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.

Outcomes of COVID-19 and Factors Associated With Its Severity Among Hospitalized Patients With and Without Systemic Rheumatic Disease During the First Wave of the Pandemic in New York City.

BACKGROUND/OBJECTIVE: Conflicting data exist regarding whether patients with systemic rheumatic disease (SRD) experience more severe outcomes related to COVID-19. Using data from adult patients hospitalized with COVID-19 in New York City during the first wave of the pandemic, we evaluated whether patients with SRD were at an increased risk for severe outcomes. METHODS: We conducted a medical records review study including patients aged ≥18 years with confirmed SARS-CoV-2 infection hospitalized at 3 NewYork-Presbyterian sites, March 3-May 15, 2020. Inverse probability of treatment weighting was applied to a multivariable logistic regression model to assess the association between SRD status and the composite of mechanical ventilation, intensive care unit admission, or death. RESULTS: Of 3710 patients hospitalized with COVID-19 (mean [SD] age, 63.7 [17.0] years; 41% female, 29% White, and 34% Hispanic/Latinx), 92 (2.5%) had SRD. Patients with SRD had similar age and body mass index but were more likely to be female, ever smokers, and White or Black, compared with those without SRD. A higher proportion of patients with versus without SRD had hypertension and pulmonary disease, and used hydroxychloroquine, corticosteroids, and immunomodulatory/immunosuppressive medications before admission. In the weighted multivariable analysis, patients with SRD had an odds ratio of 1.24 (95% confidence interval, 1.10-1.41; p < 0.01) for the composite of mechanical ventilation, intensive care unit admission, or death, compared with patients without SRD. CONCLUSIONS: During the initial peak of the pandemic in New York City, patients with versus without SRD hospitalized with COVID-19 had a 24% increased likelihood of having severe COVID-19 after multivariable adjustment.

Rho Kinase Expression in Giant Cell Arteritis: Validating Phosphorylated Ezrin/Radixin/Moesin Intensity Score to Increase Sensitivity of Temporal Artery Biopsy.

OBJECTIVE: Aberrant Rho-associated protein kinase (ROCK) activity is implicated in several vascular and immunologic disorders. We previously demonstrated increased ROCK activity in histopathologically negative temporal artery biopsies (TABs) in subjects with clinical giant cell arteritis (GCA) compared to those without GCA. This current study aimed to examine ROCK activity in a larger cohort of biopsy-negative GCA subjects and to validate the prior findings. METHODS: Based on clinical data 6 months after TAB, subjects were categorized into 2 groups: biopsy-negative GCA and controls without GCA. Paraffin-embedded TABs were stained for phosphorylated ezrin/radixin/ moesin (pERM), a surrogate of ROCK activity, and scored by 2 pathologists blinded to clinical diagnosis using a previously derived scoring system measuring staining intensity in 3 areas of the vessel. RESULTS: Thirty-six subjects with biopsy-negative GCA and 43 controls were analyzed. The mean (SD) pERM intensity score in non-GCA subjects was 3.9 (1.4), compared to 5.0 (1.4) in those with GCA (P = 0.002). Using the predetermined cut-off of 4 to define high pERM intensity, subjects with GCA were significantly more likely to have a high pERM intensity score compared to non-GCA (odds ratio 3.67, 95% CI 1.19-11.36; P = 0.02. The sensitivity of high pERM intensity score for diagnosis of GCA in histologically negative TABs was 86% (95% CI 70-95). CONCLUSION: In this well-characterized cohort, those with biopsy-negative GCA had significantly higher pERM intensity scores compared to subjects without GCA. pERM staining has diagnostic significance in enhancing the sensitivity of TAB and may help to define the clinically important group of biopsy-negative GCA.

Prevalence of frailty in patients with polymyalgia rheumatica and association with health-related quality of life, cognition and sarcopenia.

OBJECTIVE: To describe the prevalence of frailty in a single-centre cohort of patients with PMR and describe its association with health-related quality of life (HRQoL), cognition and sarcopenia. METHODS: This was a cross-sectional study of patients with PMR, according to 2012 EULAR/ACR Classification Criteria, presenting within 12 months of diagnosis and on treatment with glucocorticoids. Frailty was defined according to the Fried frailty criteria. HRQoL was assessed using Patient-Reported Outcomes Measurement Information System Computerized Adaptive Test (PROMIS-CAT) and cognition was assessed using the Mini-Mental State Examination. Sarcopenia was measured by DXA. RESULTS: Forty-one patients were enrolled. Prevalence of frailty and pre-frailty was 17% and 59%, respectively. Frail patients had higher inflammatory markers at diagnosis compared with pre-frail and robust patients. Of 27 patients with DXA results, 26% were sarcopenic. Frail patients had worse physical function, and more pain behaviour and interference compared with pre-frail and robust patients. In univariable analyses, frail patients were more likely to have worse physical function, and more pain behaviour and pain interference, which remained significant after adjusting for age. There were no significant associations between cognition or sarcopenia and frailty. CONCLUSIONS: In this cohort of PMR patients, there was a higher prevalence of frailty and pre-frailty compared with that reported in community-dwelling elderly. Frailty was associated with worse physical function, and increased pain behaviour and pain interference, differences that were also clinically meaningful. Larger prospective studies are needed to confirm these findings and analyse the association of frailty with other PMR disease outcomes.

Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study.

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10-5) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.

Localized Granulomatous with Polyangiitis (GPA): Varied Clinical Presentations and Update on Treatment.

PURPOSE OF REVIEW: Granulomatosis with polyangiitis is a primary systemic vasculitis commonly described with the typical triad of upper airway, lung, and kidney involvement. Upper and lower airway involvement is characteristic in patients with granulomatosis with polyangiitis and can sometimes represent the initial or in some instances the sole manifestation. The objective of this review is to summarize the various clinical manifestations of localized disease in GPA and their treatment. RECENT FINDINGS: Sinonasal disease is seen in up to 90% of patients. Otologic and ocular involvement is also commonly seen. Laryngeal and tracheal disease although less common is associated with significant morbidity and can be therapeutically challenging. Clinicians need to be aware of these localized GPA manifestations as they may be presenting disease features in the absence of other systemic findings. Treatment of localized GPA involves both immunosuppressive and surgical interventions for specific manifestations. Collaboration between specialists including rheumatologists, otolaryngologists, and ophthalmologists is often crucial to ensure optimal outcomes for patients. This is a narrative review that provides a comprehensive overview of localized granulomatosis with polyangiitis and current treatment options.

Management of difficult polymyalgia rheumatica and giant cell arteritis: Updates for clinical practice.

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) represent a family of systemic inflammatory diseases occurring in adults aged 50 years and above. Clinical presentation of PMR/GCA can be variable, making diagnosis at times challenging. There has been an increased appreciation of the role of various large-vessel imaging modalities to help confirm a diagnosis of GCA. Systemic corticosteroids (CS) remain the mainstay of treatment for both PMR and GCA, yet both relapses and CS-related side effects are common. Recent research has demonstrated efficacy of certain biologic agents in these diseases, with particular emphasis on the role of interleukin-6 (IL-6) blockade in GCA. This chapter discusses the latest updates on the diagnosis and treatment of PMR/GCA, with an emphasis on clinical care.

Brief Report: A Prospective Open-Label Phase IIa Trial of Tocilizumab in the Treatment of Polymyalgia Rheumatica.

OBJECTIVE: Interleukin-6 (IL-6) is a pivotal cytokine in the pathogenesis of polymyalgia rheumatica (PMR), yet the efficacy of IL-6 blockade with tocilizumab (TCZ) for the treatment of PMR is unknown. The aim of this study was to assess the efficacy and safety of TCZ in newly diagnosed PMR. METHODS: In a single-center open-label study, patients with newly diagnosed PMR who had been treated with glucocorticoids (GCs) for <1 month were treated monthly with intravenous (IV) TCZ 8 mg/kg for 1 year, with a rapid tapering of GCs according to standardized protocol. The primary end point was the proportion of patients in relapse-free remission without GC treatment at 6 months. Secondary outcome measures included duration of GC use and cumulative GC dose. Patients were followed up for 15 months. RESULTS: Ten patients were enrolled in the study. One patient withdrew after 2 months, leaving 9 patients in whom the primary end point was assessed. The primary end point of relapse-free remission without GC treatment at 6 months was achieved by all 9 of these patients. All patients who received TCZ treatment were able to discontinue GCs within 4 months of study entry. The cumulative mean ± SD prednisone dose was 1,085 ± 301 mg and the total duration of GC exposure was 3.9 ± 0.9 months. Remission persisted without relapse, in all 9 patients, throughout the entire 15-month study. CONCLUSION: Our findings suggest that TCZ may be an effective, safe, and well-tolerated treatment for newly diagnosed patients with PMR, with a robust steroid-sparing effect.

B-cell-targeted therapy in systemic vasculitis.

PURPOSE OF REVIEW: The present review discusses the evidence supporting the use of B-cell-targeted therapy in the treatment of various forms of systemic vasculitis with a focus on the use of rituximab (RTX), in the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV). RECENT FINDINGS: Long-term follow-up of the two studies establishing the efficacy of a RTX-based induction regimen for severe AAV have demonstrated noninferiority of a single course of RTX compared with conventional therapy for remission maintenance. In addition, these observations highlight an association between relapse and B-cell reconstitution in patients treated with RTX. The maintenance of remission using rituximab in systemic ANCA-associated vasculitis trial compared a regimen of RTX infusions every 6 months to azathioprine for remission maintenance and concluded that serial RTX lead to higher rates of sustained remission.RTX is also an established therapy for cryoglobulinemic vasculitis associated with hepatitis C viral (HCV) infection. Recently published data support the long-term efficacy and safety of RTX for cryoglobulinemic vasculitis. SUMMARY: B-cell depletion with RTX is an established therapy for both remission induction and maintenance in severe AAV and in HCV-related cryoglobulinemic vasculitis. There are limited data to support use of B-cell-targeted therapy in refractory cases of other forms of systemic vasculitis such as eosinophilic granulomatosis with polyangiitis and Takayasu's arteritis.

Pulmonary vasculitis.

Pulmonary vasculitis encompasses inflammation in the pulmonary vasculature with involved vessels varying in caliber from large elastic arteries to capillaries. Small pulmonary capillaries are the vessels most commonly involved in vasculitis affecting the lung. The antineutrophil cytoplasmic antibody-associated vasculitides, which include granulomatosis with polyangiitis (formerly Wegener granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), are the small vessel vasculitides in which pulmonary vasculitis is most frequently observed and are the major focus of this review. Vasculitic involvement of the large pulmonary vessels as may occur in Behçet syndrome and Takayasu arteritis is also discussed.

Increased rho kinase activity in temporal artery biopsies from patients with giant cell arteritis.

OBJECTIVE: Aberrant rho kinase (ROCK) activity is implicated in the pathogenesis of several vascular diseases and is associated with Th17 differentiation. Th17 immune response is recognized in the pathogenesis of GCA. The aim of this study was to assess ROCK activity in GCA. METHODS: All patients who underwent temporal artery biopsy (TAB) at a tertiary care centre over 5 years were identified and charts reviewed. Subjects were categorized into three groups: TAB-positive GCA, TAB-negative GCA and age- and sex-matched controls. TABs were stained for phosphorylated ezrin/radixin/moesin (pERM), a surrogate of ROCK activity, and reviewed by a pathologist blinded to clinical status. Three areas were scored for staining intensity on a scale of 0-2, with a maximum possible score of 6. RESULTS: Nineteen subjects with TAB-positive GCA, 17 with TAB-negative GCA and 18 controls were analysed. Compared with controls, GCA subjects with either positive or negative TABs had significantly higher pERM intensity scores (P = 0.0109). Adjusting for diabetes, hypertension, prednisone and statin use, GCA subjects still had higher pERM scores [odds ratio 7.3 (95% CI 1.9, 25.9), P = 0.0046]. The high pERM score had a sensitivity of 90% and a negative predictive value of 91% for the diagnosis of GCA in those with a negative TAB, compared with 51% sensitivity for histopathology alone. CONCLUSION: Subjects with GCA had more intense pERM staining in TAB specimens compared with age- and sex-matched controls, regardless of whether TAB was positive or negative by routine histopathology, suggesting increased ROCK activity in GCA. The ROCK pathway warrants further investigation in GCA, as it may have diagnostic significance in enhancing the sensitivity of TAB.

Current therapies for ANCA-associated vasculitis.

The ANCA-associated vasculitides, granulomatosis with polyangiitis (GPA, formerly Wegener's), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss), are a group of multisystem autoimmune diseases characterized by necrotizing small- to medium-vessel vasculitis and the presence of anti-neutrophil cytoplasmic antibodies. Current therapeutic strategies consist of glucocorticoids in conjunction with either conventional or biologic agents for both induction of remission and remission maintenance. Treatment goals include reducing toxicity of induction therapy, preventing disease relapse, and limiting overall accrual of both disease-related damage and treatment-related morbidity. Future research directions include investigation of the optimal duration and frequency of maintenance therapy as well as development of targeted therapeutic agents, which is enhanced by emerging insights into disease pathogenesis.

Current landscape of antineutrophil cytoplasmic antibody-associated vasculitis: classification, diagnosis, and treatment.

This article provides an update on the diagnosis and management of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, granulomatosis with polyangiitis (formerly Wegener), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss). Focus is on new schemes of classification and the importance of ANCAs in the diagnosis and prognosis of these systemic vasculitides. Current therapeutic strategies consisting of glucocorticoids in conjunction with conventional or biologic agents for both induction of remission and remission maintenance are outlined. Future research directions include investigation of the optimal duration and frequency of maintenance therapy and development of targeted therapeutic agents.

Vasculitis in antiphospholipid syndrome.

The major manifestations of antiphospholipid syndrome (APS) are caused by thrombosis within the venous or arterial vasculature, whereas the vascular lesions in systemic vasculitis result from an inflammatory infiltrate in the vessel wall. There is an association between vascular thrombosis and inflammation, however, as vasculitis can occur in APS and thromboembolic complications are seen in systemic vasculitis. Although differentiating between vasculitis and antiphospholipid-associated thrombosis can be difficult, it may be crucial to do so given the different therapeutic implications for immunosuppression or anticoagulation. This article explores the relationship between thrombosis and inflammation as it relates to APS and systemic vasculitis.

Effectiveness of rituximab for the otolaryngologic manifestations of granulomatosis with polyangiitis (Wegener's).

OBJECTIVE: Ear, nose, and throat (ENT) involvement is the most prevalent manifestation of granulomatosis with polyangiitis (Wegener's) (GPA) and correlates with permanent damage and decreased quality of life. Although prior studies have evaluated the efficacy of rituximab (RTX) for granulomatous features of GPA, none have evaluated its efficacy solely for ENT manifestations. We compared the effectiveness of RTX to other therapies for the ENT manifestations of GPA in a large, well-characterized cohort. METHODS: We performed a retrospective analysis of 975 visits from 99 GPA patients seen at a tertiary care ENT practice between 2003 and 2013. At each visit, subjects had a complete ENT examination, with ENT activity assessed by a single expert otolaryngologist. ENT disease activity during the observational period in subjects receiving RTX was compared to subjects receiving all other therapy. RESULTS: In total, 48 subjects had never received RTX and 51 received RTX at least once. There was no active ENT disease during 92.4% of the observational period (days) for subjects receiving RTX, compared with 53.7% of the observational period for subjects not receiving RTX (odds ratio 11.0 [95% confidence interval 5.5­22.0], P < 0.0001). Subjects receiving RTX, compared with those receiving methotrexate, azathioprine, cyclophosphamide, or trimethoprim-sulfamethoxazole, were significantly more likely to have no active ENT disease (P < 0.0001 for each comparison). CONCLUSION: RTX is an effective treatment for ENT manifestations of GPA. Subjects treated with RTX were significantly less likely to have active ENT disease compared with those not receiving RTX. Patients being treated with RTX were 11 times less likely to have active ENT disease than patients being treated with other therapies.

Biomarkers in ANCA-associated vasculitis.

Despite recent advances in the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), relapse remains common and patients often experience a variable clinical course after initial treatment. New biomarkers are needed to aid the management of these complex diseases. Discoveries regarding the pathogenesis of AAV, from the importance both of activated B and T cells and the alternative complement pathway to genomic data, may lay the groundwork for identification of novel biomarkers.