CONCLUSIONS: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
OBJECTIVE: Introduction of new medications to health-system formularies is often not accompanied by assessments of their clinical impact on the local patient population. The growing availability of electronic health record (EHR) data and advancements in pharmacoepidemiology methods offer institutions the opportunity to monitor the medication implementation process and assess clinical effectiveness in the local clinical context. In this study, we applied novel causal inference methods to evaluate the effects of a formulary policy introducing tocilizumab therapy for critically ill patients with coronavirus disease 2019 (COVID-19).
METHODS: We conducted a medication use evaluation utilizing EHR data from patients admitted to a large medical center during the 6 months before and after implementation of a formulary policy endorsing the use of tocilizumab for treatment of COVID-19. The impact of tocilizumab on 28-day all-cause mortality was assessed using a difference-in-differences analysis, with ineligible patients serving as a nonequivalent control group, and a matched analysis guided by a target trial emulation framework. Safety endpoints assessed included the incidence of secondary infections and liver enzyme elevations. Our findings were benchmarked against clinical trials, an observational study, and a meta-analysis.
RESULTS: Following guideline modification, tocilizumab was administered to 69% of eligible patients. This implementation was associated with a 3.1% absolute risk reduction in 28-day mortality (odds ratio, 0.86; number needed to treat to prevent one death, 32) attributable to the inclusion of tocilizumab in the guidelines and an additional 8.6% absolute risk reduction (odds ratio, 0.65; number needed to treat to prevent one death, 12) linked to its administration. These findings were consistent with estimates from published literature, although the effect estimates from the difference-in-differences analysis exhibited imprecision.
CONCLUSIONS: Evaluating formulary management decisions through novel causal inference approaches offers valuable estimates of clinical effectiveness and the potential to optimize the impact of new medications on population outcomes.

Adult-onset Still\'s disease (AOSD) is a rare autoinflammatory disease characterized by intermittent fever and a combination of symptoms, such as an evanescent rash synchronous with fever, arthralgia/arthritis, lymphadenopathy and hepatosplenomegaly. The diagnosis is based on a characteristic constellation of symptoms and the exclusion of infections, hemato-oncological diseases, infectious diseases and alternative rheumatological causes. The systemic inflammatory reaction is reflected by high levels of ferritin and C‑reactive protein (CRP). The pharmacological treatment concept includes glucocorticoids often in combination with methotrexate (MTX) and ciclosporine (CSA) for reduction of steroids. The interleukin 1 (IL-1) receptor antagonist anakinra, the IL-1beta antibody canakinumab or an IL‑6 receptor blockage with tocilizumab (off label for AOSD) are used where there is no response to MTX or CSA. Anakinra or canakinumab can be used as a primary option in AOSD in cases of moderate and severe disease activity.
UNASSIGNED: Das adulte Still-Syndrom (engl. „adult-onset Still’s disease“ [AOSD]) ist eine seltene, autoinflammatorische Erkrankung, die durch intermittierendes Fieber und eine Kombination aus Symptomen wie flüchtigem, fiebersynchronem Exanthem, Arthralgien/Arthritis, Lymphadenopathie, Hepatosplenomegalie u. a. charakterisiert ist. Die Diagnose stützt sich auf eine charakteristische Symptomkonstellation und den Ausschluss von Infektionen, hämatoonkologischen Erkrankungen, Infektionserkrankungen und alternativen rheumatologischen Ursachen. Hohe Ferritin- und C‑reaktives Protein-Werte spiegeln die systemische Entzündungsreaktion wider. Therapeutisch werden Glukokortikoide oft in Kombination mit Methotrexat (MTX) oder Ciclosporin (CSA) zu Steroidreduktion eingesetzt. Der IL(Interleukin)-1-Rezeptorantagonist Anakinra, der IL-1β-Antikörper Canakinumab oder eine IL-6-Rezptorblockade mit Tocilizumab (bei AOSD „off label“) werden bei fehlendem Ansprechen auf MTX oder CSA eingesetzt. Anakinra oder Canakinumab können bei moderater und hoher Krankheitsaktivität auch primär eingesetzt.

Adult-onset Still\'s disease (AOSD) is a rare autoinflammatory disease characterized by intermittent fever and a combination of symptoms, such as an evanescent rash synchronous with fever, arthralgia/arthritis, lymphadenopathy and hepatosplenomegaly. The diagnosis is based on a characteristic constellation of symptoms and the exclusion of infections, hemato-oncological diseases, infectious diseases and alternative rheumatological causes. The systemic inflammatory reaction is reflected by high levels of ferritin and C‑reactive protein (CRP). The pharmacological treatment concept includes glucocorticoids often in combination with methotrexate (MTX) and ciclosporine (CSA) for reduction of steroids. The interleukin 1 (IL-1) receptor antagonist anakinra, the IL-1beta antibody canakinumab or an IL‑6 receptor blockage with tocilizumab (off label for AOSD) are used where there is no response to MTX or CSA. Anakinra or canakinumab can be used as a primary option in AOSD in cases of moderate and severe disease activity.
UNASSIGNED: Das adulte Still-Syndrom (engl. „adult-onset Still’s disease“ [AOSD]) ist eine seltene, autoinflammatorische Erkrankung, die durch intermittierendes Fieber und eine Kombination aus Symptomen wie flüchtigem, fiebersynchronem Exanthem, Arthralgien/Arthritis, Lymphadenopathie, Hepatosplenomegalie u. a. charakterisiert ist. Die Diagnose stützt sich auf eine charakteristische Symptomkonstellation und den Ausschluss von Infektionen, hämatoonkologischen Erkrankungen, Infektionserkrankungen und alternativen rheumatologischen Ursachen. Hohe Ferritin- und C‑reaktives Protein-Werte spiegeln die systemische Entzündungsreaktion wider. Therapeutisch werden Glukokortikoide oft in Kombination mit Methotrexat (MTX) oder Ciclosporin (CSA) zu Steroidreduktion eingesetzt. Der IL(Interleukin)-1-Rezeptorantagonist Anakinra, der IL-1β-Antikörper Canakinumab oder eine IL-6-Rezptorblockade mit Tocilizumab (bei AOSD „off label“) werden bei fehlendem Ansprechen auf MTX oder CSA eingesetzt. Anakinra oder Canakinumab können bei moderater und hoher Krankheitsaktivität auch primär eingesetzt.

The use of chimeric antigen receptor T cells (CAR-T) has increased since their approval in the treatment of several relapsed/refractory B cell malignancies. The management of their specific toxicities, such as cytokine release syndrome (CRS), tends to be better understood and well-defined. During the twelfth edition of practice harmonization workshops of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), a working group focused its work on the management of patients developing CRS following CAR-T cell therapy. A special chapter has been allocated to macrophage activation syndrome (MAS), a rare but life-threatening complication post-CAR-T. In addition to symptomatic measures and preemptive broad-spectrum antibiotics, immunomodulators such as tocilizumab and corticosteroids remain the corner stone for the treatment of CRS. Tocilizumab/corticosteroids-resistant CRS associated with haemophagocytosis markers (spleen and liver enlargement, hyperferritinaemia>10,000ng/mL, hypofibrinogenemia…) should direct the diagnosis towards an overlapping CRS/MAS. An adapted treatment will be based on high-dose IV anakinra and corticosteroids and chemotherapy with etoposide at late refractory stages. These complications and others delignate the need of close collaboration with an intensive care unit.

In COVID-19, there are states of hyperinflammation in severely or critically ill people, where immunosuppression and blocking of IL-6 receptors could be beneficial. Faced with this situation, with the support of a methods group using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, about the use of tocilizumab for patients with severe and critical illness coronavirus. This guide focuses on making recommendations for the use of tocilizumab in patients with severe and critical COVID-19. This clinical practice guideline was prepared following the WHO guideline development methods. A multidisciplinary development group was formed, with clinical and health policy experts, methodologists and users. Panel and methods group members signed a declaration of conflict of interest. We searched the Epistemonikos Foundation\'s LOVE database for randomized studies up to April 17, 2021. The synthesis and evidence profiles were prepared using the GRADE approach and an economic model was developed. Among hospitalized adults with progressive severe or critical COVID-19, the guideline panel su ggests tocilizumab. (Conditional recommendation, Moderate certainty of evidence) Implementation considerations. A. Dose: 8 mg/kg of actual weight, single-dose, intravenously), maximum dose 800 mg; B. Administer dexamethasone 8 mg (or equivalent) for 10 days together with tocilizumab; C. The recommendation applies to: 1. patients with severe disease defined as SpO2 = 92% with room air and/or patients receiving supplemental oxygen (including a high-flow nasal cannula and non-invasive ventilation); 2. critically ill patients: requiring invasive mechanical ventilation.
En COVID-19, existen estados de hiperinflamación, donde la inmunosupresión y bloqueo de receptores de IL-6 podría ser beneficiosa. Se desarrolló una guía de práctica clínica con apoyo del grupo metodológico, utilizando el método GRADE (Grading of Recommendations Assessment, Development and Evaluation) acerca del uso de tocilizumab para pacientes con COVID-19 grave y crítica. Siguiendo métodos de elaboración de guías de la OMS, se conformó un grupo multidisciplinario compuesto por expertos temáticos clínicos y en políticas públicas, metodólogos y usuarios. Todos lo s participantes del panel y del grupo desarrollador firmaron una declaración de conflicto de interés. Se realizaron búsquedas de estudios aleatorizados hasta el 17 de abril de 2021, en la base de datos LOVE de la fundación Epistemonikos. Se elaboró la síntesis y los perfiles de evidencia utilizando el enfoque GRADE y se desarrolló un modelo para valorar el impacto presupuestario de la incorporación de tociliuzmab. Posteriormente, la recomendación fue graduada en un panel de expertos temáticos. Se sugiere utilizar tocilizumab en hospitalizados con COVID-19 grave y crítica. Recomendación condicional, certeza en la evidencia moderada. Consideraciones para la implementación. A. Dosis: 8 mg/kg de peso real, única dosis, por vía endovenosa, dosis máxima 800 mg; B. Administrar dexametasona 8 mg (o equivalente) por 10 días conjuntamente con tocilizumab; C. La recomendación aplica a: 1. pacientes con enfermedad grave definida como SpO2 = 92% con aire ambiente y/o pacientes que reciben oxígeno suplementario (incluyendo cánula nasal de alto flujo y ventilación no invasiva); 2. pacientes con enfermedad crítica (ventilación mecánica invasiva).

In SARS-CoV-2 infection (COVID-19), the most common manifestations involve the upper airways; in complicated cases, bilateral interstitial pneumonia, severe acute respiratory failure and multiple organ failure occur, which require hospital treatment and ventilatory support with nasal cannula or mask and high flow oxygen, or orotracheal intubation and mechanical ventilation. There are no specific antivirals, and thus management is symptomatic, as well as with antiplatelet drugs (acetylsalicylic acid, dipyridamole), low molecular weight heparin when there is hypercoagulability (increased D-dimer), dexamethasone when inflammation indicators are elevated; experimentally, under informed consent, antibiotics are used according to microbiological results, as well as interferon beta 1b, favipiravir, tocilizumab, ivermectin and immunoglobulin G. When gastroenteritis occurs, nitazoxanide can be indicated.
En infección por SARS-CoV-2 (COVID-19), las manifestaciones más comunes son las de vías aéreas superiores; en casos complicados se presenta neumonía intersticial bilateral, insuficiencia respiratoria aguda grave y falla orgánica múltiple que ameritan tratamiento hospitalario y soporte ventilatorio por puntas nasales o mascarilla, así como oxígeno con flujo a presión alta o intubación orotraqueal y ventilación mecánica. No hay antivirales específicos por lo que el manejo es sintomático, así como con antiplaquetarios (ácido acetilsalicílico, dipiridamol), heparina de bajo peso molecular ante hipercoagulabilidad (dímero D aumentado), dexametasona ante indicadores altos de inflamación. Previo consentimiento informado, experimentalmente se emplean antibióticos según los resultados microbiológicos, interferón beta 1b, favipiravir, tocilizumab, ivermectina e inmunoglobulina G. Cuando se presenta gastroenteritis se puede indicar nitazoxanida.

The healthcare sector has been overwhelmed by the global rise in the number of COVID-19 cases. The primary care physicians at the forefront of this pandemic are being provided with multiple guidelines (state, national, international). The aim of this review was to examine the existing guidelines for congruence and critically analyze them in light of current evidence. A discordance was noted between the national and state guidelines with respect to indication, duration and dosage of antivirals, steroids/immunomodulators, anticoagulation and convalescent plasma. The lack of concordance between various guidelines mandates the need for a unified national guideline that is regularly updated.

Systemic juvenile idiopathic arthritis is a rare febrile arthritis of childhood characterized by a potentially severe course, including prolonged glucocorticoid exposure, growth failure, destructive arthritis, and life-threatening macrophage activation syndrome. Early cytokine-blocking biologic therapy may improve long-term outcomes, although some systemic juvenile idiopathic arthritis patients respond well to non-biologic treatment, leaving optimal management undefined. Consequently, treatment of new-onset systemic juvenile idiopathic arthritis by expert clinicians varies widely.
To describe a pragmatic, observational comparative effectiveness study that takes advantage of diversity in the management of a rare disease: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST), comparing non-biologic and biologic consensus treatment plans for new-onset systemic juvenile idiopathic arthritis within the 60-center Childhood Arthritis and Rheumatology Research Alliance Registry (CARRA).
FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) is a multicenter, prospective, non-randomized study that compares four Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis: (1) glucocorticoids alone, (2) methotrexate, (3) interleukin-1 blockade, and (4) interleukin-6 blockade. Patients consenting to participation in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry are started on one of four Consensus Treatment Plans at the discretion of the treating physician. The outcome of primary interest is clinically inactive disease off glucocorticoids at 9 months, comparing non-biologic (Consensus Treatment Plans 1 + 2) versus biologic (Consensus Treatment Plans 3 + 4) strategies. Bayesian analytic methods will be employed to evaluate response rates, using propensity scoring to balance treatment groups for potential confounding. With 200 patients in a 2:1 ratio of biologic to non-biologic, there is a >90% probability of finding biologic consensus treatment plans more effective if the rate of clinically inactive disease is 30% higher than for non-biologic therapy. Additional outcomes include Patient-Reported Outcomes Measurement Information System measures and other parent-/patient-reported outcomes reported in real time using smartphone technology. Routine operation of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry will allow assessment of outcomes over at least 10 years.
FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) began enrollment in November 2016.
The observational design may not provide balance in measured and unmeasured confounders. Use of consensus treatment plan (CTP) strategies at frequencies more unbalanced than predicted could reduce the chance of finding differences in efficacy.
FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) will provide the first prospective comparison of Childhood Arthritis and Rheumatology Research Alliance\'s (CARRA\'s) consensus-derived non-biologic versus biologic management strategies in systemic juvenile idiopathic arthritis, performed in a real-world setting wherein each patient receives standard-of-care treatment selected by the treating physician. Outcomes include clinician- and patient-/family-reported outcomes, empowering both physician and patient decision making in new-onset systemic juvenile idiopathic arthritis.

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies.
OBJECTIVE: To review, from an Infectious Diseases perspective, the safety profile of agents targeting interleukins, immunoglobulins and complement factors and to suggest preventive recommendations.
METHODS: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family.
BACKGROUND: Patients receiving interleukin-1 (IL-1) -targeted (anakinra, canakinumab or rilonacept) or IL-5-targeted (mepolizumab) agents have a moderate risk of infection and no specific prevention strategies are recommended. The use of IL-6/IL-6 receptor-targeted agents (tocilizumab and siltuximab) is associated with a risk increase similar to that observed with anti-tumour necrosis factor-α agents. IL-12/23-targeted agents (ustekinumab) do not seem to pose a meaningful risk of infection, although screening for latent tuberculosis infection may be considered and antiviral prophylaxis should be given to hepatitis B surface antigen-positive patients. Therapy with IL-17-targeted agents (secukinumab, brodalumab and ixekizumab) may result in the development of mild-to-moderate mucocutaneous candidiasis. Pre-treatment screening for Strongyloides stercoralis and other geohelminths should be considered in patients who come from areas where these are endemic who are receiving IgE-targeted agents (omalizumab). C5-targeted agents (eculizumab) are associated with a markedly increased risk of infection due to encapsulated bacteria, particularly Neisseria spp. Meningococcal vaccination and chemoprophylaxis must be administered 2-4 weeks before initiating eculizumab. Patients with high-risk behaviours and their partners should also be screened for gonococcal infection.
CONCLUSIONS: Preventive strategies are particularly encouraged to minimize the occurrence of neisserial infection associated with eculizumab.

Giant cell arteritis and Takayasu arteritis are the two major forms of idiopathic large vessel vasculitis. High doses of glucocorticoids are effective in inducing remission in both conditions, but relapses and recurrences are common, requiring prolonged glucocorticoid treatment with the risk of the related adverse events. Areas covered: In this article, we will review the standard and biological treatment strategies in large vessel vasculitis, and we will focus on the current approaches to these diseases. Expert commentary: The results of treatment trials with conventional immunosuppressive agents such as methotrexate, azathioprine, mycophenolate mofetil, and cyclophosphamide have overall been disappointing. TNF-α blockers are ineffective in giant cell arteritis, while observational evidence and a phase 2 randomized trial support the use of tocilizumab in relapsing giant cell arteritis. Observational evidence strongly supports the use of anti-TNF-α agents and tocilizumab in Takayasu patients with relapsing disease. However biological agents are not curative, and relapses remain common.