Interferon Inhibition for Lupus with Anifrolumab: Critical Appraisal of the Evidence Leading to FDA Approval.

JOURNAL CLUB: Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol 2017;69:376-86. Objective To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate-to-severe systemic lupus erythematosus (SLE). Methods Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4-gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI [4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI [4], British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA], modified SRI [6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent-to-treat (ITT) population and type I IFN-high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2-sided), within each of the 2 study populations for the primary end point analysis. Results The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo-treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ-specific end points. Herpes zoster was more frequent in the anifrolumab-treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively). Conclusion Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate-to-severe SLE. https://onlinelibrary.wiley.com/doi/10.1002/art.39962 Furie RA, Morand EF, Bruce IN, Manzi S, Kalunian KC, Vital EM, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol 2019;1:E208-19. Background Type I interferons are involved in systemic lupus erythematosus (SLE) pathogenesis. In a phase 2 trial, anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1, suppressed interferon gene signatures and substantially reduced SLE disease activity. Here, we sought to confirm the efficacy of anifrolumab versus placebo in a phase 3 trial of adult patients with SLE and moderate-to-severe disease activity despite standard-of-care treatment. Methods TULIP-1 was a double-blind, randomised, controlled, phase 3 trial done at 123 sites in 18 countries. Included patients were aged 18-70 years, with moderate-to-severe SLE, and ongoing stable treatment with either prednisone or equivalent, an antimalarial, azathioprine, mizoribine, mycophenolate mofetil or mycophenolic acid, or methotrexate. Patients were randomly assigned (2:1:2) to receive placebo, anifrolumab 150 mg, or anifrolumab 300 mg intravenously every 4 weeks for 48 weeks. Stable standard-of-care treatment continued except for mandatory attempts at oral corticosteroid tapering for patients receiving prednisone or equivalent of 10 mg/day or more at baseline. The primary outcome was the difference between the proportion of patients who achieved an SLE responder index-4 (SRI-4) response at week 52 with anifrolumab 300 mg versus with placebo. Key secondary outcomes were the difference between the anifrolumab 300 mg group and the placebo group in: proportion of patients in the interferon gene signature test-high subgroup who achieved SRI-4 at week 52; proportion of patients on 10 mg/day or more corticosteroids at baseline who achieved a sustained dose reduction to 7·5 mg/day or less from week 40 to 52; proportion of patients with a cutaneous lupus erythematosus disease area and severity index (CLASI) activity score of 10 or higher at baseline who achieved a 50% or more reduction in CLASI score by week 12; proportion of patients who achieved SRI-4 at week 24; and annualised flare rate through week 52. Other measures of disease activity were also assessed at week 52, including the British Isles Lupus Assessment Group-based composite lupus assessment (BICLA). Safety was also assessed. Efficacy and safety analyses were done in the population of patients who received at least one dose of study drug. This trial was registered at ClinicalTrials.gov (NCT02446912). Findings Between June 9, 2015, and June 16, 2017, 457 patients were randomly assigned to the anifrolumab 300 mg group (n = 180), the anifrolumab 150 mg group (n = 93), or the placebo group (n = 184). The proportion of patients at week 52 with an SRI-4 response was similar between anifrolumab 300 mg (65 [36%] of 180) and placebo (74 [40%] of 184; difference - 4·2 [95% CI -14·2 to 5·8], p = 0·41). Similarly, proportions of patients with an SRI-4 response at week 24, and at week 52 in patients in the interferon gene signature test-high subgroup, did not differ between the anifrolumab and placebo groups. In patients with baseline oral corticosteroids of at least 10 mg/day, sustained dose reduction to 7·5 mg/day or less was achieved by 42 (41%) of 103 patients in the anifrolumab 300 mg group and 33 (32%) of 102 patients in the placebo group (difference 8·9 [95% CI -4·1 to 21·9]). In patients with CLASI activity score of at least 10 at baseline, at least 50% reduction by week 12 was achieved by 24 (42%) of 58 patients in the anifrolumab 300 mg group and 14 (25%) of 54 in the placebo group (difference 17·0 [95% CI -0·3 to 34·3]). Annualised flare rates were 0·60 for anifrolumab and 0·72 for placebo (rate ratio 0·83 [95% CI 0·60 to 1·14]). BICLA response was achieved by 67 (37%) of 180 patients receiving anifrolumab 300 mg versus 49 (27%) of 184 receiving placebo (difference 10·1 [95% CI 0·6 to 19·7]). Anifrolumab's safety profile was similar to that observed in phase 2, with similar proportions of patients having a serious adverse event between groups (25 [14%] of 180 for anifrolumab 300 mg, ten [11%] of 93 for anifrolumab 150 mg, and 30 [16%] of 184 for placebo). Interpretation The primary endpoint was not reached. However, several secondary endpoints, including reduction in oral corticosteroid dose, CLASI responses, and BICLA responses, suggest clinical benefit of anifrolumab compared with placebo. Conclusive evidence for the efficacy of anifrolumab awaits further phase 3 trial data. Despite the inherent limitations of a 1-year phase 3 study, such as incomplete knowledge of applicability to the general population and scarce detection of rare safety signals, in addition to complications from prespecified restricted medication rules, our results suggest that anifrolumab might have the potential to provide a treatment option for patients who have active SLE while receiving standard therapy. Funding AstraZeneca. https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(19)30076-1/fulltext Morand EF, Furie R, Tanaka Y, Bruce IN, Askanase AD, Richez C, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med 2020;382:211-21. Background Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point. Methods We randomly assigned patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) or placebo every 4 weeks for 48 weeks. The primary end point of this trial was a response at week 52 defined with the use of the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). A BICLA response requires reduction in any moderate-to-severe baseline disease activity and no worsening in any of nine organ systems in the BILAG index, no worsening on the Systemic Lupus Erythematosus Disease Activity Index, no increase of 0.3 points or more in the score on the Physician Global Assessment of disease activity (on a scale from 0 [no disease activity] to 3 [severe disease]), no discontinuation of the trial intervention, and no use of medications restricted by the protocol. Secondary end points included a BICLA response in patients with a high interferon gene signature at baseline; reductionsin the glucocorticoid dose, in the severity of skin disease, and in counts of swollen and tender joints; and the annualized flare rate. Results A total of 362 patients received the randomized intervention: 180 received anifrolumab and 182 received placebo. The percentage of patients who had a BICLA response was 47.8% in the anifrolumab group and 31.5% in the placebo group (difference, 16.3 percentage points; 95% confidence interval, 6.3 to 26.3; P = 0.001). Among patients with a high interferon gene signature, the percentage with a response was 48.0% in the anifrolumab group and 30.7% in the placebo group; among patients with a low interferon gene signature, the percentage was 46.7% and 35.5%, respectively. Secondary end points with respect to the glucocorticoid dose and the severity of skin disease, but not counts of swollen and tender joints and the annualized flare rate, also showed a significant benefit with anifrolumab. Herpes zoster and bronchitis occurred in 7.2% and 12.2% of the patients, respectively, who received anifrolumab. There was one death from pneumonia in the anifrolumab group. Conclusions Monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT02446899.) https://www.nejm.org/doi/full/10.1056/nejmoa1912196.

Interstitial Lung Disease and Myositis in a Patient With Antisynthetase Syndrome and PL12 and Ro52 Co-positivity in a Retired Medical Officer.

Antisynthetase syndrome (ASS) is an idiopathic inflammatory myopathy characterized by myositis, arthritis, interstitial lung disease (ILD), Raynaud's phenomenon, and distinctive cutaneous manifestations. Anti-PL12 is a rare myositis-specific autoantibody classically associated with an amyopathic presentation and rapidly progressive ILD. Anti-Ro52 is a myositis-associated antibody that has been postulated to be directly pathogenic in inflammatory myopathy patients. The disease phenotype, course, and response to treatment associated with anti-PL12 and anti-Ro52 co-positivity is not well described.A 58-year-old man with anti-PL12 and anti-Ro52 ASS presented with rapidly progressive ILD and myositis refractory to high-dose prednisone. He ultimately required a dexamethasone burst with intravenous immunoglobulin and mycophenolate mofetil for disease control.Severe and rapidly progressive myositis is infrequently reported in anti-PL12 ASS. This case suggests that concurrent anti-Ro52 positivity predicts a more aggressive disease phenotype and may require more initial immunosuppression. If rapid progression of this disease were to occur in an active duty service member, it would have significant implications for readiness and potentially catastrophic outcomes in the deployed setting. Early identification and treatment of the disease are imperative. The question must also be raised of an occupational exposure from military service.

Adult-Onset Still's Disease: Is This Truly a Diagnosis of Exclusion?

Adult-onset Still's Disease is a rare, idiopathic, inflammatory disorder characterized by arthralgia, evanescent, salmon-colored rash, and daily fevers as well as lymphadenopathy, pharyngitis, splenomegaly, myalgias, and serositis. The inciting etiology of this syndrome is unknown, though it has been hypothesized that infection triggers an autoimmune response. The Yamaguchi Criteria, the most sensitive and widely used diagnostic criteria, requires both a minimum set of criteria to be met as well other potential etiologies to be excluded. By definition, evidence of concomitant infection, malignancy, vasculitis, or connective tissue disease precludes the diagnosis of Adult-onset Still's Disease from being made. We present a very rare case of a patient who met all diagnostic criteria for Adult-onset Still's Disease, had a protracted course refractory to numerous immunosuppressant treatments, and also had evidence of coxsackie B infection with fourfold rise in viral titers on two occasions (both associated with disease flare). Although coxsackie B virus has been linked to Adult-onset Still's Disease at disease presentation, this case is unique in its protracted course and serological evidence of infection temporally related to disease flare. While accepted diagnostic criteria call for this disease to be a diagnosis of exclusion, our case supports the fact that ongoing infection may in fact be an important antigenic driver in persistent and refractory Adult-onset Still's Disease.

Vancomycin vs. Vancomycin/Piperacillin-Tazobactam-Associated Acute Kidney Injury in Noncritically Ill Patients at a Tertiary Care Military Treatment Facility.

BACKGROUND: Broad-spectrum antibiotics are often used as initial empiric therapy in patients at risk for infections by multidrug-resistant organisms. Emerging literature and anecdotal reports within Tripler Army Medical Center indicate an increased incidence of vancomycin-associated acute kidney injury when used in combination with piperacillin-tazobactam. This is a retrospective, single-center study comparing the incidence of acute kidney injury in noncritically ill patients receiving either vancomycin or vancomycin in combination with piperacillin-tazobactam in a 206-bed tertiary care military training facility. METHODS: Data were collected from electronic medical records between May 2012 and October 2014 and evaluated via multivariable logistic regression models. Patients included for analysis were 17 years of age and older, were admitted to medical/surgical wards, and received vancomycin or vancomycin in combination with piperacillin-tazobactam for at least 48 hours. A vancomycin trough level, baseline serum creatinine level, and at least two follow-up serum creatinine levels were required for inclusion. Patients were excluded if they were pregnant, admitted to an intensive care unit while on antimicrobial therapy, or their baseline serum creatinine was equal to or greater than 1.5 mg/dL. RESULTS: Of 1,133 patients evaluated retrospectively, 455 were included for analysis. Of 202 patients, 49 (24%) taking vancomycin in combination with piperacillin-tazobactam developed acute kidney injury in contrast to 28 of the 253 patients (11%) given vancomycin without piperacillin-tazobactam (unadjusted odds ratio 2.57 [95% confidence interval (CI) 1.55-4.28], p < 0.001). Dual therapy remained significant after adjusting for age, sex, body mass index, concomitant nephrotoxic agents, and preexisting comorbid status as evaluated by Charlson comorbidity index (adjusted odds ratio 2.14 [95% CI 1.26-3.6], p = 0.005). Contrast administration (p < 0.001), fluoroquinolone administration (p < 0.001), and Charlson Comorbidity Index > 6 (p = 0.008) were also found to be independent risk factors for acute kidney injury. CONCLUSION: Significant increased incidence of nephrotoxicity was noted with vancomycin and piperacillin-tazobactam as compared to vancomycin within Tripler Army Medical Center. This finding influenced our institution's decision to add ceftaroline as a formulary agent in the treatment of skin and soft-tissue infections and further supported the need for rapid de-escalation of antibiotics within our military training facility.