Fatigue in Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis: Analysis from a Longitudinal Observation Cohort Mohamed Bedaiwi, Ismail Sari, Arane Thavaneswaran, Renise Ayearst, Nigil Haroon, and Robert D. Inman ABSTRACT. Objective. In this study, we aimed to address the prevalence of fatigue, its associated factors, and the effect of tumor necrosis factor inhibitors (TNFi) on this subgroup of patients in a large axial spondy- loarthritis (axSpA) cohort. Methods. The study included 681 patients [ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA)]. The Fatigue Severity Scale (FSS) and the Bath AS Disease Activity Index question 1 (BASDAI Q1) indices were used for fatigue assessment. Severe fatigue was defined as an FSS ≥ 4 or a BASDAI Q1 ≥ 5. Disease activity, function, and quality of life (QoL) measures were recorded. Patients who had been treated with TNFi were identified, and baseline and followup data were analyzed. Results. Of the cohort, 67.3% had severe fatigue, and the prevalence was similar between AS (67.2%) and nr-axSpA (68.2%). Severely fatigued patients tended to have higher disease activity scores, increased acute-phase proteins, and decreased QoL measures. TNFi therapy was associated with improvement in disease activity, and although this treatment led to significantly decreased fatigue scores, this reduction was not optimal in the majority of patients with 80% continuing to have severe fatigue according to their posttreatment scores. Health Assessment Questionnaire, mean scores of BASDAI Q5 and Q6, and BASDAI enthesitis were independent predictors of fatigue severity. Conclusion. Fatigue is a common symptom in axSpA, and the burden of fatigue among patients with nr-axSpA is similar to that seen in AS. While biologics are effective in improving disease activity, their effect on fatigue is more limited. In axSpA, fatigue remains unresponsive to TNFi in nearly 80% of patients. (First Release November 1 2015; J Rheumatol 2015;42:2354–60; doi:10.3899/jrheum.150463) Keyword Indexing Terms: ANKYLOSING SPONDYLITIS QUALITY OF LIFE INFLAMMATION α FATIGUE TUMOR NECROSIS FACTOR- SPONDYLOARTHROPATHIES Ankylosing spondylitis (AS) is a chronic inflammatory as a state of reduced muscle capacity and decreased work disease that primarily affects the axial skeleton. Fatigue, one ability accompanied by feelings of tiredness, weariness, and 1,2 of the major clinical features of rheumatic diseases, is defined lack of energy . In addition to pain and stiffness, fatigue is a major clinical feature of AS, yet it has often been ignored 1,2,3 From the Division of Rheumatology, Toronto Western Hospital, University in clinical practice . On the other hand, fatigue forms one of Toronto, Toronto, Ontario, Canada; Department of Medicine, Division of the components of the Bath AS Disease Activity Index of Rheumatology, King Khalid University Hospital, King Saud University, (BASDAI), which is commonly used for defining disease Riyadh, Saudi Arabia; Department of Rheumatology, School of Medicine, 4 Dokuz Eylul University, Izmir, Turkey. activity in AS . Thus, increased fatigue levels may yield M. Bedaiwi, MD, Division of Rheumatology, Toronto Western Hospital, higher BASDAI scores and may affect decision making University of Toronto, and Department of Medicine, Division of regarding treatment. AS can adversely affect quality of life Rheumatology, King Khalid University Hospital, King Saud University; (QoL), as well as the psychological and economic status of I. Sari, MD, Division of Rheumatology, Toronto Western Hospital, 5 University of Toronto, and Department of Rheumatology, School of patients . Fatigue is a common problem even in the Medicine, Dokuz Eylul University; A. Thavaneswaran, MSc, Division of population at large, with 14–25% of healthy subjects Rheumatology, Toronto Western Hospital, University of Toronto; complaining of fatigue6. Fatigue is reported in more than half R. Ayearst, BSc, Division of Rheumatology, Toronto Western Hospital, 1,2,3,7,8,9,10,11,12 University of Toronto; N. Haroon, MD, PhD, DM, Division of of patients with AS . Current understanding of Rheumatology, Toronto Western Hospital, University of Toronto; fatigue and its related factors in axial spondyloarthropathy R.D. Inman, MD, FRCPC, FACP, FRCP, Division of Rheumatology, (axSpA) is still limited. Although fatigue is a key element of Toronto Western Hospital, University of Toronto. Address correspondence to Dr. R.D. Inman, Division of Rheumatology, disease activity scores in AS, the effect of pharmacological Toronto Western Hospital, University of Toronto, Toronto, Ontario therapy is incompletely understood. Better understanding of M5G 2R2, Canada. E-mail: [email protected] factors that exacerbate or ameliorate fatigue can provide Accepted for publication August 13, 2015. valuable clues for the optimal management of axSpA. In our Personal non-commercial use only. The Journal of Rheumatology Copyright © 2015. All rights reserved. 2354 The Journal of Rheumatology 2015; 42:12; doi:10.3899/jrheum.150463 Downloaded on October 2, 2021 from www.jrheum.org study, we aimed to address the prevalence of fatigue, its anemia were subjected to linear regression analysis to evaluate multi- associated factors, and the effect of TNFi on this subgroup collinearity among the predictors or the independent variables. The results of the analysis showed that ASDAS-CRP, spinal pain, and BASFI had a of patients in a large axSpA cohort. tolerance statistic below 0.2. Thus, as a violation of multicollinearity assumption, these variables were excluded from the model25. Baseline and MATERIALS AND METHODS followup comparison of the patients were done by using the Wilcoxon Patients. The patients were drawn from the database of the spondylitis clinic. signed-rank and McNemar tests. A double-tailed p value of < 0.05 was This database was derived from a longitudinal observation cohort composed considered statistically significant. of all consecutive patients seen between 2003 and 2014. The referral sources for the spondylitis clinic included community rheumatologists, family physi- RESULTS cians, gastroenterologists, and ophthalmologists. Patients with axSpA were evaluated according to a standard protocol in which full demographic, Demographics and disease characteristics. There were 681 clinical, and laboratory details were recorded at yearly intervals. For our patients (489 men and 192 women) in our study. The median current study, we included subjects who were ≥ 18 years old and had been age of the patients was 40.5 (IQR 31–51) years. Sixty-six out 13 14 diagnosed with AS or nonradiographic axSpA (nr-axSpA) . Our study of 681 patients (9.7%) were diagnosed with nr-axSpA. The was approved by the hospital’s Research Ethics Board. median disease duration of the group was 8 years (IQR 3–16) Outcome assessments. The primary outcome measure in our study was the and 77.7% were HLA-B27–positive. Nearly half the patients Fatigue Severity Scale (FSS), which measures motivation, physical activity, and social and functional effects of fatigue. FSS consists of 9 questions, (48.2%) were receiving TNFi therapies. The median FSS was scored on a 0–10 numerical rating scale, and the final value is the mean of 4.7 (IQR 2.6–7.4) and the median fatigue level according to all items15. Fatigue score was also recorded from the BASDAI question 1 BASDAI Q1 was 5 (IQR 2–7). According to the FSS ≥ 4 and (BASDAI Q1)4. Disease activity was evaluated by the BASDAI4 and the BASDAI Q1 ≥ 5, 58.4% and 54.9% of the group were AS Disease Activity Score (ASDAS)16 indices. Functional activity was 17 classified as severely fatigued, respectively. The frequency determined by the Bath AS Functional Index (BASFI) score . Radiological of total severe fatigue (patients who have total FSS ≥ 4 or changes were evaluated by using modified Stokes AS Spinal Score (mSASSS)18. QoL and health status were assessed by the AS Quality of Life BASDAI fatigue ≥ 5) was 67.3. Table 1 summarizes the (ASQoL)19 and the EQ-5D20 health questionnaires. The Medical Outcomes clinical and laboratory characteristics of the patients. Study Short Form-36 (SF-36)21 and the Health Assessment Questionnaire Comparison of severe versus low fatigue patients. 22 (HAQ) were used to assess the functional health and well-being status of Comparison of patients with severe (n = 458) versus low the patients. Besides clinical and laboratory features, we also identified (n = 223) fatigue states revealed that these factors were patients who had been treated with TNFi. Prior to starting a biologic, as part significantly higher in the severely fatigued subset: enthesitis, of protocol, all patients received baseline blood work and were reviewed after 3 months of therapy to evaluate the response to treatment. Responses arthritis, acute-phase measures (CRP and ESR), at 3 months were analyzed for our study. ASDAS-CRP, total BASDAI, BASDAI inflammation, Definition of variables. Severe fatigue was defined as a value of ≥ 4 based BASDAI spinal pain, BASDAI arthralgia, BASDAI enthe- on the FSS15 or ≥ 5 according to the BASDAI Q112,23. Total severe fatigue sitis, BASFI, HAQ, ASQoL, and age (p < 0.05). SF-36 is defined as patients who have total FSS ≥ 4 or BASDAI fatigue ≥ 5. mental component summary (MCS), SF-36 physical BASDAI inflammation refers to the mean of BASDAI questions 5 and 6. component summary (PCS), and EQ-5D indices were signifi- BASDAI spinal pain, arthralgia, and enthesitis refer to questions 2, 3, and cantly higher in the low fatigue