Relapses in Patients With Giant Cell Arteritis

Giant cell arteritis (GCA) is a relapsing disease. However, the nature, chronology, therapeutic impact, and clinical consequences of relapses have been scarcely addressed. We conducted the present study to investigate the prevalence, timing, and characteristics of relapses in patients with GCA and to analyze whether a relapsing course is associated with disease-related complications, increased glucocorticoid (GC) doses, and GC-related adverse effects. The study cohort included 106 patients, longitudinally followed by the authors for 7.8 3.3 years. Relapses were defined as reappearance of disease-related symptoms requiring treatment adjustment. Relapses were classified into 4 categories: polymyalgia rheumatica (PMR), cranial symptoms (including ischemic complications), systemic disease, or symptomatic large vessel involvement. Cumulated GC dose during the first year of treatment, time required to achieve a maintenance prednisone dose <10mg/d (T10), <5mg/d (T5), or complete prednisone discontinuation (T0), and GC-related side effects were recorded. Sixty-eight patients (64%) experienced at least 1 relapse, and 38 (36%) experienced 2 or more. First relapse consisted of PMR in 51%, cranial symptoms in 31%, and systemic complaints in 18%. Relapses appeared predominantly, but not exclusively, within the first 2 years of treatment, and only 1 patient developed visual loss. T10, T5, and T0 were significantly longer in patients with relapses than in patients without relapse (median, 40 vs 27 wk, p <0.0001; 163 vs 89.5 wk, p 1⁄4 0.004; and 340 vs 190 wk, p1⁄40.001, respectively). Cumulated prednisone dose during the first year was significantly higher in relapsing patients (6.2 1.7g vs 5.4 0.78g, p1⁄40.015). Osteoporosis was more common in patients with relapses compared to those without (65% vs 32%, p1⁄40.001). In conclusion, the results of the present study provide evidence that a relapsing course is associated with higher and prolonged GC requirements and a higher frequency of osteoporosis in GCA. (Medicine 2014;93: 194–201) Abbreviations: CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, GC = glucocorticoids, GCA = giant cell arteritis, Hb = hemoglobin, IQR = interquartile range, PDN = prednisone, PMR = polymyalgia rheumatica, SD = standard deviation, SIR = systemic inflammatory response, TNF = tumor necrosis factor. INTRODUCTION Giant cell arteritis (GCA) is a granulomatous arteritis predominantly affecting large and medium-sized vessels. Treatment with high-dose glucocorticoids (GC) results in prompt and remarkable improvement of symptoms and reduces the risk of ischemic complications. However, reduced GC doses do not completely abolish essential pathways involved in disease persistence, and consequently, the course of GCA may be troubled by relapses. Recrudescence of GCA activity is common, occurring in at least 43% of patients in population-based studies and up to 80% in clinical trials with adjuvant therapies. The remarkable variability in the reported prevalence of relapses may be related to heterogeneity in the definition of relapses and to variability in the GC-tapering schedules. Definition of relapse, flare, or recurrence considerably varies across different studies. While in some publications definition of relapse has been based on clinical grounds, in others, isolated increases in acute-phase reactants have been considered disease flares. In addition, although this has not been formally evaluated, initial doses and tapering schedules seem to influence relapse rate in GCA. In this regard, it is noteworthy that the higher relapse rates have been observed in the context of clinical trials with adjuvant therapies where GC tapering is more aggressive than in standard of care settings, and when alternate-day GC tapering is applied. Consistently, a detailed review of treatments received by patients with isolated polymyalgia rheumatica (PMR) suggests that starting with lower GC doses is associated with higher relapse rates. Relapse rate is a commonly used primary endpoint in clinical trials with patients with GCA. However, although frequency of relapses has been reported in various studies, limited information exists regarding the From the Vasculitis Research Unit (MAA, AG-M, SP-G, IT-B, MC-B, EP-R, GE-F, MB, JH-R, MCC), Department of Autoimmune Diseases, Hospital Cl ınic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain. Correspondence: Maria C. Cid, MD, Vasculitis Research Unit, Department of Systemic Autoimmune Diseases, Hospital Cl ınic, Villarroel 170, 08036 Barcelona, Spain (e-mail: [email protected]). Results partially presented at the Annual Scientific Meeting of the American College of Rheumatology 2012, Washington, DC (November 10–14, 2012). Conflicts of Interest and Funding Sources: The authors declare no conflicts of interest. Supported by Ministerio de Econom ıa y Competitividad (SAF 08/04328 y SAF 11/30073). MA Alba was supported by Consejo Nacional de Ciencia y Tecnolog ıa (CONACyT), Mexico and by the Agencia de Gesti o d’Ajuts Universitaris i de Recerca (AGAUR) (Generalitat de Catalunya). G Esp ıgol-Frigol e was supported by Instituto de Salud Carlos III. M Butjosa and S Prieto-Gonz alez were supported by Premi Fi de Residència (Hospital Cl ınic). Copyright © 2014 by Lippincott Williams & Wilkins. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000033 194 | www.md-journal.com Medicine • Volume 93, Number 5, July 2014 clinical characteristics and predictors of relapses, and accompanying blood test abnormalities, which have been only specifically addressed in a previous study. Moreover, it has not been clearly demonstrated whether a relapsing course results in increased disease or treatment-related morbidity in these patients. Therefore, we conducted the present study to investigate the prevalence, timing, predictors, and main features of relapses in a longitudinally followed cohort of patients with GCA with long-term follow-up. In addition, we analyzed whether a relapsing course was associated with disease-related ischemic complications, higher cumulated GC doses, more prolonged treatment periods, and/or higher frequency of GC-related adverse effects. PATIENTS AND METHODS Between 1995 and 2007, 187 individuals were diagnosed with biopsy-proven GCA at our institution (Hospital Cl ınic, Barcelona, Spain). Among them, patients treated by the authors who underwent a regular follow-up for at least 4 years were selected. From the initial 187 patients diagnosed, 81 were excluded for the following reasons: 31 were subsequently treated at other departments or institutions, 19 died early during follow-up, 14 were transferred to nursing homes for advanced dementia, and 17 moved to other regions or had deficient compliance with the scheduled follow-up visits. The remaining 106 patients were uniformly evaluated, treated, and longitudinally followed by the authors for an average of 7.8 3.3 years (range, 4–15 yr). Clinical and laboratory findings at disease diagnosis were recorded. A combination of clinical and blood test abnormalities was used to evaluate the intensity of the systemic inflammatory response (SIR) as previously reported. These included fever >38 °C, weight loss 34kg, hemoglobin (Hb) <11g/L, and erythrocyte sedimentation rate (ESR) 385mm/h. Patients with 3 or 4 of these items were considered to have a strong SIR, whereas patients with 2 were considered to have a weak SIR. Patients underwent clinical assessments in our outpatient facility every 3 months for the first 2 years after diagnosis and approximately every 4–6 months thereafter. ESR, C-reactive protein (CRP), blood cell counts, and Hb concentration were determined at each visit. The treatment protocol consisted of an initial prednisone (PDN) dose of 1 mg/kg per day (up to 60mg/d) for 1 month. Intravenous methylprednisolone pulse therapy (1g daily for 3d) was initially administered to patients with recent (<48h) visual loss. PDN was subsequently tapered at 10mg/wk. When reaching 20mg/d, this dose was maintained for 1–2 weeks and then reduced to 15mg/d, which was maintained for 1 month. A further reduction to a maintenance dose of 10mg/d was attempted. If tolerated, a reduction to 7.5mg/d was tried after 3– 6 months. Subsequent tapering was more variable. In general, a reduction to 5mg/d was attempted approximately 3–6 months later and maintained for 1 year, after which a reduction of 1.25 mg/d was attempted every 6 months. Methotrexate at 15 mg/wk was added when patients experienced 32 relapses or had developed GC side effects. Reduction in PDN dose was performed 1 month before the scheduled follow-up visit to evaluate tolerance to the adjustment and to avoid severe relapses. If disease-related symptoms (cranial manifestations or PMR), fever, weight loss, or anemia not attributable to other reasons after the necessary work-up occurred, PDN dose was increased by 10–15mg/d above the previous effective dose. If asymptomatic increases in acute-phase reactants were detected, PDN dose was held until the next visit. When a relapse could be defined, patients were managed as discussed above. If not, a reduction was attempted regardless of the ESR or CRP levels. We used a consensus definition of relapse established in the context of international multicenter clinical trials. Relapse or recurrence were indistinctly defined as reappearance of disease-related symptoms, usually accompanied by elevation of acute-phase reactants that required treatment adjustment. Relapses were categorized according to the clinical manifestation into 4 categories: 1) PMR, 2) cranial symptoms (headache, scalp tenderness, jaw claudication, cranial ischemic complications), 3) systemic disease (anemia, fever, and/or weight loss), or 4) symptomatic large vessel involvement (extremity claudication). Cranial ischemic manifestations included stroke, transient ischemic attacks, amaurosis fugax, GCA-related visual loss, or diplopia. Number of relapses, time (in weeks) from the initiation of treatment to first relapse, time required to reach a PDN maintenance dose <10mg/d (T10), <5mg/d (T5), and time required to complete GC withdrawal (T0), not followed by a relapse for at least 3 months, were recorded. Cumulated PDN doses received after the first year of treatment were calculated. For each episode of relapsing activity, the ESR, serum CRP, and Hb concentrations were determined, as well as the PDN dose received at that time. In addition, GC-related adverse effects including new or worsening hypertension, diabetes mellitus, hypercholesterolemia, osteoporosis, cataracts, and Cushing appearance were recorded. Measurement of bone mineral density with dual energy X-ray absorptiometry was performed at disease diagnosis and thereafter approximately every 2 years. Osteoporosis was diagnosed using the World Health Organization criteria–that is, bone mineral density T-score of 2.5 standard deviations (SDs) or more below the young adult mean. For screening of diabetes and hyperlipidemia, patients had blood tests prior to each visit, and blood pressure was periodically assessed both at their scheduled visits and by their primary care physicians. We recorded events as adverse events when they appeared or worsened after GC treatment and required new treatment or intensification of previous therapy. The study was approved by the Ethics Committee of Hospital Cl ınic (Barcelona, Spain). Statistical Analysis Continuous variables are presented as mean SD and/or median and interquartile range (IQR) and categorical data as percentages. Association between relapses and selected covariates was analyzed using the T-test (paired and unpaired) for quantitative variables and the chi-square test for categorical data. Time required to achieve maintenance PDN dose <10 mg/d, <5mg/d, and time to treatment discontinuation were compared between patients with and without relapses by the Kaplan-Meier survival analysis method. Statistical significance was defined as p<0.05. Calculations were performed with the statistical package PAWS statistics v 18 (SPSS Inc, Chicago, IL) and GraphPad Prism v 5.04 for Windows (GraphPad Software, La Jolla, CA). RESULTS We analyzed 106 patients. Mean age at diagnosis was 75 7 years (range, 58–89 yr) with a male to female ratio of 1:2.6. Demographic data and main clinical features at disease onset are depicted in Table 1. ã 2014 Lippincott Williams & Wilkins www.md-journal.com | 195 Medicine • Volume 93, Number 5, July 2014 Relapses in Giant Cell Arteritis