Oct. 06, 2010

Brain Involvement in an International Cohort of Lupus Patients

Prospective analysis of neuropsychiatric events in an international disease inception cohort of patients with system lupus erythematosus
Hanly, JG, Urowitz MB, Su L, Bae SC, Gordon C, Wallace DJ, Clarke A, Bernatsky S, Isenberg D, Rahman A, Alarcón GS, Gladman DD, Fortin PR, Sánchez-Guerrero J, Romero-Diaz J, Merrill JT, Ginzler E, Bruce IN, Steinsson K, Khamashta M, Petri M, Manzi S, Dooley MA, Ramsey-Goldman R, Van Vollenhoven R, Nived O, Sturfelt G, Aranow C, Kalunian K, Ramos-Casals M, Zoma A, Douglas J, Thompson K, Farewell V, for the Systemic Lupus International Collaborating Clinics (SLICC). (2010).  
Annals of the Rheumatic Diseases 69: 529-535.

What is the topic?
The reported frequency of “neuropsychiatric lupus” (NPL) (brain inflammation) varies widely, from 37% to 95%, in people with lupus, but severe inflammation of the brain is quite rare. The high degree of complications and variability reported across studies stems largely from differences in definitions used in studies of NPL, as well as the lumping together of very mild and very serious events without always separating symptoms that may be due to fatigue or pain from those that are really caused by inflammation. Even with more clinically significant events, some studies have lacked consistency in determining if the events are related to lupus.  

What did the researchers hope to learn?
The researchers hoped to accurately determine the frequency and outcome of NPL, as well as its impacts on quality of life. This ongoing study will follow people with newly diagnosed lupus over 10 years. This paper is an early report of this study. 

Who was studied?
1,206 people with recently diagnosed lupus in the U.S., Canada, Mexico, Europe, and Asia participated in the study. The patients were mostly Caucasian women with an average age of 34 years and a disease duration of five months. The patients had a wide variety of clinical symptoms of lupus, and were taking a variety of treatments such as steroids, anti-malarials, immunosuppressives, aspirin, warfarin, anti-depressants, and others.   

How was the study conducted?
1,206 people with lupus have been enrolled in the study within 15 months of lupus diagnosis and are being evaluated each year. The current paper is reporting the outcomes after patients have been followed, so far, for an average of two years.  

Among the information being collected about the patients at a yearly visit are the following: age, gender, ethnicity, education, medications, and lupus disease activity (SLEDAI and SDI), as well as any impact of lupus on various organs (SLICC Damage Index). A number of laboratory measures were reviewed each year as well.  
New NPL events since the last visit were recorded at each visit. NPL events were strictly defined by use of the American College of Rheumatology case definitions for NPL. 

For each patient, the time to resolution and outcome of NPL events were recorded and patient-perceived quality of life was determined by use of a questionnaire called the SF-36, in which a person can rate how they are functioning both mentally and physically.  

What did the researchers find?
If you did not factor in whether an event was minor or severe or whether or not it was due to lupus, then 486 (40.3%) patients had at least one NPL event during the study and 210 (17.4%) had two or more. The most common event was headaches, which are common events in any group of people and usually not due to lupus. (The types of headaches described were migraine, 49%; tension, 38%, and intractable headaches, 9%). Other NPL events included mood disorders, seizures, problems thinking clearly or performing mental tasks, anxiety disorders, acute confusional states, and nerve inflammation (usually in the arms or legs). There are 10 other NPL types among the American College of Rheumatology case definitions that affected less than 2% of patients. One such type, myasthenia gravis, did not occur in any patient in this study. 

There were two sets of rules that the researchers came up with to see if these events affecting the brain or nervous system should be attributed to lupus or not. When the most stringent set of rules was applied, only 17% of the events were attributed to lupus. The most common events attributed to lupus were seizures, mood disorders, and acute confusional states; these were not very common overall.  

No differences were observed in how frequently events were attributed to lupus if they were new, recurring, or ongoing. Interestingly, the rate that the events resolved or went away with treatment was higher in those attributed to lupus than in those not attributed to lupus. Outcomes were better for events attributable to lupus. Outcomes were worse for patients who were older, as well as for those who had been diagnosed with lupus for longer when the event occurred, and those with more active lupus in other organs. 

People who had NPL events that were attributed to lupus reported more impact on their mental state when filling out the questionnaire compared to those without any NPL events. After accounting for other factors such as age and lupus duration, the patients who reported that their mental state was affected had higher active lupus disease activity (SLEDAI), as well as greater impact on organs (SDI) and physical functioning. 

What were the limitations of the study?
The frequency of patients with unavailable data (29%) or no follow-up (15.8%) by the final study assessment was high compared to those of other studies. This may be related to the fact that patients are only seen once a year for this international study. Also, formal neuropsychological assessment and/or brain imaging studies were only conducted in a small subset of patients. If that kind of sophisticated information was more widely available, it would be a major asset to this kind of study. On the other hand, the physicians involved in this study were all members of the Systemic Lupus International Collaborating Clinics, experts on lupus, and working in major centers. Therefore, to a large extent, it is likely that when more complicated (and expensive) testing was not ordered, it was not needed. It will also be important to see the information over time, when the patients have had lupus for a longer period of time.     

What do the results mean for you?
The frequency of NPL events in people with lupus, which can really be attributed to lupus, is probably less than previously thought, and severe or irreversible events are not common. This information is holding up internationally. Furthermore, those NPL events that are attributed to lupus result in better outcomes. NPL events seem to have more impact on older patients with more active disease in other organs, and who have had lupus for a longer period of time. For this reason, it will be important for this study to continue over time to see whether these early predictions hold up and/or whether new treatments that emerge will have an impact on NPL. NPL events can affect a person’s perceptions about both mental and physical functioning and, therefore, can potentially have a high impact on quality of life when they occur. 

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