In this study, we examined the course of fatigue severity in a large, multi-ethnic cohort of early SSc patients. To our knowledge, the current study represents the first longitudinal examination of fatigue in SSc. FSS levels did not increase or decrease during the follow up time in the overall cohort, though patients with lower baseline DLco levels experienced an increase in their fatigue severity over time. Demographic, clinical, and psychosocial variables were all independent predictors of sequentially obtained FSS scores. Severity of GI and joint involvement and presence of anti-U1 RNP antibodies were independent predictors of FSS in the multivariable model of clinical factors. Baseline perceived pain levels, coping skills (IBQ), and GI involvement were independent predictors of longitudinal FSS in the final extended multivariable model.
Higher baseline scores of the Medsger Gastrointestinal Severity Index were predictive of higher FSS scores. This supports a reported association of GI involvement and higher fatigue scores in a cross sectional study of SSc patients 
. GI involvement is very common in SSc patients and its strong association with depression has been previously reported 
. The association of GI dysmotility with fatigue severity may have several direct and indirect causes. Patients with diarrhea and decreased intestinal absorption might develop nutritional deficiencies with subsequent muscular and electrolyte abnormalities. Moreover, diarrhea and abdominal pain might interfere with sleep, resulting in higher fatigue scores. In patients with chronic fatigue syndrome, abdominal pain was stressful, but nocturnal diarrhea was found to further disrupt an already disrupted sleep pattern 
. Fatigue is also a prominent feature of autoimmune diseases with primary GI manifestation such as Crohn's disease. In a randomized controlled study examining the effects of adalimumab therapy in patients with moderate to severe Crohn's disease, adalimumab maintenance therapy provided sustained improvement in fatigue severity compared to conventional immunosuppressive therapy 
In the current study, higher Medsger Joint Severity Index predicted higher FSS scores. The role of joint involvement as contributor to fatigue severity in SSc has not been previously reported. However, fatigue is also a prominent feature of other autoimmune diseases that primarily affect joints such as rheumatoid arthritis (RA) 
. The effect of conventional disease modifying antirheumatic drugs (DMARD) on fatigue severity compared to placebo in RA has not been investigated but a significant improvement in fatigue severity in patients with moderate to severe RA was reported with adalimumab treatment compared to conventional DMARD therapy 
. Furthermore, aerobic exercise, with most regimens consisting of 3 times weekly for 30–60 minutes exercises, was effective in treatment of fatigue in patients with RA (reviewed in 
). Similar to RA, exercise habits were the only demographic variable predictive of fatigue severity in our study. This finding supports future interventional studies examining the efficacy of exercise regimens for treatment of fatigue in SSc.
Presence of U1-RNP antibodies were predictive of higher sequentially obtained FSS levels. Autoantibodies are important predictors of various disease manifestations in SSc 
. The association of SSc-related antibodies with fatigue severity has not been examined in previous publications. The U1-RNP antibodies are associated with overlap cases of SSc with other connective tissue diseases such as SLE and polymyositis. It is possible that experiencing features of multiple connective tissue diseases can lead to more severe fatigue.
In the final model, two patient-reported outcomes (pain and IBQ) were predictive of higher FSS levels. The blockwise hierarchical analysis indicated that patient-reported variables contributed to fatigue beyond the effect of clinical and demographic factors. Although the relationship of the patient-reported variables to FSS might be bidirectional (e.g. pain and IBQ influence FSS and vice versa). The reported multivariable model with objective clinical variables is least susceptible to problems arising from the bidirectional relationship between the predictor and outcome variables. However, we did not confine our study to objective clinical predictors because this would have ignored important subjective determinants of FSS. Furthermore, we did not only investigate the relationship of the above mentioned independent variables with the concomitantly obtained FSS levels but we also investigated whether they have predictive significance for FFS levels obtained on subsequent visits.
Inappropriate illness behavior (coping) captured by a higher IBQ score was an independent predictor of longitudinal FSS. The IBQ assesses a spectrum of illness behaviors or modes of perceiving, evaluating, or acting in relation to one's own state of health that may be in contradistinction to an accurate appraisal of the condition and prescribed treatment 
. Similar to our results, the LUMINA study has demonstrated the association of higher IBQ scores with higher scores of perceived fatigue in SLE 
. Furthermore, it has also been shown that higher IBQ scores reflecting worse coping behavior can affect the quality of life in SLE patients 
. In patients with RA, group cognitive behavioral therapy for fatigue self-management (coping) was found be effective in treating fatigue severity in a recently published randomized controlled trial 
. Our study provides further support for similar interventional studies in SSc, examining the efficacy of self management and coping strategies for treatment of fatigue.
Pain was another patient-reported variable that predicted higher FSS levels in our study. This finding is in agreement with longitudinal studies of fatigue in patient with SLE 
. Pain in SSc can be caused by various disease manifestations such as joint pain, digital ulcer, heartburn, and tendon friction rub 
. Better treatment of pain and more effective management of its underlying causes might alleviate fatigue severity in patient with SSc.
FSS scores did not increase or decrease during the follow up time in the overall cohort. Factors leading to worsening fatigue such as increasing age and disease damage might be counterbalanced by improving adaptive behaviors leading to stable longitudinal fatigue severity in SSc. A study of a longitudinal cohort of 122 patients with RA also reported that FSS scores did not change appreciably over time 
. Furthermore, studies in patients with chronic fatigue syndrome indicated that patients with longer disease duration had better adaptive coping strategies than those with shorter disease duration, supporting the hypothesis that patients with chronic illnesses develop better coping skills for dealing with fatigue over time. Another possible explanation for stable longitudinal fatigue levels is that fatigue might be related to inherent perceived health or coping mechanisms. Although the success of exercise regimens 
, behavioral 
and pharmacological 
interventions for treatment of fatigue in other rheumatic diseases indicates that this disease manifestation is modifiable and not solely related to related inherent and non-modifiable patient characteristics.
DLco% predicted was the only baseline variable that was predictive of change in fatigue severity. A similar trend was observed for FVC although it did not reach statistical significance. This finding indicates that patients with more extensive lung involvement are more likely to experience an increase in their fatigue levels over time. Several medications are effective in treatment of pulmonary arterial hypertension (reviewed in 
) and cyclophosphamide is beneficial for treatment of interstitial lung disease in SSc 
. It is unclear whether treatment with these agents can lead to a reduction in fatigue severity in SSc. Furthermore, the role of pulmonary rehabilitation in treatment of lung impairment and fatigue also has not been investigated in SSc. In patients with chronic obstructive pulmonary disease, pulmonary rehabilitation for 3 months was effective for treatment of dyspnea and fatigue 
The current study had some limitations. The majority of study subjects were recruited from tertiary medical centers, which might skew the study population toward patients with more severe involvement. Furthermore, we did not have information on sleep disturbances in the GENISOS cohort, a factor that might be an independent predictor of fatigue in SSc. Furthermore, we did not use a designated questionnaire for capturing depressive symptoms in the GENISOS.
Fatigue is a prominent and debilitating problem for a large number of SSc patients. Our results indicate that potentially modifiable clinical and psychological factors predict longitudinal fatigue severity. Measures to decrease physical burden of disease such as respiratory, GI and joint involvement, as well as interventions focusing on improving coping skills and pain could potentially improve fatigue severity in SSc.