Single dose tocilizumab for COVID-19 associated cytokine storm syndrome: Less is more.

AIMS: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). METHODS: MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 µg/L or D-dimers >1500 µg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration-time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. RESULTS: In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 µg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. CONCLUSIONS: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.

Unusually Rapid Development of Pulmonary Hypertension and Right Ventricular Failure after COVID-19 Pneumonia.

COVID-19 is a novel viral disease caused by SARS-CoV-2. The mid- and long-term outcomes have not yet been determined. COVID-19 infection is increasingly being associated with systemic and multi-organ involvement, encompassing cytokine release syndrome and thromboembolic, vascular and cardiac events. The patient described experienced unusually rapid development of pulmonary hypertension (PH) and right ventricular failure after recent severe COVID-19 pneumonia with cytokine release syndrome, which initially was successfully treated with methylprednisolone and tocilizumab. The development of pulmonary hypertension and right ventricular failure - in the absence of emboli on multiple CT angiograms - was most likely caused by progressive pulmonary parenchymal abnormalities combined with microvascular damage of the pulmonary arteries (group III and IV pulmonary hypertension, respectively). To the best of our knowledge, these complications have not previously been described and therefore awareness of PH as a complication of COVID-19 is warranted. LEARNING POINTS: COVID-19 increasingly presents with systemic and multi-organ involvement with vascular, thromboembolic and cardiac events.Patients with severe COVID-19 pneumonia and concomitant cytokine release syndrome may be particularly at risk for the development of secondary pulmonary hypertension and right ventricular failure.Pulmonary hypertension can develop unusually rapidly following COVID-19 pneumonia and probably results from progressive pulmonary interstitial and microvascular abnormalities due to COVID-19.

Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study.

OBJECTIVES: To prospectively investigate in patients with severe COVID-19-associated cytokine storm syndrome (CSS) whether an intensive course of glucocorticoids with or without tocilizumab accelerates clinical improvement, reduces mortality and prevents invasive mechanical ventilation, in comparison with a historic control group of patients who received supportive care only. METHODS: From 1 April 2020, patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two out of three biomarkers with important elevations (C-reactive protein >100 mg/L; ferritin >900 µg/L; D-dimer >1500 µg/L), received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2-5). If the respiratory condition had not improved sufficiently (in 43%), the interleukin-6 receptor blocker tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Control patients with COVID-19-associated CSS (same definition) were retrospectively sampled from the pool of patients (n=350) admitted between 7 March and 31 March, and matched one to one to treated patients on sex and age. The primary outcome was ≥2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital. Secondary outcomes were hospital mortality and mechanical ventilation. RESULTS: At baseline all patients with COVID-19 in the treatment group (n=86) and control group (n=86) had symptoms of CSS and faced acute respiratory failure. Treated patients had 79% higher likelihood on reaching the primary outcome (HR: 1.8; 95% CI 1.2 to 2.7) (7 days earlier), 65% less mortality (HR: 0.35; 95% CI 0.19 to 0.65) and 71% less invasive mechanical ventilation (HR: 0.29; 95% CI 0.14 to 0.65). Treatment effects remained constant in confounding and sensitivity analyses. CONCLUSIONS: A strategy involving a course of high-dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated CSS.

Validation of two frailty questionnaires in older patients with rheumatoid arthritis: a cross-sectional study.

OBJECTIVES: Several questionnaires exist to assess frailty, a geriatric syndrome. None of these has been validated in older patients with rheumatoid arthritis (RA). Our objective was to assess aspects of validity of two frailty questionnaires: Groningen Frailty Indicator (GFI) and Geriatric 8 (G8) among RA patients. METHODS: In a cross-sectional study among patients ≥65 years information was collected on socio-demographics, disease characteristics including comorbidities and physical function and on frailty using the GFI and G8. Content validity was assessed by linking items of the GFI and G8 to the International Classification of Functioning, Disability and Health (ICF). Classic psychometric methods were used to test hypotheses on construct validity and interpretability. RESULTS: Eighty patients (74.6 years (SD 5.9); 66% female) participated. The GFI has more items on social and mental functions; the G8 more on functions of the digestive system (e.g. nutritional status). As hypothesised, correlations (r) with physical function (RGFI=0.54; RG8=0.56) and disease activity (RGFI=0.24; RG8=0.36) were moderate to weak. However, correlations with age (RGFI=0.20; RG8=0.11) or comorbidities (RGFI=0.30; RG8=0.16) were lower than expected. Instrument-specific thresholds classified 43 (54%) of participants as frail on the GFI and 44 (55%) on the G8; 33 (41%) were frail on both instruments. CONCLUSIONS: The GFI and G8 differ in content with more emphasis on nutritional status for the G8. Both instruments are insensitive to age and comorbidities. Before deciding on their usefulness in RA, their predictive validity for mortality and resource utilisation independent of disease activity and physical function should be further evaluated.

Cotreatment with methotrexate in routine care patients with rheumatoid arthritis receiving biological treatment yields better outcomes over time.

Objectives: We aimed to evaluate the effects of methotrexate (MTX) comedication added to biological disease-modifying antirheumatic drugs (bDMARD) on disease activity measures in patients with rheumatoid arthritis (RA) in routine care. Methods: Patients with RA on treatment with either bDMARDs or conventional synthetic DMARDs were included in this prospective cohort study. The effect of (time-varying) combination therapy with bDMARD and MTX compared with bDMARD monotherapy was tested in longitudinal generalised estimating equation models using as outcomes: (1) the likelihood to be in remission according to the 28-joint Disease Activity Score (DAS28) erythrocyte sedimentation rate (ESR) (<2.6) and to the Routine Assessment of Patient Index Data 3 (RAPID3) (0-30; ≤3), a patient-reported outcome measure about RA symptoms; and (2) DAS28-ESR and RAPID3 as continuous variables. All models were adjusted for potential confounders: age, gender, drugs for comorbidities (yes/no), oral steroids (yes/no) and non-steroidal anti-inflammatory drug (yes/no). Results: In total, 330 patients were included (mean (SD) follow-up; 10.7 (9.7) months). Compared with bDMARD monotherapy, MTX combination therapy was significantly associated with a 55% higher likelihood to be in DAS28 remission, but not RAPID3 remission, over time. Combination therapy resulted in slightly, but statistically significant, lower levels of DAS28-ESR over time (ß=-0.42 (95% CI -0.67 to - 0.17)), but not RAPID3 (ß=-0.58 (95% CI -0.65 to 0.49)). The effect on DAS28-ESR was entirely explained by lower swollen joint counts and was persistent after correction for confounders. Conclusion: These results give support to the policy that MTX should be continued in routine care patients with RA on biological therapy since this leads to better objective but not subjective clinical outcomes.

Routine Assessment of Patient Index Data 3 (RAPID3) alone is insufficient to monitor disease activity in rheumatoid arthritis in clinical practice.

Objective: To test the longitudinal association between patient-reported outcome, Routine Assessment of Patient Index Data 3 (RAPID3) and the Disease Activity Score in 28 joints that includes the erythrocyte sedimentation rate (DAS28-ESR) in routine-care patients with rheumatoid arthritis (RA). Methods: Patients with RA treated with disease-modifying antirheumatic drugs were included in this prospective observational cohort. The longitudinal association between RAPID3 (0-10) and DAS28-ESR and its individual components (swollen joint count (SJC), erythrocyte sedimentation rate (ESR) (mm/hour), tender joint count (TJC) and patient global assessment (PGA)) was tested using generalised estimating equations in patients with more than two consecutive visits with data on RAPID3 and DAS28-ESR. Interactions between RAPID3 and gender, pain, PGA and age at baseline were tested, and if significant (p<0.20) and clinically relevant, models were fit in the corresponding strata. Results: In total, 330 patients were included (mean follow-up 10.7 (SD 9.7) months, female gender 67.9%). The longitudinal association between RAPID3 and DAS28-ESR was weak (ß=0.29 (95% CI 0.24 to 0.35), n=207), meaning that one unit increase in RAPID3 corresponded to a 0.29 unit increase in Disease Activity Score in 28 joints (DAS28). RAPID3 was most strongly associated with subjective (TJC: ß=0.89 (95% CI 0.61 to 1.17); PGA: ß=0.94 (95% CI 0.84 to 1.04)) and not with objective components of DAS28 (SJC: ß=0.29 (95% CI 0.17 to 0.41), n=172). The association between RAPID3 and ESR was poor but modified by gender, being only significant in men (ß=0.37 (95% CI 0.08 to 0.67)). Conclusions: These data suggest that RAPID3 does not sufficiently capture changes in objective inflammatory signs. Monitoring by RAPID3 alone is therefore insufficient to follow disease activity in patients wth RA in clinical practice.

Disease and management beliefs of elderly patients with rheumatoid arthritis and comorbidity: a qualitative study.

To explore in elderly patients with rheumatoid arthritis (RA) and comorbidity (1) in which order and why patients prioritize their morbidities with regard to functioning and health, (2) their beliefs about common (age-related) musculoskeletal complaints, and (3) experiences about the influence of comorbidity on medication treatment of RA. Patients between 50 and 85 years with RA and ≥ 1 comorbidity or lifestyle risk factor were invited for a semi-structured interview. Two readers coded the transcripts of the interviews, by using NVivo11 software. Fifteen patients (14 women; mean age 67 years (range 51-83 years); mean disease duration 14 years (range 1-39 years)) were interviewed. Only 3 (20%) out of 15 patients prioritized RA over their comorbidity; these patients often experienced severe functional limitations. The level of current or (perceived) future disability, risk of dependency, and the perceived lethality of a condition were considered by participants when prioritizing morbidities. Most participants had misconceptions about common age-related musculoskeletal complaints. Consequently, these participants attributed all joint complaints or even all physical complaints to RA, disregarding degenerative joint disease and physiological aging as alternative diagnoses. Half of the participants ever had to change RA medication because of comorbidity. Most of these patients had prioritized the comorbidity, sometimes even over treatment of RA disease activity. Most elderly RA patients with comorbidity prioritize the importance and treatment of comorbidity over RA. Better understanding of patients' beliefs on RA and comorbidity is essential when managing chronic conditions in elderly patients.

Rheumatologists' Views and Experiences in Managing Rheumatoid Arthritis in Elderly Patients: A Qualitative Study.

OBJECTIVE: In this qualitative study we analyzed the (1) influence of age, comorbidity, and frailty on management goals in elderly patients with RA; (2) experiences of rheumatologists regarding the use of the Disease Activity Score at 28 joints (DAS28) to monitor disease activity; and (3) differences in management strategies in elderly patients with RA compared to their younger counterparts. METHODS: Rheumatologists were purposively sampled for a semistructured interview. Two readers independently read and coded the interview transcripts. Important concepts were taxonomically categorized and combined in overarching themes by using NVivo 11 software. RESULTS: Seventeen rheumatologists (mean age 44.8 yrs, SD 7.7 yrs; 29% male) from 9 medical centers were interviewed. Preserving an acceptable level of functioning was the most important management goal in patients ≥ 80 years and in patients with high levels of comorbidity and frailty. The DAS28 score less frequently steered the management strategy, because rheumatologists commented that comorbidity and an age-related erythrocyte sedimentation rate elevation might distort the DAS28 score. Instead, management of elderly patients highly depended on comorbidity, frailty, and their subsequent effects such as cognitive and physical decline, dependency, and polypharmacy. Presence of 1 or more of these factors frequently resulted in a less future-oriented management approach with less emphasis on the maximal prevention of joint erosions. CONCLUSION: The treat-to-target model is not automatically adopted in the elderly patient population. Future evidence-based RA management recommendations for elderly patients with RA are needed and should account for factors such as comorbidity and frailty.

[Anakinra in refractory adult onset Still's disease]. / Anakinra bij moeilijk behandelbare ziekte van Still.

BACKGROUND: Adult onset Still's disease (AOSD) is a rare--but potentially dangerous and difficult to treat--generalized auto-inflammatory disease which shares some similarities with the systemic form of juvenile idiopathic arthritis (SoJIA or Still's disease). CASE DESCRIPTION: AOSD was diagnosed in 2 young adult women of 21 and 23 years old. The disease was found to be resistant to treatment in these patients. The patients were treated successively with NSAIDs, glucocorticoids, methotrexate and anti tumour necrosis factor(TNF)-α antagonists, with only partial effects or none at all. Treatment with the interleukin-1 receptor antagonist anakinra was subsequently started, which led to remission of AOSD. CONCLUSION: These cases illustrate the clinical spectrum of AOSD and the possibility of an important addition to the therapeutic arsenal for treatment of refractory AOSD.