Primary headache in SLE -systematic review and meta-analysis

To systematically review and synthesize literature on: 1) the overall prevalence of primary headaches and specifically migraines, in patients with lupus since previous systematic review published in 2004; 2) the risk factors associated with primary headaches in patients with lupus; 3) the association of primary headaches with structural brain changes; and 4) "lupus headaches".

This review used (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) PRISMA guidelines and literature searches in four databases: Ovid-based Medline, Embase, PsycINFO, and Cochrane Database of Systematic Reviews from inception until 4/2022. Papers on primary headaches in patients with lupus were identified. Included studies were critically appraised and analyzed. Since a systematic review on this topic was published in 2004, only papers published in 2004 and later were included in this review. Statistical and publication bias was assessed using funnel plots.

A total of 5096 references were identified, 189 were selected for detailed review and 11 papers were included in the final analysis. 1) The pooled prevalence of primary headaches in lupus was 26.8 % (95 %CI 25.1-28.6). The prevalence of primary headaches was similar between patients with lupus and healthy controls, odds ratio (OR) 2.14, 95 %CI 0.97-4.76, p value=0.06, however publication bias was significant according to the Egger test. Lupus patients seem to have a higher prevalence of primary headaches compared to patients with rheumatoid arthritis (RA) and primary Sjogren's syndrome (pSS), OR 2.5, 95 % CI 1.56-4, p < 0.0001. Regarding the prevalence of migraines specifically, no difference was found between patients with lupus compared to healthy controls and patients with RA or pSS. 2) Primary headaches seem to be associated with depression and impaired health related quality of life rather than lupus activity or damage. There is insufficient data to conclude whether specific lupus treatments affected primary headaches in lupus, however, one study did suggest hydroxychloroquine reduced the frequency of primary headaches. Raynaud phenomenon was associated with migraines. 3) One study which examined MRI scans of patients with lupus compared to healthy controls did suggest that larger gray matter volumes reduced the odds for headaches in general (OR 0.98, p = 0.048) and for migraines in particular (OR 0.95, p = 0.004), and larger white matter volumes increased the odds for migraine (OR 1.04, p = 0.007). However, these findings might reflect disease activity or damage, therefore further studies are required to clarify this issue. 4) The only study which specifically addressed the prevalence of "lupus headaches" is Hanly's study from 2013 of the SLICC cohort. In this large cohort, only 1.5 % of patients had "lupus headaches", as defined by SLE Disease Activity Index-2000 (SLEDAI-2 K). Therefore "Lupus headache" is a rare entity in SLE and should be suspected after excluding other possible explanations for headaches, especially when there is no known prior history of primary headaches.

Patients with lupus seem to have a similar prevalence of primary headaches, and specifically migraines, compared to healthy controls. These primary headaches are associated with depression and Raynaud phenomenon and not with disease activity nor damage. Scarce data is published regarding structural changes associated with primary headaches. Currently is seems "lupus headaches" are a distinct rare manifestation of lupus and more data are needed.