Tocilizumab for uncontrollable systemic inflammatory response syndrome complicating adult-onset Still disease

Masui-Ito, Asami; Okamoto, Ryuji; Ikejiri, Kaoru; Fujimoto, Mika; Tanimura, Muneyoshi; Nakamori, Shiro; Murata, Tetsuya; Ishikawa, Eiji; Yamada, Norikazu; Imai, Hiroshi; M, Ito

doi:10.1097/md.0000000000007596

Cited by 14 publications

(11 citation statements)

References 36 publications

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“…Tocilizumab, an IL-6 receptor inhibitor, has been previously studied for its ability to mitigate systemic inflammatory disease states 25 , 26 and explored for COVID-19–related inflammation, given the early link between IL-6 and mortality. 7 COVID-19 cytokine storm is associated with high levels of inflammatory cytokines often IL-6, CRP, and ferritin.…”

Section: Discussionmentioning

confidence: 99%

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk

Brosnahan

Chen²,

Chung³

et al. 2021

Ann Pharmacother

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Background Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven. Objectives The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure. Methods A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit. Results The steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), P = 0.005] without increasing the risk of infection. Conclusion and Relevance Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.

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Section: Discussionmentioning

confidence: 99%

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk

Brosnahan

Chen²,

Chung³

et al. 2021

Ann Pharmacother

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“…We cannot yet explain differences between the human syndrome and phenotypes seen in animal models. Nonetheless, patients with AOSD have been treated with non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, methotrexate and cyclosporine, and more recently with anti-IL-1 receptor or anti-IL-6 receptor antibodies 33 , 59 ; however, consistent strategies useful to treat AOSD are not yet established. Our study provides valuable information relevant to possible therapeutic options for auto-inflammatory syndromes.…”

Section: Discussionmentioning

confidence: 99%

IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse

Oike

Kanagawa

Sato

et al. 2018

Sci Rep

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Auto-inflammatory syndrome, a condition clinically distinct from rheumatoid arthritis, is characterized by systemic inflammation in tissues such as major joints, skin, and internal organs. Autonomous innate-immune activation is thought to promote this inflammation, but underlying pathological mechanisms have not been clarified nor are treatment strategies established. Here, we newly established a mouse model in which IL-1 signaling is conditionally activated in adult mice (hIL-1 cTg) and observed phenotypes similar to those seen in auto-inflammatory syndrome patients. In serum of hIL-1 cTg mice, IL-6 and IL-17 levels significantly increased, and signal transducer and activator of transcription 3 (Stat3) was activated in joints. When we crossed hIL-1 cTg with either IL-6- or IL-17-deficient mice or with Stat3 conditional knockout mice, phenotypes seen in hIL-1 cTg mice were significantly ameliorated. Thus, IL-6, IL-17 and Stat3 all represent potential therapeutic targets for this syndrome.

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“…AOSD is a rare systemic inflammatory disorder with unknown pathogenesis. [ 6 ] Traditional treatments for AOSD include nonsteroid anti-inflammatory drugs (NSAIDs) and steroids. Patients treated with steroid doses of 0.8 to 1 mg/kg/day achieve faster remissions and have fewer relapses than those who receive lower doses of steroids.…”

Section: Discussionmentioning

confidence: 99%

Acute appendicitis complicated with necrotizing fasciitis in a patient with adult-onset Still's disease

Huang

Chiu

Ho³

et al. 2018

Medicine

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Rationale:Adult-onset Still disease (AOSD) is a rare systemic inflammatory disease of unknown etiology characterized by evanescent salmon-pink rash, spiking fever, arthralgia/ arthritis, and lymphadenopathy. AOSD sometimes was fatal when it is complicated by macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH). Nonetheless, the literature provides no recommendations for treatment of AOSD patients with severe sepsis.Patient concerns:A previously healthy 65-year-old man with history of AOSD was referred to our hospital for persistent right lower quadrant abdominal pain for 2 days. One week later, an abdominal wall abscess and hematoma developed by extravasation from the inferior epigastric vessels, complicated by necrotizing fasciitis of the right thigh and groin region. To our best knowledge, this case was the first reported case of a perforated appendix complicated with necrotizing fasciitis in a patient with AOSD.Diagnoses:The patient was diagnosed as acute appendicitis complicated with necrotizing fasciitis and abdominal wall abscess.Interventions:This case received intravenous tigecycline injection and daily 10 mg prednisolone initially, and shifted to daily intravenous hydrocortisone 200 mg for suspected MAS or HLH. This patient underwent surgical intervention and debridement for necrotizing fasciitis.Outcomes:The patient's symptoms progressed worse rapidly. He died from cytomegalovirus viremia and bacterial necrotizing fasciitis complicated by septic shock.Lessons:(1) The steroid dose was difficult to titrate when AOSD complicated by sepsis. The differential diagnosis from MAS/HLH with bacterial/viral infection related severe sepsis was difficult but critical for decision making from clinicians and rheumatologists. (2) The conservative treatment with antibiotics for perforated appendix is safe but has a higher failure rate in immunocomprised patients such as systemic lupus erythematosus and AOSD. Early surgical intervention might contribute to better outcome. (3) The abdominal wall abscess can be spread from intra-abdominal lesion through the inferior epigastric vessels which were as weak points of abdominal wall. Imaging examinations contribute to acute diagnosis and help surgeons perform surgical interventions to prevent morbidity and mortality.

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Tocilizumab for uncontrollable systemic inflammatory response syndrome complicating adult-onset Still disease

Cited by 14 publications

References 36 publications

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk

IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse

Acute appendicitis complicated with necrotizing fasciitis in a patient with adult-onset Still's disease

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