Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. RESULTS: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. CONCLUSIONS: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).

Recommendations for early referral of individuals with suspected polymyalgia rheumatica: an initiative from the international giant cell arteritis and polymyalgia rheumatica study group.

OBJECTIVE: To develop international consensus-based recommendations for early referral of individuals with suspected polymyalgia rheumatica (PMR). METHODS: A task force including 29 rheumatologists/internists, 4 general practitioners, 4 patients and a healthcare professional emerged from the international giant cell arteritis and PMR study group. The task force supplied clinical questions, subsequently transformed into Population, Intervention, Comparator, Outcome format. A systematic literature review was conducted followed by online meetings to formulate and vote on final recommendations. Levels of evidence (LOE) (1-5 scale) and agreement (LOA) (0-10 scale) were evaluated. RESULTS: Two overarching principles and five recommendations were developed. LOE was 4-5 and LOA ranged between 8.5 and 9.7. The recommendations suggest that (1) each individual with suspected or recently diagnosed PMR should be considered for specialist evaluation, (2) before referring an individual with suspected PMR to specialist care, a thorough history and clinical examination should be performed and preferably complemented with urgent basic laboratory investigations, (3) individuals with suspected PMR with severe symptoms should be referred for specialist evaluation using rapid access strategies, (4) in individuals with suspected PMR who are referred via rapid access, the commencement of glucocorticoid therapy should be deferred until after specialist evaluation and (5) individuals diagnosed with PMR in specialist care with a good initial response to glucocorticoids and a low risk of glucocorticoid related adverse events can be managed in primary care. CONCLUSIONS: These are the first international recommendations for referral of individuals with suspected PMR, which complement the European Alliance of Associations for Rheumatology/American College of Rheumatology management guidelines for established PMR.

An international survey of current management practices for polymyalgia rheumatica by general practitioners and rheumatologists.

OBJECTIVES: To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment. METHODS: An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group. RESULTS: In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR >2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing >25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials. CONCLUSION: This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials.

Temporal Artery Ultrasound for the Diagnosis of Giant Cell Arteritis in the Emergency Department.

Giant cell arteritis (GCA), known as temporal arteritis, is a serious condition requiring immediate treatment to prevent complications. GCA can be difficult to diagnose, especially in emergency department (ED) settings where ophthalmology and rheumatology services may be unavailable. Temporal artery ultrasound (TAUS) is a valuable tool for diagnosing GCA. In the ED, TAUS can be used to quickly rule out GCA and avoid unindicated steroid treatment, which can cause serious morbidity in elderly patients. This article discusses the use of TAUS for evaluating patients with suspected GCA in the ED and its potential to expedite treatment and ensure appropriate, timely follow-up for patients with this potential vision and life-threatening condition.

Treatment for giant cell arteritis with 8 weeks of prednisone in combination with tocilizumab: a single-arm, open-label, proof-of-concept study.

BACKGROUND: Even after the approval of tocilizumab, substantial glucocorticoid exposure (usually ≥6 months) and toxicity continue to be important problems for patients with giant cell arteritis. We aimed to assess the outcomes of a group of patients with giant cell arteritis treated with tocilizumab in combination with 8 weeks of prednisone. METHODS: This prospective, single arm, proof-of-concept study was conducted at Massachusetts General Hospital (Boston, MA, USA). Individuals aged 50 years or older who had new-onset or relapsing giant cell arteritis with active disease were eligible for inclusion. Participants received 12 months of tocilizumab 162 mg weekly subcutaneously in combination with 8 weeks of prednisone. The primary endpoint was sustained prednisone-free remission at week 52. Adverse events were also evaluated. This trial is registered with ClinicalTrials.gov (NCT03726749), and is complete. FINDINGS: Between Nov 28, 2018, and Nov 2, 2020, we enrolled 30 patients (mean age 73·7 years [SD 8·1], 18 [60%] women and 12 [40%] men, 30 [100%] White race, 15 [50%] new-onset disease, 23 [77%] temporal artery biopsy-proven, 14 [47%] imaging-proven). The initial prednisone doses were 60 mg (n=7), 50 mg (n=1), 40 mg (n=7), 30 mg (n=6), and 20 mg (n=9). All patients entered remission within 4 weeks from baseline. 23 (77%) of 30 patients were in sustained prednisone-free remission at week 52 and seven (23%) patients relapsed, with a mean time to relapse of 15·8 weeks (SD 14·7). Overall, four (13%) participants developed a serious adverse event, including one related or probably related to prednisone exclusively, two related or probably related to tocilizumab exclusively, and one related or probably related to prednisone, tocilizumab, or both. Two of the non-responder patients stopped tocilizumab and withdrew from the study prematurely after having a second disease relapse. No cases of giant cell arteritis-related permanent vision loss occurred during the study. INTERPRETATION: These results suggest that 12 months of tocilizumab in combination with 8 weeks of prednisone could induce and maintain remission in patients with giant cell arteritis. Confirmation of these findings in a randomised controlled trial is required. FUNDING: Genentech.

Outcomes during and after long-term tocilizumab treatment in patients with giant cell arteritis.

OBJECTIVE: To assess outcomes in giant cell arteritis (GCA) patients during and after long-term tocilizumab (TCZ) treatment. METHODS: Retrospective analysis of GCA patients treated with TCZ at a single centre (2010-2022). Time to relapse and annualised relapse rate during and after TCZ treatment, prednisone use, and safety were assessed. Relapse was defined as reappearance of any GCA clinical manifestation that required treatment intensification, regardless of C reactive protein levels and erythrocyte sedimentation rate. RESULTS: Sixty-five GCA patients were followed for a mean (SD) of 3.1 (1.6) years. The mean duration of the initial TCZ course was 1.9 (1.1) years. The Kaplan-Meier (KM)-estimated relapse rate at 18 months on TCZ was 15.5%. The first TCZ course was discontinued due to satisfactory remission achievement in 45 (69.2%) patients and adverse events in 6 (9.2%) patients. KM-estimated relapse rate at 18 months after TCZ discontinuation was 47.3%. Compared with patients stopping TCZ at or before 12 months of treatment, the multivariable adjusted HR (95% CI) for relapse in patients on TCZ beyond 12 months was 0.01 (0.00 to 0.28; p=0.005). Thirteen patients received >1 TCZ course. Multivariable adjusted annualised relapse rates (95% CI) in all periods on and off TCZ aggregated were 0.1 (0.1 to 0.2) and 0.4 (0.3 to 0.7), respectively (p=0.0004). Prednisone was discontinued in 76.9% of patients. During the study, 13 serious adverse events occurred in 11 (16.9%) patients. CONCLUSION: Long-term TCZ treatment was associated with remission maintenance in most patients with GCA. The estimated relapse rate by 18 months after TCZ discontinuation was 47.3%.

Abatacept in IgG4-related disease: a prospective, open-label, single-arm, single-centre, proof-of-concept study.

Background: There is strong rationale for interference with T cell co-stimulation in IgG4-related disease (IgG4-RD), but the literature to evaluate this is limited to a single case report. Methods: We conducted a ten-subject proof-of-concept trial of abatacept in active IgG4-RD. All subjects met the ACR/EULAR Classification Criteria for IgG4-RD. Subjects received subcutaneous abatacept 125 mg weekly for 24 weeks. Concurrent glucocorticoid treatment was permitted but if used had to be discontinued by week four. The primary endpoint, complete remission at 24 weeks, was defined as an IgG4-RD Responder Index score of 0. Peripheral blood mononuclear cells were collected at baseline, four weeks, and 12 weeks. B and T cell subsets were quantified using a 25-parameter flow cytometry panel. Findings: The subjects' median age was 68 years; seven subjects were male and nine were Caucasian. Baseline organ involvement was diverse with a median of 5 organs affected at the time of enrollment. The median serum IgG4 concentration was 597 mg/dL (IQR 304-913 mg/dL). Three subjects received concomitant prednisone at baseline. Six subjects (60%) had a disease response by week 12, five of whom maintained this response at week 24. Abatacept was stopped in the remaining five subjects (50%) due to flare (N = 1) or lack of response by week 12 (N = 4). Three subjects (30%) achieved the primary endpoint.Baseline proportions of unswitched memory B cells predicted responsiveness to abatacept. Reductions in serum IgE, circulating plasmablasts, and activated type 2 T follicular helper (TFH2) cells correlated with response to treatment. One adverse event (grade two thrombocytopenia) was attributed to abatacept. Interpretation: Abatacept was associated with variable treatment responses in IgG4-RD. Half of the subjects achieved sustained treatment responses to abatacept alone, without glucocorticoids. Correlates of clinical response included reductions in serum IgE, circulating plasmablasts, and activated TFH2 cells. Response to abatacept was predicted by higher proportions of unswitched memory B cells at baseline.

Identifying Potential Classification Criteria for Calcium Pyrophosphate Deposition Disease: Item Generation and Item Reduction.

OBJECTIVE: Classification criteria for calcium pyrophosphate deposition (CPPD) disease will facilitate clinical research on this common crystalline arthritis. Our objective was to report on the first 2 phases of a 4-phase process for developing CPPD classification criteria. METHODS: CPPD classification criteria development is overseen by a 12-member steering committee. Item generation (phase I) included a scoping literature review of 5 literature databases and contributions from a 35-member combined expert committee and 2 patient research partners. Item reduction and refinement (phase II) involved a combined expert committee meeting, discussions among clinical, imaging, and laboratory advisory groups, and an item-rating exercise to assess the influence of individual items toward classification. The steering committee reviewed the modal rating score for each item (range -3 [strongly pushes away from CPPD] to +3 [strongly pushes toward CPPD]) to determine items to retain for future phases of criteria development. RESULTS: Item generation yielded 420 items (312 from the literature, 108 from experts/patients). The advisory groups eliminated items that they agreed were unlikely to distinguish between CPPD and other forms of arthritis, yielding 127 items for the item-rating exercise. Fifty-six items, most of which had a modal rating of +/- 2 or 3, were retained for future phases. As numerous imaging items were rated +3, the steering committee recommended focusing on imaging of the knee and wrist and 1 additional affected joint for calcification suggestive of CPP crystal deposition. CONCLUSION: A data- and expert-driven process is underway to develop CPPD classification criteria. Candidate items comprise clinical, imaging, and laboratory features.

Ustekinumab for the Treatment of Giant Cell Arteritis.

OBJECTIVE: To evaluate the efficacy and safety of ustekinumab (UST) in giant cell arteritis (GCA). METHODS: We conducted a prospective, open-label trial of UST in patients with active new-onset or relapsing GCA. Active disease was defined as the presence of GCA symptoms and elevation of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level within 6 weeks of baseline. All patients received a 24-week prednisone taper and subcutaneous UST 90 mg at baseline and at weeks 4, 12, 20, 28, 36, and 44. The primary endpoint, prednisone-free remission, was defined as the absence of relapse through week 52 and normalization of the ESR and CRP level. Relapse was defined as the recurrence of GCA symptoms requiring treatment intensification. A sensitivity analysis excluding ESR/CRP level normalization from the prednisone-free remission definition was performed. RESULTS: The study enrolled 13 patients (target sample size 20). Enrollment was closed prematurely after 7 of the initial 10 patients relapsed. Five patients (39%) had new-onset disease. The initial prednisone doses were 20 mg (1 patient), 40 mg (9 patients), and 60 mg (3 patients). All patients entered disease remission within 4 weeks of baseline. Only 3 (23%) achieved the primary endpoint. Of the 10 patients (77%) who failed to achieve the primary endpoint, 7 relapsed after a mean period of 23 weeks. The remaining 3 patients met the alternative definition of prednisone-free remission that did not require ESR/CRP level normalization. One serious adverse event occurred. CONCLUSION: UST combined with 24 weeks of prednisone was associated with a high rate of treatment failure in this prospective GCA trial.

Using electronic visits (E-visits) to achieve goal serum urate levels in patients with gout in a rheumatology practice: A pilot study.

OBJECTIVE: Achieving goal serum urate levels in patients with gout remains difficult in primary care and rheumatology practices. This study measured the ability of an asynchronous electronic visit (E-visit) program to facilitate achieving a goal serum urate (SU) of less than 6.0 mg/dL. METHODS: We performed a retrospective cohort study in a large academic medical center rheumatology practice between April 1, 2017 and May 31, 2018. Patients with gout and SU levels over 6.0 mg/dL were enrolled in an E-visit program and were compared with historical controls who received usual care, matched 1:1 for age and sex. The primary outcome of interest was the proportion of patients achieving SU target of less than 6.0 mg/dL at six months. RESULTS: Sixty-two patients were enrolled by their rheumatologist in the gout asynchronous E-visit program and were compared to 62 historical controls who were seen within one year prior to E-visit program initiation. Baseline characteristics including age, sex, body mass index, renal function, and initial SU were similar among patients enrolled in the E-visit program and controls. At six months, a significantly higher proportion of patients in the E-visit program achieved goal SU of less than 6.0 mg/dL compared to controls (63.8% vs 33.9%, respectively, p < 0.01), and the E-visit patients had a lower mean SU level than historical controls (5.5 mg/dL versus 6.7 mg/dL, respectively, p < 0.01). CONCLUSION: A physician-initiated E-visit program led to a substantial improvement in the rate of achieving goal SU among patients with gout within an academic rheumatology practice.

Immunoglobulin G4-related Disease.

Immunoglobulin G4 (IgG4)-Related Disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ and lead to organ dysfunction and irreversible damage. In addition to frequent involvement of the salivary glands, lacrimal glands, and/or pancreas, IgG4-RD often affects the chest. Thoracic manifestations include lung nodules and consolidations, pleural thickening, aortitis, and lymphadenopathy. The diagnosis is made after careful clinicopathologic correlation because there is no single diagnostic test with excellent sensitivity or specificity. Biopsy of pulmonary lesions can be useful for distinguishing IgG4-RD from common mimickers. Immunosuppressive regimens, such as glucocorticoids and/or glucocorticoid-sparing agents, form the cornerstone of treatment.