Abstract: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology, characterized by a wide range of manifestations that can vary from mild to severe or even life-threatening multiple organ system involvement. SLE predominantly affects women and has a peak incidence during women’s reproductive age. Given the complexity of SLE, managing pregnancy in these women is particularly challenging, as the disease itself can impact pregnancy outcomes, and conversely, pregnancy can exacerbate SLE symptoms. This thesis aims to explore pregnancy complications among women with SLE and to assess the feasibility of utilizing specific biomarkers for evaluating the risk of adverse outcomes in SLE pregnancies, as well as their potential to predict these outcomes. Paper I: A descriptive study on adverse pregnancy outcomes (APOs) in a Swedish population was conducted, involving 28 women diagnosed with SLE and 59 pregnancies monitored from 2002 to 2018 at Skåne University Hospital. The study aimed to determine the prevalence of each APO and to assess demographic, clinical, and laboratory risk factors. Most pregnancies experienced at least one APO, although only a small number were categorized as severe. It was shown that a history of lupus nephritis was the clinical feature most strongly associated with APOs. Moreover, the co-occurrence of SLE and antiphospholipid syndrome was linked to an increased risk of miscarriage, and the presence of one or more antiphospholipid antibodies was correlated with APOs overall. In papers II and III, the aim was to investigate, in 100 healthy women with 100 normal pregnancies selected from the pregnancy register and biobank at Linköping University (GRABB), if pregnancy influences the normal reference values of biomarkers such as complement proteins and pentraxins, to establish a reference interval that is more appropriate for the pregnancy period. Paper II: This study investigated the complement system, which is a vital component of the humoral innate immune system that exhibits increased activity during pregnancy. This function is necessary for maintaining the host's defense and ensuring fetal survival. However, excessive or unbalanced activation of the complement system in the placenta has been linked to various APOs. The study found that maternal plasma C1q and the C3d/C3 ratio had their highest mean values during the first trimester, while C3, C4, and C3d levels increased until delivery. However, the reference limits for complement analyses used for the general population were generally suitable for most of the samples in the study. This suggests that while there were some deviations from the norm in complement levels in certain pregnant women, the standard reference values still adequately captured the overall trends in complement activity during pregnancy in this population. Paper III: This study investigated the same population as in paper II and focused on two types of pentraxins: the liver-produced short pentraxin C-reactive protein (CRP), which is commonly used in clinical practice, and the leukocyte-produced long pentraxin 3 (PTX3), which is structurally and functionally related to CRP. Both pentraxins were previously described as biomarkers related to various APOs. The study found that both CRP and PTX3 levels were significantly elevated in the third trimester compared to the other trimesters. This suggests that during pregnancy, particularly in the later stages, reference values for these biomarkers may need to be adjusted to account for these physiological changes, highlighting the importance of considering pregnancy-specific reference values for these markers. Paper IV: Plasma levels of CRP, PTX3, C3, and C4 were assessed during 123 pregnancies in 102 patients with SLE and 170 pregnancies in women from the general population concerning the risk of APOs. All the patients and controls were recruited from three Swedish cohorts: the Lund cohort, referenced in Paper I; the GRABB cohort, which is mentioned in Papers II and III; and the SLE-Placenta cohort (SLE-PLAC) which is a multicenter Swedish cohort. Only PTX3 showed higher levels in the first and third trimesters of SLE pregnancies with APOs. Even after including control pregnancies with APOs, PTX3 levels remained significantly higher in complicated pregnancies, suggesting that PTX3 could serve as a potential biomarker for identifying at-risk complicated pregnancies.

Conclusion: The incidence of APOs in pregnancies affected by SLE is significantly higher than in the general population, highlighting the urgent need for risk stratification and increased attention to specific clinical and serological risk factors in these cases. It is essential to note that reference intervals for some biomarkers may require adjustment during the pregnancy period to ensure accurate interpretation. While our findings need to be confirmed, the pentraxins especially PTX3 could be used for the risk stratification of pregnant women with SLE. 

Hematologic abnormalities are common manifestations of SLE, although neutropenia is observed less frequently and is not included in the classification criteria. Nonetheless, neutropenia is a risk factor for infections, especially those caused by bacteria or fungi. We aimed to evaluate the impact of neutropenia in SLE through a systematic investigation of all infections in a large cohort of well-characterized patients, focusing on neutropenia, lymphopenia, and hypocomplementemia. Longitudinal clinical and laboratory parameters obtained at visits to the Rheumatology Unit, Link & ouml;ping University Hospital, and linked data on all forms of healthcare utilization for all the subjects included in our regional SLE register during 2008-2022 were assessed. Data regarding confirmed infections were retrieved from the medical records. Overall, 333 patients were included and monitored during 3,088 visits to a rheumatologist during the study period. In total, 918 infections were identified, and 94 occasions of neutropenia (ANC < 1.5 x 10(9)/L) were detected in 40 subjects (12%). Thirty neutropenic episodes in 15 patients occurred in association with infections, of which 13 (43%) required in-hospital care, 4 (13%) needed intensive care, and 1 (3%) resulted in death. Bayesian analysis showed that patients with >= 1 occasion of neutropenia were more likely to experience one or more infections (OR = 2.05; probability of association [POA] = 96%). Both invasiveness (OR = 7.08; POA = 98%) and severity (OR = 2.85; POA = 96%) of the infections were significantly associated with the present neutropenia. Infections are common among Swedish SLE patients, 12% of whom show neutropenia over time. Importantly, neutropenia is linked to both the invasiveness and severity of infections. Awareness of the risks of severe infections in neutropenic patients is crucial to tailor therapies to prevent severe illness and death.

ObjectiveVariations in prevalence and incidence of systemic lupus erythematosus (SLE) within a geographically defined area of central Sweden over a time period of 14 years were examined. Longitudinal differences in disease activity, laboratory test results, and damage accrual were investigated. MethodsAdults (aged & GE;18 years) residing in ostergotland County between 2008 and 2021 (mean adult population: 357,000 citizens) with confirmed SLE were identified and followed prospectively until death, December 31, 2021, or emigration. We estimated annual incidence per 100,000 inhabitants stratified by sex and age. Linear regression with year of diagnosis as the outcome assessed whether each clinical measurement at diagnosis varied over time. ResultsPrevalence on December 31, 2021, was 71.5 of 100,000 (87% female). One hundred twenty-six new cases were identified during the study period, yielding a mean annual incidence of 3.0 of 100,000 inhabitants; this was higher in females (4.8/100,000) than in males (1.2/100,000). Mean age at diagnosis was 43.7 years (SD 17.3). Age at diagnosis and disease activity measures increased over the calendar year of diagnosis (P < 0.05) whereas disease manifestations, including lupus nephritis, did not vary significantly. Accrual of organ damage was demonstrated over time since diagnosis and stratified by sex, lupus nephritis, and corticosteroid-related damage. Approximately 40% developed damage within 5 years. ConclusionSLE prevalence and incidence estimates remained constant over 14 years, and disease phenotypes at SLE onset were similar. SLE was diagnosed also among older individuals with a smaller female-to-male ratio. Estimates of prevalence and incidence were comparable to previous Scandinavian reports but lower than observed in registry data from the US and the UK.

BackgroundAn increased risk of pregnancy complications is seen in women with systemic lupus erythematosus (SLE), but the specific immunopathological drivers are still unclear. Hallmarks of SLE are granulocyte activation, type I interferon (IFN) overproduction, and autoantibodies. Here we examined whether low-density granulocytes (LDG) and granulocyte activation increase during pregnancy, and related the results to IFN alpha protein levels, autoantibody profile, and gestational age at birth.MethodsRepeated blood samples were collected during pregnancy in trimesters one, two, and three from 69 women with SLE and 27 healthy pregnant women (HC). Nineteen of the SLE women were also sampled late postpartum. LDG proportions and granulocyte activation (CD62L shedding) were measured by flow cytometry. Plasma IFN alpha protein concentrations were quantified by single molecule array (Simoa) immune assay. Clinical data were obtained from medical records.ResultsWomen with SLE had higher LDG proportions and increased IFN alpha protein levels compared to HC throughout pregnancy, but neither LDG fractions nor IFN alpha levels differed during pregnancy compared to postpartum in SLE. Granulocyte activation status was higher in SLE relative to HC pregnancies, and it was increased during pregnancy compared to after pregnancy in SLE. Higher LDG proportions in SLE were associated with antiphospholipid positivity but not to IFN alpha protein levels. Finally, higher LDG proportions in trimester three correlated independently with lower gestational age at birth in SLE.ConclusionOur results suggest that SLE pregnancy results in increased peripheral granulocyte priming, and that higher LDG proportions late in pregnancy are related to shorter pregnancy duration but not to IFN alpha blood levels in SLE.

Although several biomarkers are available to monitor the acute phase response, the short pentraxin C-reactive protein (CRP) is dominating in clinical practice. The long pentraxin 3 (PTX3) is structurally and functionally related to CRP, but not liver-derived. In addition, increased levels of PTX3 have been linked to preeclampsia. Reference intervals are usually based on healthy blood donors. Several physiological and immunological alterations occur during normal pregnancy with subsequent potential effects on blood analytes. Hence, this study aims to determine pregnancy-specific reference intervals for CRP and PTX3. Longitudinal clinical data and blood plasma samples from the 1(st), 2(nd) and 3(rd) trimester of 100 healthy, non-medicating, females aged 18-40 at the time-point of conception were available to us. High-sensitivity CRP measurements were performed by turbidimetry and enzyme-linked immunosorbent assay (ELISA) was used to quantify PTX3. CRP and PTX3 levels followed each other during the first two trimesters and both increased during the third trimester. CRP showed a median of 4.12 mg/L in the third trimester, and were significantly higher compared to the first (median 2.39 mg/L, p < 0.0001) and the second (median 2.44 mg/L, p=0.0006) trimesters. In the third trimester PTX3 levels reached a median of 7.70 mu g/L, and were significantly higher compared to the first (median 3.33 mu g/L, p < 0.0001) and the second (median 3.70 mu g/L, p < 0.0001) trimesters. Plasma albumin was inversely correlated with CRP (rho=-0.27, p < 0.0001), but not with PTX3. In conclusion, it is important to consider pregnancy-specific reference values as elevations of CRP and PTX3 during the later phase may occur in absence of infection.

Objective The progress of accelerated atherosclerosis in systemic lupus erythematosus (SLE) is incompletely understood. Circulating osteopontin (OPN) is increased in autoimmune conditions, e.g. SLE, and its serum concentration was recently reported to associate with subclinical atherosclerosis in SLE, as measured by carotid intima-media thickness. The aim of this study was to investigate whether OPN may be used as a surrogate biomarker of subclinical atherosclerosis in SLE patients with different disease phenotypes. Methods We recruited 60 well-characterised SLE cases and 60 age- and sex-matched healthy controls. The SLE cases were divided into three different disease phenotypes: SLE with antiphospholipid syndrome (APS), lupus nephritis, and isolated skin and joint involvement. Plasma OPN was detected by ELISA (Quantikine (R), R&D Systems). Common carotid arteries intima media thickness was compared between the studied groups in relation to OPN levels and risk factors for vascular changes. Intima media thickness of common carotid arteries was measured by using a sensitive ultrasound technique (LOGIQ (TM) E9 ultrasound, GE Healthcare). Results OPN levels were significantly higher among the entire SLE group (n = 60) compared to the healthy controls (P = 0.03). SLE cases with concomitant APS (n = 20) showed higher OPN levels than the controls (P = 0.004), whereas none of the other two subgroups differed significantly from the healthy controls. OPN and intima media thickness were correlated to several traditional risk factors of atherosclerosis, as well as to SLE-related factors. Yet, no significant correlation was observed between OPN levels and ultrasound findings of the common carotid arteries. Conclusions In line with previous studies, we observed increased OPN levels among SLE patients as compared to matched controls. However, the OPN concentrations did not correlate with intima media thickness of the common carotid arteries. Based on our findings, the use of OPN as a surrogate biomarker of subclinical atherosclerosis in SLE subjects, regardless of clinical phenotypes, cannot be recommended.

While the management of pregnant patients with systemic lupus erythematosus (SLE) has improved over the last decades, the risk of maternal, foetal, and neonatal complications is still substantial. We evaluated the occurrence of adverse pregnancy outcomes (APO) occurring in 2002-2018 among patients with SLE from the catchment area of the Department of Rheumatology in Lund, Sweden. Longitudinal clinical and laboratory data were collected and analysed. Results were stratified according to the sequence of conception. We investigated a total of 59 pregnancies in 28 patients. Prior lupus nephritis was the clinical feature that, in a multivariable regression analysis, displayed the strongest association with APO overall (OR 6.0,p= 0.02). SLE combined with antiphospholipid syndrome (APS) was associated with the risk of miscarriage (OR 3.3,p= 0.04). The positivity of multiple antiphospholipid antibodies (aPL) was associated with APO overall (OR 3.3,p= 0.05). IgG anti-cardiolipin during pregnancy resulted in a higher risk of preterm delivery (OR 6.8,p= 0.03). Hypocomplementaemia was associated with several APO, but only in the first pregnancies. We conclude that, despite the close follow-up provided, a majority of pregnancies resulted in >= 1 APO, but a few of them were severe. Our study confirms the importance of previous lupus nephritis as a main risk factor for APO in patients with SLE.

Objective. To study the clinical and laboratory characteristics of patients with biopsy-proven giant cell arteritis (GCA) with visual complications, and to evaluate the incidence rate of visual complications in GCA compared to the background population.

Methods. Data from 840 patients with GCA in the county of Skåne, Sweden, diagnosed between 1997 and 2010, were used for this analysis. Cases with visual complications were identified from a diagnosis registry and confirmed by a review of medical records. The rate of visual complications in patients with GCA was compared with an age- and sex-matched reference population.

Results. There were 85 patients (10%) who developed ≥ 1 visual complication after the onset of GCA. Of the patients, 18 (21%) developed unilateral or bilateral complete visual loss. The mean age at diagnosis was 78 years (± 7.3); 69% were women. Compared with patients without visual complications, those with visual complication had lower C-reactive protein levels at diagnosis and were less likely to have headache, fever, and palpable abnormal temporal artery. The use of β-adrenergic inhibitors was associated with visual complications. The incidence of visual complications among patients with GCA was 20.9/1000 person-years of followup compared to 6.9/1000 person-years in the reference population, resulting in a rate ratio of 3.0 (95% CI 2.3–3.8).

Conclusion. Ten percent of patients with GCA developed visual complications, a rate substantially higher than that of the general population. Patients with GCA who had visual complications had lower inflammatory responses and were more likely to have been treated with β-adrenergic inhibitors compared with patients without visual complications.