Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes.

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.

Referral Patterns for Dual-Energy Computed Tomography in Diagnosis and Management of Gout: Ten-Year Experience at a Canadian Institution.

PURPOSE: To analyze the utilization, indications, and outcomes of dual-energy computed tomography (DECT) gout imaging in clinical practice. METHODS: This retrospective study was ethics approved. Radiology reports of DECT gout scans between 2007 and 2016 were analyzed for trends of utilization, referral pattern, indication, and diagnosis. RESULTS: DECT gout referrals increased substantially (2007: 37; 2008: 72; 2016: 385; total: 1877). The largest number of referrals were from rheumatology (1160), emergency medicine (283), and family medicine (177). Most referrals (92%) were requested to aid an initial diagnosis of gout. Other reasons included estimating the disease burden (6%) or monitoring disease progression and effectiveness of treatment (2%). Rheumatology accounted for most referrals for the latter two reasons (81% and 97%). Imaging findings of urate presence were similar in referrals from rheumatology (62%), family medicine (62%), and other medical specialties (62%). The urate positive rates were slightly lower in referrals from emergency medicine (47%) and surgical specialties (41%). The most common differential diagnoses by referring specialties were calcium pyrophosphate dihydrate crystal deposition disease (CPPD) and other inflammatory or erosive arthritides (rheumatology, family medicine), CPPD and infections (other medical specialties), infections and fractures (emergency medicine), neoplasm and infections (surgical specialties). CONCLUSIONS: The increasing utilization of DECT for gout imaging validates its clinical value. Varying clinical presentation could explain differences of urate positive rates among specialties. Our results support a multispecialty collaborative approach to the diagnosis and management of gout, with direct access to DECT gout imaging provided to various physician specialties.

IL-6 expression is correlated with increased T-cell proliferation and survival in the arterial wall in giant cell arteritis.

Giant cell arteritis (GCA) is the most common vasculitis in adults affecting large and medium-sized arteries. IL-6 and T cell accumulation within the arterial wall contribute to the pathogenesis of GCA, and blockade of IL-6 activity is efficacious in its treatment. We examined the relationship between levels of IL-6 expression and immunological processes that control the expansion of T cells in GCA-positive temporal artery biopsies. CD4 T cells accumulated in clusters within the media and deep intima of all GCA lesions. There was a significant positive correlation between the expression of IL-6 mRNA and increased frequency of proliferating CD4 T cells. The expansion of T cells can be inhibited by T regs but IL-6 expression was not correlated with differences in T reg accumulation. Increased IL-6 levels were also significantly correlated with lower frequencies of CD4 T cells undergoing apoptotic cell death. In conclusion, IL-6 may contribute to the accumulation of CD4 T cells in GCA by supporting their proliferation and survival within the arterial wall through mechanisms that are independent of effects on local T reg expansion.

Introduction to economic modeling for clinical rheumatologists: application to biologic agents in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, debilitating inflammatory, progressive musculoskeletal disease that affects 0.5-1.0% of the adult population in Western countries. The joint destruction and progressive functional disability associated with uncontrolled RA result in tremendous impacts on health-related quality of life, ability to work, and mortality. In addition, the treatment of the disease and associated complications exact a substantial economic burden to the patients, their families, and society. In the last decade, several biological agents (biologics) have been approved for use in RA, revolutionizing treatment. These biologics, which target cytokines such as tumor necrosis factor or lymphocytes such as B or T cells, reduce functional disability and substantially slow the progression of joint damage. However, because these agents typically cost ten to 100 times more than existing available older drug therapies, there has been worldwide concern regarding their impact on healthcare budgets. As such, there has been increased attention towards economic evaluation as a means to determine whether, and in which subgroup of patients, these newer, more expensive agents confer appropriate value for their additional cost. Indeed, evaluations have guided coverage decisions for both private and public health insurance agencies such as the National Institute for Health and Clinical Excellence in the UK. The use of economic evaluations to determine value for money for these agents has attracted both debate and controversy. Some of the controversy is related to the appropriateness of the structure of, and assumptions underlying, the decision models employed to estimate the long-term costs and benefits of these agents over existing therapies. To fully appreciate the debate, one must first understand the basic principles of economic evaluation and the necessity for using decision models to evaluate cost effectiveness. To understand the basic principles of economic evaluation, we refer the reader to an introductory article aimed at clinical rheumatologists. This paper attempts to explain the rationale for the use of economic modeling approaches to assess the value of biologics for RA using specific examples from the literature.

Test of Memory Malingering (TOMM) scores are not affected by chronic pain or depression in patients with fibromyalgia.

Neuropsychologists routinely give effort tests, such as the Test of Memory Malingering (TOMM). When a person fails one of these tests, the clinician must try to determine whether the poor performance was due to suboptimal effort or to chronic pain, depression, or other problems. Participants were 54 community-dwelling patients who met American College of Rheumatology criteria for fibromyalgia (FM). In addition to the TOMM, they completed the Beck Depression Inventory-Second Edition, Multidimensional Pain Inventory-Version 1, Oswestry Disability Index-2.0, British Columbia Cognitive Complaints Inventory, and the Fibromyalgia Impact Questionnaire. The majority endorsed at least mild levels of depressive symptoms (72%), and 22% endorsed "severe" levels of depression. The average scores on the TOMM were 48.8 (SD = 1.9, range = 40-50) for Trial 1, 49.8 (SD = 0.5, range = 48-50) for Trial 2, and 49.6 (SD = 0.9, range = 45-50) for Retention. Despite relatively high levels of self-reported depression, chronic pain, and disability, not a single patient failed the TOMM. In this study, the TOMM was not affected by chronic pain, depression, or both.

Psoriasis and pustular dermatitis triggered by TNF-{alpha} inhibitors in patients with rheumatologic conditions.

BACKGROUND: New onset or worsening of psoriasis has been reported in patients treated with tumor necrosis factor alpha (TNF-alpha) inhibitors for a variety of rheumatologic conditions. There is mounting evidence that a key innate immune pathway for triggering common human autoimmune disease, including psoriasis, involves plasmacytoid dendritic cell precursors (PDCs) and type 1 interferon (IFN) production. We present herein a case series with clinical and histopathologic evidence of psoriasis in patients with rheumatologic disease treated with TNF-alpha inhibitors. We propose that the cross regulation between TNF-alpha and IFN may have a role in the pathogenesis of this reaction. OBSERVATIONS: We observed new-onset psoriasis (n = 13) or severe exacerbation of psoriasis (n = 2) in 15 patients with a variety of rheumatologic conditions-rheumatoid arthritis (n = 13), psoriatic arthritis (n = 1), and seronegative arthritis (n = 1)-during treatment with etanercept (n = 6), infliximab (n = 5), and adalimumab (n = 4). Immunohistochemical staining of skin biopsy specimens for myxovirus-resistance protein A (MxA, a surrogate marker for lesional type 1 IFN activity) showed increased staining in TNF-alpha inhibitor-induced psoriasis compared with psoriasis vulgaris. CONCLUSIONS: New onset or severe exacerbation of psoriasis is a rare complication of TNF-alpha inhibitor therapy. The finding of increased production of IFN-alpha in TNF-alpha inhibitor-induced psoriasis is a possible pathophysiologic explanation for this reaction.

An overview of economic evaluations for drugs used in rheumatoid arthritis : focus on tumour necrosis factor-alpha antagonists.

Rheumatoid arthritis (RA) is a chronic, progressive, inflammatory disease that affects approximately 0.5-1% of the adult population. The introduction of new disease-modifying antirheumatic drugs (DMARDs) such as leflunomide, anakinra and the tumour necrosis factor (TNF)-alpha antagonists (infliximab, etanercept and adalimumab) have transformed the management of RA. In particular, the last class of agents has generated substantial controversy. Costing between 16,000 US dollars and 20,000 US dollars per patient-year (2001 values), the potential greater efficacy of treatment with TNFalpha antagonists comes at much higher drug costs, making these agents natural candidates for cost-effectiveness analyses (CEAs).A MEDLINE search (until 31 January 2004) identified six original CEAs evaluating TNFalpha antagonists in RA. The aim of a CEA is to facilitate the allocation of scarce health resources and to inform policy decisions. However, to enhance the reliability and relevance of these analyses to policy makers, there must be similarity between the methodologies used. Recently, the OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) group produced a document to define such a reference case; the OMERACT document was used as a foundation to structure comparisons and highlight discrepancies. The methodologies employed in each analysis differed; in particular, disparate time horizons, comparators, quantities of drug and treatment sequences prohibit the comparison of cost effectiveness between studies. Outcomes also differed between the analyses. Most reported health-related quality of life (HR-QOL) in quality-adjusted life-years (QALYs). The QALYs metric was based on preference scores that were typically derived from linear regressions using the Health Assessment Questionnaire (HAQ). However, models also used American College of Rheumatology (ACR) criteria, as well as the disease activity score (DAS). Common to all studies was the lack of data from long-term randomised studies where efficacy and resource consumption in comparison with standard care has been investigated. As such, investigators combined short-term randomised control trial data with that of a long-term observational cohort, and modelled cost effectiveness over an appropriate time horizon. In addition, most analyses lacked rigorous sensitivity analysis to examine the impact of uncertainty in the parameters. Those analyses that examined time horizons of 6 months and 1 year published incremental cost-effectiveness ratios (ICERs) of 34,800 US dollars per ACR 70% response criteria (ACR70) weighted response (duration 6 months, 1999 values) and 96,166 US dollars (duration 1 year, 2002 values). Analyses that modelled costs and health outcomes beyond the first year reported ICER estimates ranging between 26,800 US dollars (patients' lifetime, 1998 values) and 40,308 US dollars (10 years, 2002 values). In terms of HR-QOL, the analyses reported incremental QALYs that ranged from 0.116 (over 19 years) to 1.6 (over 10 years). Discounted costs of therapy ranged from 30,362 US dollars (10 years, 2002 values) to 93,000 US dollars (22 years, 1998 values), and comparator costs ranged from 22,593 US dollars (10 years, 2002 values) to 84,000 US dollars (22 years, 1998 values).

Cardiovascular risk factor screening in systemic lupus erythematosus.

OBJECTIVE: To evaluate the frequency of cardiovascular (CV) disease risk factor screening in systemic lupus erythematosus (SLE). METHODS: Medical records of patients from a lupus clinic and 5 private practices were assessed for CV disease risk factors, including hyperlipidemia, hypertension, diabetes mellitus, smoking, family history of CV disease, antiphospholipid antibodies, hyperhomocysteinemia, postmenopausal status, obesity, and nephrotic syndrome. RESULTS: A total of 183 records were included: 60 (33%) from the lupus clinic and 123 (67%) from private practices. Serum lipid profiles were measured in 56/183 (31%): 37/60 (62%) in the lupus clinic vs 19/123 (15%) private practice. Of the 56 with lipids measured, the individual tests obtained were as follows: total cholesterol in 56 (100%), HDL in 50 (89%), triglycerides in 49 (88%), LDL in 48 (86%), and VLDL in 33 (59%). Thirty-one of 56 patients (55%) had elevated lipids. Only 9/25 (36%) with hyperlipidemia who had a subsequent visit had a response to the hyperlipidemia charted. Of 9 nonlipid risk factors, a median of 8 were assessed in the lupus clinic vs 3 in private practices. The most frequent risk factors screened were nephrotic syndrome (91%), hypertension (74%), and smoking (59%). CONCLUSION: Despite an inordinately high risk of CV disease in SLE, assessment of CV risk factors was surprisingly uncommon among the practices assessed. Greater attention needs to be paid to CV disease risk factor screening in patients with lupus.