the adverse syndromes secondary to the administration of immunostimulating agents, such as anti-CD28 antibodies or bioengineered immune cells, i.e., CAR T-cell therapy. Currently, the concept of cytokine storm has been better elucidated and extended to the pathogenesis of many other conditions, such as sepsis, autoinflammatory disease, primary and secondary hemophagocytic lymphohistiocytosis, and multicentric Castleman disease. Moreover, cytokine storm has recently emerged as a key aspect in the novel Coronavirus disease 2019, as affected patients show high levels of several key pro-inflammatory cytokines, such as IL-1, IL-2, IL-6, TNF-α, IFN-γ, IP-10, GM-CSF, MCP-1, and IL-10, some of which also correlate with disease severity. Therefore, since the onset of the pandemic, numerous agents have been tested in the effort to mitigate the cytokine storm in COVID-19 patients, some of which are effective in reducing mortality, especially in critically ill patients, and are now becoming standards of care, such as glucocorticoids or some cytokine inhibitors. However, the challenge is still far from being met, and other therapeutic strategies are being tested in the hope that we can eventually overcome the disease.

In the clinic, chimeric antigen receptor–modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell–mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies. IL-1 blockade prevents cytokine-release syndrome and neurotoxicity by CAR T cells.

IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. Hunter and Jones discuss the effect of IL-6 on innate and adaptive immunity, and consider how the immunobiology of IL-6 may inform clinical decisions. Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.

Severe coronavirus disease (COVID-19) is currently managed with systemic glucocorticoids. Opportunistic fungal infections are of concern in such patients. While COVID-19 associated pulmonary aspergillosis is increasingly recognized, mucormycosis is rare. We describe a case of probable pulmonary mucormycosis in a 55-year-old man with diabetes, end-stage kidney disease, and COVID-19. The index case was diagnosed with pulmonary mucormycosis 21 days following admission for severe COVID-19. He received 5 g of liposomal amphotericin B and was discharged after 54 days from the hospital. We also performed a systematic review of the literature and identified seven additional cases of COVID-19 associated mucormycosis (CAM). Of the eight cases included in our review, diabetes mellitus was the most common risk factor. Three subjects had no risk factor other than glucocorticoids for COVID-19. Mucormycosis usually developed 10–14 days after hospitalization. All except the index case died. In two subjects, CAM was diagnosed postmortem. Mucormycosis is an uncommon but serious infection that complicates the course of severe COVID-19. Subjects with diabetes mellitus and multiple risk factors may be at a higher risk for developing mucormycosis. Concurrent glucocorticoid therapy probably heightens the risk of mucormycosis. A high index of suspicion and aggressive management is required to improve outcomes.

PurposeTrials of tocilizumab in patients with severe COVID-19 pneumonia have demonstrated mixed results, and the role of tocilizumab in combination with other treatments is uncertain. Here we evaluated whether tocilizumab plus remdesivir provides greater benefit than remdesivir alone in patients with severe COVID-19 pneumonia.MethodsThis randomized, double-blind, placebo-controlled, multicenter trial included patients hospitalized with severe COVID-19 pneumonia requiring > 6 L/min supplemental oxygen. Patients were randomly assigned (2:1 ratio) to receive tocilizumab 8 mg/kg or placebo intravenously plus ≤ 10 days of remdesivir. The primary outcome was time from randomization to hospital discharge or “ready for discharge” (defined as category 1, assessed by the investigator on a 7-category ordinal scale of clinical status) to day 28. Patients were followed for 60 days.ResultsAmong 649 enrolled patients, 434 were randomly assigned to tocilizumab plus remdesivir and 215 to placebo plus remdesivir. 566 patients (88.2%) received corticosteroids during the trial to day 28. Median time from randomization to hospital discharge or “ready for discharge” was 14 (95% CI 12–15) days with tocilizumab plus remdesivir and 14 (95% CI 11–16) days with placebo plus remdesivir [log-rank P = 0.74; Cox proportional hazards ratio 0.97 (95% CI 0.78–1.19)]. Serious adverse events occurred in 128 (29.8%) tocilizumab plus remdesivir and 72 (33.8%) placebo plus remdesivir patients; 78 (18.2%) and 42 (19.7%) patients, respectively, died by day 28.ConclusionsTocilizumab plus remdesivir did not shorten time to hospital discharge or “ready for discharge” to day 28 compared with placebo plus remdesivir in patients with severe COVID-19 pneumonia.