Matthew J. Koster

Predictors of relapse and treatment outcomes in biopsy-proven giant cell arteritis: a retrospective cohort study

OBJECTIVE To evaluate characteristics of relapse, relapse rates, treatment and outcomes among patients with biopsy-proven GCA in a large, single-institution cohort. METHODS We conducted a retrospective review of all patients with biopsy-proven GCA from 1998 to 2013. Demographic, clinical, laboratory and treatment data at presentation and during follow-up were collected. Comparisons by relapse rate were performed using chi-square tests. Prednisone discontinuation by initial oral dose ≤40 and >40 mg/day was compared using Cox models. RESULTS The cohort included 286 patients [74% female, mean age at diagnosis 75.0 years (s.d. 7.6), median follow-up 5.1 years). During follow-up, 73 patients did not relapse, 80 patients had one relapse and 133 had two or more relapses. The first relapse occurred during the first year in 50% of patients, by 2 years in 68% and by 5 years in 79%. More patients with established hypertension (P = 0.007) and diabetes (P = 0.039) at GCA diagnosis were in the high relapse rate group ( ≥ 0.5 relapses/year) and more females were in the low or high relapse groups than in the no relapse group (P = 0.034). Patients receiving an initial oral prednisone dose >40 mg/day were able to reach a dose of <5 mg/day [hazard ratio (HR) 1.46 (95% CI 1.09, 1.96)] and discontinue prednisone [HR 1.56 (95% CI 1.09, 2.23)] sooner than patients receiving ≤40 mg/day without an increase in observed glucocorticoid-associated adverse events. CONCLUSION Females and patients with hypertension or diabetes at GCA diagnosis have more relapses during follow-up. Patients treated with an initial oral prednisone dose >40 mg/day achieved earlier prednisone discontinuation.

Coronary artery disease in giant cell arteritis: A systematic review and meta-analysis

OBJECTIVE To investigate the association between giant cell arteritis (GCA) and risk of coronary artery disease (CAD). METHODS We conducted a systematic review and meta-analysis of observational studies that reported relative risks, hazard ratios, or standardized incidence ratios with 95% confidence interval comparing CAD risk in patients with GCA versus non-GCA controls. Pooled risk ratios and 95% confidence intervals were calculated using a random-effect, generic inverse variance of DerSimonian and Laird. RESULT Six studies with 10,868 patients with GCA and 245,323 controls were identified and included in our data analysis. The pooled risk ratio of CAD in patients with GCA was 1.51 and did not achieve statistical significance (95% CI: 0.88-2.61). The statistical heterogeneity was high with an I(2) of 97%. CONCLUSION In contrast to other chronic systemic inflammatory disorders, our meta-analysis did not show any statistically significant increased risk of CAD among patients with GCA.

Recent advances in the clinical management of giant cell arteritis and Takayasu arteritis.

Purpose of reviewThis article critically reviews the advances in medical management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) with a focus on recent developments in targeted biologic therapy. Recent findingsThe role of biologics in the treatment of large vessel vasculitis (LVV) is expanding. TNF&agr; inhibitors appear to be effective in the treatment of TAK but have little benefit in GCA. Preliminary clinical trial data suggest that abatacept and tocilizumab reduce the risk of relapse in GCA. Increasing observational evidence supports the use of interleukin-6 inhibitors in TAK. Based on a small open-label study, ustekinumab appears safe and potentially effective for refractory GCA. A possible role of B cell dysregulation may contribute to pathogenic mechanisms in LVV, but support for the use of B cell depleting therapy is limited. SummaryInterleukin-6 inhibitors appear efficacious in the treatment of refractory cases of LVV; however, utility in newly diagnosed immunosuppressive-naïve patients is less well established. Abatacept and ustekinumab are promising targets for therapy in LVV but further investigation is needed before routine use is considered.

Cerebrovascular accident in patients with giant cell arteritis: A systematic review and meta-analysis of cohort studies

OBJECTIVES To investigate the risk of cerebrovascular accident (CVA) among patients with giant cell arteritis (GCA). METHODS We conducted a systematic review and meta-analysis of cohort studies that reported relative risks, hazard ratios, or standardized incidence ratios comparing CVA risk in patients with GCA versus non-GCA comparators. Pooled risk ratio and 95% confidence interval were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS Eight studies with 17,919 patients with GCA were identified and included in our data analysis. The pooled risk ratio of CVA in patients with GCA versus non-GCA controls was 1.40 (95% CI: 1.27-1.56). The statistical heterogeneity was low with an I2 of 31%. CONCLUSIONS Our study indicates a significantly increased risk of CVA among patients with GCA.

Venous thromboembolism and cerebrovascular events in patients with giant cell arteritis: A population-based retrospective cohort study

Objective To investigate the incidence of venous thromboembolism (VTE) and cerebrovascular events in a community-based incidence cohort of patients with giant cell arteritis (GCA) compared to the general population. Methods A population-based inception cohort of patients with incident GCA between January 1, 1950 and December 31, 2009 in Olmsted County, Minnesota and a cohort of non-GCA subjects from the same population were assembled and followed until December 31, 2013. Confirmed VTE and cerebrovascular events were identified through direct medical record review. Results The study population included 244 patients with GCA with a mean ± SD age at diagnosis of 76.2 ± 8.2 years (79% women) and an average length of follow-up of 10.2 ± 6.8 years. Compared to non-GCA subjects of similar age and sex, patients diagnosed with GCA had a higher incidence (%) of amaurosis fugax (cumulative incidence ± SE: 2.1 ± 0.9 versus 0, respectively; p = 0.014) but similar rates of stroke, transient ischemic attack (TIA), and VTE. Among patients with GCA, neither baseline characteristics nor laboratory parameters at diagnosis reliably predicted risk of VTE or cerebrovascular events. Conclusion In this population-based study, the incidence of VTE, stroke and TIA was similar in patients with GCA compared to non-GCA subjects.

Classification of large vessel vasculitis: Can we separate giant cell arteritis from Takayasu arteritis?

The two main variants of large vessel vasculitis include Takayasu arteritis and giant cell arteritis. While these two conditions have historically been considered different conditions, recent evidence questions whether they are a spectrum of the same disease. Classification criteria are limited in distinguishing between cases with phenotypic overlap. The limitations of the current criteria and directions of future research are reviewed.

Large-vessel giant cell arteritis: Diagnosis, monitoring and management

GCA is a chronic, idiopathic, granulomatous vasculitis of medium and large arteries. It comprises overlapping phenotypes including classic cranial arteritis and extra-cranial GCA, otherwise termed large-vessel GCA (LV-GCA). Vascular complications associated with LV-GCA may be due, in part, to delayed diagnosis, highlighting the importance of early identification and prompt initiation of effective therapy. Advancements in imaging techniques, including magnetic resonance angiography, CT angiography, PET and colour duplex ultrasonography, have led to improvements in the diagnosis of LV-GCA; however, the role imaging modalities play in the assessment of disease activity and long-term outcomes remains unclear. Glucocorticoids are the mainstay of therapy in LV-GCA, but their prolonged use is associated with multiple, sometimes serious, adverse effects. Recent data suggest that biologic therapies, such as tocilizumab, may be effective and safe steroid-sparing options for patients with GCA. However, data specifically evaluating the management of LV-GCA are limited.

Large-Vessel Dilatation in Giant Cell Arteritis: A Different Subset of Disease?

To compare patients with large‐vessel giant cell arteritis (LV‐GCA) characterized by wall thickening, stenosis, and/or occlusion of subclavian arteries to those with subclavian dilatation.

Assessment of the frequency of cardiovascular risk factors in patients with Takayasu’s arteritis

Objectives The prevalence of atherosclerotic risk factors and disease in Takayasus arteritis (TAK) has not been well defined. We aimed to assess the frequency of cardiovascular (CV) risk factors and the incidence of CV events (CVEs) in patients with TAK from two ethnically different populations. Methods Patients with TAK followed at Mayo Clinic, Rochester, MN, USA and Marmara University, Istanbul, Turkey were included in this retrospective study. Patients with TAK were compared with age-, sex- and calendar year-matched controls from the same geographical region without TAK. The 2008 Framingham 10-year general CV risk score (FRS) was used for the evaluation of CV risk at the time of TAK incidence/index date. Results In total, 191 patients with TAK and 191 non-TAK controls were included. Hypertension and the prevalence of lipid-lowering treatments were significantly more frequent in TAK. Prior to the incidence/index date, occurrence of CVE was significantly higher in TAK. The FRS was significantly higher in TAK compared with non-TAK at incidence/index date. The cumulative incidence of CVE was 15.4% at 10 years in TAK vs 5.8% in non-TAK; the risk of CVE was increased among patients with TAK (hazard ratio = 4.36; 95% CI: 1.25, 15.13). Conclusion CV risk factors are more common in patients with TAK, particularly hypertension. The FRS is higher in patients with TAK at the time of diagnosis. The cumulative incidence of CVE was also significantly higher during follow-up in TAK. Our results suggest that patients with TAK should undergo careful assessment of CV risk factors, and an aggressive risk modification approach is warranted.

Efficacy of biological agents in the treatment of Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a histiocytic neoplasm characterized by tissue infiltration of CD68CD1a histiocytes. Recently, identification of activating MAP-ERK pathway somatic mutations has led to successful treatment with BRAF and MEK inhibitors (Diamond et al, 2016a,b). However, these treatments are not yet approved by the US Food and Drug Administration, and not all ECD patients who need systemic therapy have an identifiable mutation or tissue available for genetic testing. Tissue samples of ECD have demonstrated disruption of various cytokines and chemokines (Arnaud et al, 2011). Hence, there are reports of treatment with biological agents, such as interlukin-1 (IL1) receptor antagonists (anakinra) and anti-tumour necrosis factor-alpha (TNF-a) inhibitors (infliximab, etanercept) (Henter et al, 2001; Aouba et al, 2010; Dagna et al, 2012; Killu et al, 2013; Cohen-Aubart et al, 2016; Diamond et al, 2016c). In this study, we describe a large, single-institution experience utilizing biological agents in the treatment of ECD. This study was a retrospective review of ECD patients treated with biologicals from 1 January 998, to 6 April 2016 at Mayo Clinic. In all cases, the diagnosis was made according to the established clinicopathological criteria. All records were independently reviewed by 3 investigators. As post-therapy responses were not uniformly assessed, we used clinical and radiological response criteria previously described (Goyal et al, 2017). For clinical response, the following criteria were used based on change in symptoms: complete response (CR; complete resolution), partial response (PR; partial resolution), stable disease (SD; no change for ≥3 months), and progressive disease (PD; progression or worsening). In our series, most patients did not undergo positron emission tomography– computed tomography (PET-CT). Hence, we reviewed other available imaging studies, including radiographs, magnetic resonance imaging, CT and radionuclide bone scans. For radiological response, the following categories were used based on change in radiological appearance of the proven or suspected ECD lesion(s): CR, PR, SD and PD. A total of 63 adult ECD patients were identified, with a median age of 54 years (range 34–80). Of these, 12 (19%) received treatment with a biological agent (Table I). The median age at diagnosis of this cohort was 59 5 years (range, 34–76). Most common sites of disease involvement were bone (91%), kidney/retroperitoneum (67%), and central nervous system (CNS; 42%). BRAF V600E mutation was detected in 8 of 9 patients who were tested. Overall, the 3 biological agents were used 14 times in the treatment course. The median duration of therapy was 12 months (range, 1–133). Anakinra was most commonly used (8/14). Overall clinical response rate with anakinra was 50% (1 CR, 3 PR, and 3 PD). The median duration of response was 42 5 months (range, 29–133); one patient had an ongoing response after 33 months of therapy. Radiological responses were seen in 25% of patients (2 PR, 3 SD, 2 PD, 1 unknown) (Fig 1). One of the patients had cerebellar lesions that progressed on anakinra. Treatment-related adverse effects were seen in 3/8 (38%) patients: one patient with grade 2 thrombocytopenia, and 2 others had grade 1 liver enzyme elevations. Infliximab was used in 5 patients. No clinical or radiological responses were seen with its use, although one patient noted stability of dizziness for 25 months. Infusion-related grade 3 adverse reaction was seen in 1 patient with the third dose of infliximab, and 1 patient had grade 1 liver enzyme abnormalities. Etanercept was used in 2 patients, with progressive disease in both. Both these patients had worsening bone pain after etanercept, indicating disease progression. Our series demonstrates that the IL1 inhibitor anakinra has moderate clinical efficacy in ECD patients. One of the patients showed a reduction in activity of the right atrial mass on PET-CT scan. The disease sites that demonstrated response included bone, heart and lungs. One of the patients had CNS disease that failed to respond to anakinra, the reason for which is unclear. A recent case series of 12 ECD patients treated with anakinra demonstrated a similar 50% clinical response rate (Cohen-Aubart et al, 2016). The ECD sites that responded to anakinra in this series were spine, pleura and bones. This study included 2 patients who had CNS involvement, and they failed to response to anakinra. However, both of these patients had already been exposed to interferon-a (IFN-a) prior to receiving anakinra. There was a subsequent report of 2 patients with ECD involving the CNS who were IFN-a na€ıve and responded to anakinra clinically as well as radiologically (Diamond et al, 2016c). Similarly, prior studies of anakinra have shown responses in disease sites like bones, kidney/retroperitoneum, (Aouba et al, 2010) and heart (Killu et al, 2013). In our study, the TNF-a monoclonal antibodies, infliximab and etanercept, did not result in any responses. A prior report of infliximab use showed responses in cardiac and peri-aortic disease along with improved symptoms of dyspnea. None of the patients with cardiac involvement in our series received infliximab therapy so it might be a therapeutic Correspondence