Our comparative cross-sectional study extends the current understanding of the intricate relationship between SLE and headaches, integrating insights from studies that explore diverse facets of this association [3–24] [Table 5].
The prevalence of headaches in systemic lupus erythematosus (SLE) patients, ranging from 28.5% up to 82% in previous studies [3-24], aligns with our findings where headaches were observed in 55% of our SLE cohort. This huge variance in prevalence among studies can be explained by methodological differences, variable numbers of patients and the headache types and criteria to define headache types varied widely. Despite observing a female predominance in our SLE cohort, in line with established epidemiological patterns, we found no significant differences in age, sex distribution, or disease duration between SLE patients with and without headaches.
In a related study focusing on childhood SLE, Santos and colleagues, examined a population of 1463 SLE patients, revealing that 29.9% presented 869 neuropsychiatric SLE events, averaging 2.48 events per patient. Headache was reported in 52.2% of these cases [23].
However, it is noteworthy that a meta-analysis conducted by Mitsikostas and colleagues, presents a contrasting perspective. Pooled data from seven controlled studies in their analysis showed that the prevalence of all headache types, including migraine, did not differ significantly from controls [8].
As for headache subtypes, notably, migraine (27%) and tension-type (65%) headaches emerged as the predominant subtypes, consistent with existing literature. None of our patients found to have SLE headache, this comes in agreement with other studies where it was 1.5% in the study by Hanly and colleagues [18], and none in the study of Aloleimy and colleagues. [4], questioning this type of headache and its clinical significance, emphasizing the need for a standardized classification system for lupus-related headaches to enhance diagnostic precision as the available evidence fall short in supporting the concept of a distinct entity known as 'lupus headache.
In recent decades, researchers have explored the intersection of migraines and immunological/autoimmune disorders due to substantial evidence linking both conditions. Epidemiologically, both conditions predominantly affect females, with an onset typically at young ages [31, 32]. Pathologically, shared genetic components, particularly involving human leukocyte antigens (HLA) and cytokine polymorphisms [33], establish a connection between migraine pathogenesis and autoimmune disorders. This association is further underscored by elevated levels of pro-inflammatory cytokines like TNF-α, IL-1β, IL-6, and IL-8 in migraines, indicative of a persistent pro-inflammatory environment [34]. Notably, during migraine attacks, there is an increase in IL-10 levels, suggesting a compensatory anti-nociceptive response [35]. Additionally, immune cell subsand colleaguesterations, involving natural killer cells, as well as CD4+ and CD8+ lymphocytes [36], hint at potential dysregulation contributing to the underlying pathophysiology of migraines.
As for lupus headache, its pathophysiology exhibits two primary pathways. The ischemic-vascular mechanism involves antiphospholipid antibodies (aPL), immune complexes, and leuko-agglutination, contributing to focal neuropsychiatric manifestations. The inflammatory-neurotoxic mechanism includes complement activation, increased blood-brain barrier permeability, migration of intrathecal autoantibodies, and local production of pro-inflammatory cytokines, associated with diffuse neuropsychiatric manifestations [28].
Shifting focus to tension-type headaches, although they have received limited attention in terms of immune system derangement, there are indications of increased pro-inflammatory cytokines, particularly in the cerebrospinal fluid [37]. For cluster headaches, there is also evidence suggesting a role for immunological dysfunctions in the pathogenesis of this disorder, indicated by a negative association with HLA-B14, an increase in natural killer (NK) cytotoxicity, elevated receptor expression of classical neurotransmitters associated with pain, and elevated levels of proinflammatory cytokines such as IL-1β [38].
We noted that headache sufferers exhibiting a higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score in comparison to SLE patients without headache (p < 0.0001). This aligns with the conclusions drawn in the study by Appenzeller and colleagues (2004), where migraine in SLE patients was linked to elevated MEX-SLEDAI scores [12]. The association emphasizes the potential clinical relevance of headaches as a marker for increased SLE disease activity.
Although we observed a non-significant correlation between the severity of headaches and the disease activity assessed through the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), consistent with findings reported by Katsiari and colleagues (2011) and other researchers [3–9].
Unexpectedly, our investigation did not uncover a substantial link between the existence of headaches and specific clinical manifestations. This discovery contradicts certain studies that highlighted musculoskeletal and neuropsychiatric manifestations as prevalent in individuals experiencing headaches [4]. On the other hand there was notable correlation between migraine and tension headache and mucocutaneous manifestations. Notably, Appenzeller identified a significant association between migraine and Raynaud's phenomenon as well as organ damage [12].
Additionally, APL antibody positivity showed a statistically significant association with migraine and cluster headache.
Our findings are consistent with prior research that underscores the potential involvement of anti-phospholipid (aPL) antibodies in SLE-related headache [4], going on line with previous studies that explored the role of autoantibodies in neuropsychiatric manifestations. Faust and colleagues.'s investigation into neurotoxic lupus autoantibodies [25], and Toubi and Shoenfeld's identification of the association of anti-P antibodies with neuropsychiatric symptoms [26], offer compelling evidence of a direct immunological link between SLE and neurological dysfunction. Yoshio and colleagues.'s focus on IgG anti-NR2 glutamate receptor autoantibodies adds another layer to our understanding, connecting inflammatory processes to neurological symptoms, including headaches [27].
In Fragoso-Loyo's study, patients with headaches displayed elevated cerebrospinal fluid (CSF) levels of IL-6, IL-8, IP-10 RANTES, and MIG compared to non-NPSLE and non-autoimmune disease patients. Autoantibodies, such as anti-ribosomal-P, anti-DNA/NR2, antiphospholipid (aPL), and anticardiolipin (aCL), significantly contribute to neuropsychiatric systemic lupus erythematosus (NPSLE), contributing to neurotoxicity and blood-brain barrier (BBB) dysfunction [29]. Notably, associations of autoantibodies to β2-glycoprotein I (β2GPI) with non-specific intractable headaches, ischemic stroke, and seizures in NPSLE patients suggest their potential to surpass the predictive value of other autoantibodies like aCL or lupus anticoagulant [30].
In our patient cohort, nearly 92% exhibited no abnormalities in brain MRI scans. Consistent with findings from other studies [1], we did not observe any significant association between cerebral lesions and headache characteristics, including types. Nevertheless, our investigation pinpointed ischemic stroke followed by cerebral venous thrombosis as the primary MRI abnormalities. Both cases of CVT were having TTH, 4/5 cases with ischemic stroke were migrainous. Only one case had hyperintensities on MRI.
Several studies have delved into brain imaging findings in SLE patients, providing valuable insights. Nobili and colleagues (2006) noted focal hypoperfusion in 83% of SLE patients with migraines using brain SPECT [39]. Bicakci and colleagues (2008) established a correlation between abnormal MRI findings and prolonged disease duration, suggesting progressive neurological involvement in SLE [16]. In a study by Sarbu and colleagues (2015), brain abnormalities were identified in 59.3% of neuropsychiatric lupus patients, with small vessel disease predominantly correlated with lupus anticoagulant [20]. Zaky and colleagues (2015) reported brain abnormalities in 38.2% of SLE patients, with those diagnosed with NPSLE showing higher frequencies of white matter changes, ischemia, hemorrhage, and encephalopathy [40]. Tjensvoll and colleagues (2016) associated migraine in SLE with reduced cerebral grey matter volume [21], while Son and colleagues. (2016) linked chronic daily headache in SLE with neuronal dysfunction and neurometabolic changes [41]. Papadaki and colleagues (2018) explored cerebral perfusion abnormalities using perfusion-weighted MRI, emphasizing cerebral hypoperfusion in SLE patients with headaches and suggesting a potential vascular component [22]. A recent study by Aloleimy and colleagues (2021) found brain imaging abnormalities in 25.8%, with white matter hyperintensities being the most frequent pathology [4].
The MRI findings in SLE patients with headaches highlight a convergence of structural, vascular, and immunologic aspects. The evidence of progressive structural abnormalities, cerebral hypoperfusion, and the correlation with autoantibodies enhance our understanding of the intricate neurobiological landscape in SLE.
While the study has yielded valuable insights, it is crucial to recognize its limitations, which include a single-center design, the cross-sectional nature of the investigation, potential selection bias, reliance on self-reported headache data, and limited neurological parameters.
Future research avenues may involve exploring biomarkers associated with neuroinflammation or vascular dysfunction in SLE patients with headaches, conducting longitudinal studies to evaluate the impact of various SLE treatment modalities on headache prevalence and severity, investigating genetic factors contributing to the co-occurrence of SLE and headaches, and designing interventions to assess the efficacy of headache management strategies in SLE patients.