Inge-Margrethe Gilboe

Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity

Background: Antibodies targeting citrullinated antigens are specific for rheumatoid arthritis (RA). Citrullination is catalysed by the peptidylarginine deiminase (PAD) enzyme family. Critical enzymes are often targeted by disease-specific antibodies in complex immune-mediated diseases. Here, we have tested for autoantibodies against human recombinant PAD4 (hPAD4) in Caucasian RA patients. Methods: A time-resolved fluorometric immunoassay based on hPAD4 was developed to analyse sera from two RA cohorts (n = 237 and n = 177), one systemic lupus erythaematosus (SLE) cohort (n = 84) and 148 healthy controls. Simple and multiple analyses were performed to examine possible associations between anti-hPAD4 and disease variables. Results: Raised levels of anti-hPAD4 IgG were found in both RA cohorts compared to the controls, and 23% of the RA patients were anti-hPAD4 IgG positive. Anti-hPAD4 was associated with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF), as well as increased physical disability. Anti-hPAD4 was also associated with higher longitudinal radiographic damage scores and increased clinical joint pathology, but weaker than anti-CCP. No associations were found between anti-hPAD4 and selected Human leukocyte antigen (HLA)-DRB1 variants. Conclusions: Approximately 23% of Caucasian RA patients have serum IgG antibodies against hPAD4.The presence of serum anti-hPAD4 IgG was in simple analyses associated with a more severe disease phenotype, and the association with physical disability was maintained in multiple analyses.

Recurrent lupus nephritis after kidney transplantation: a surveillance biopsy study

Objectives To determine the incidence of recurrent lupus nephritis (LN) in renal transplant recipients with systemic lupus erythematosus (SLE). Methods All patients with SLE that had undergone transplant with a functioning graft were asked in 2008 to participate in a cross-sectional study. The study included a standardised clinical examination, laboratory tests and a biopsy of the transplanted kidney. Results A total of 41 (93%) of a cohort of 44 patients with SLE with renal transplants participated. Of the biopsies, 3 were indication biopsies and 38 were surveillance biopsies. In all, 22 patients (54%) had biopsy-proven recurrence of LN. The majority of the cases were subclinical and characterised as class I/class II LN. Proteinuria (mg protein/mmol creatinine) was significantly increased in patients with recurrence, 70.6 (104.9) mg/mmol versus 11.9 (6.7) mg/mmol in patients without recurrence (p=0.038). Lupus anticoagulant was found more frequently in the patients with recurrence, nine versus two patients (p=0.033). Recurrence of LN was associated with receiving a kidney from a living donor (p=0.049). In all, 83% (34 of 41) had chronic allograft nephropathy in the transplanted kidneys with no difference between patients with recurrence or without. Conclusions Subclinical recurrence of LN is common in patients with renal transplants with SLE. The majority of the patients have chronic allograft nephropathy.

The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients

Objectives Mixed connective tissue disease (MCTD) is an immune-mediated, systemic disorder of unknown aetiology. As the epidemiology of the disease is largely unknown, the authors performed a nationwide cross-sectional retrospective study to assess the prevalence and incidence of MCTD in Norway. Methods Every adult patient (≥18 years) with MCTD seen at one of the departments of rheumatology was reviewed for inclusion. Only patients who satisfied the following four criteria were included: clinical diagnosis of MCTD verified by a rheumatologist; positive serum anti-ribonucleoprotein antibody test; fulfilment of at least one of three of following criteria sets: the modified Sharps criteria, the criteria of Alarcón-Segovia and Villareal and those of Kasukawa; and exclusion of other connective tissue diseases. Results The four inclusion criteria were fulfilled by 147 adult Caucasian patients. The female to male ratio was 3.3 and the mean age at diagnosis of adult-onset MCTD was 37.9 years (95% CI 35.3 to 40.4 years). At the end of 2008, the point prevalence of living adult MCTD patients in Norway was 3.8 (95% CI 3.2 to 4.4) per 100 000 adults. The incidence of adult-onset MCTD in Norway during the period from 1996 to 2005 was 2.1 (95% CI 1.7 to 2.5) per million per year. Conclusions MCTD has a female predominance and the incidence and prevalence of MCTD is low, and lower than reported figures for polymyositis, dermatomyositis, systemic sclerosis and systemic lupus erythematosus. The prevalence estimates were similar across the three criteria sets of MCTD.

Prevalence of pulmonary hypertension in an unselected, mixed connective tissue disease cohort: results of a nationwide, Norwegian cross-sectional multicentre study and review of current literature

OBJECTIVES The aim of this study was to assess the overall prevalence of pulmonary hypertension (PH) in an unselected MCTD cohort and review the current knowledge with a systematic database search. METHODS A nationwide multicentre cohort of 147 adult MCTD patients were initially screened for PH by echocardiography, high-resolution computed tomography (HRCT), pulmonary function tests and N-terminal pro-brain natriuretic peptide (NT-proBNP) and then followed up for a mean of 5.6 years. Right-sided heart catheterization was performed when estimated pulmonary artery systolic pressure was >40 mmHg on echocardiography. PH was diagnosed according to the 2009 European Society of Cardiology and European Respiratory Society guidelines. RESULTS At inclusion, 2.0% (3/147) had established PH. Two additional PH patients were identified during follow-up, giving a total PH frequency in the cohort of 3.4% (5/147). All five had elevated serum NT-proBNP. Two had isolated pulmonary arterial hypertension (PAH) and three PH associated with interstitial lung disease (PH-ILD). Three PH patients died during follow-up. Nine other patients in the cohort also died, but none of them had echocardiographic signs of PH prior to death. CONCLUSION The data from the current unselected MCTD cohort suggest that the prevalence of PH is much lower than expected from previous studies but confirm the seriousness of the disease complication.

High incidence and prevalence of systemic lupus erythematosus in Norway.

Our aim was to identify all patients with systemic lupus erythematosus (SLE) within the city of Oslo from 1999–2008 and to estimate the incidence and prevalence of SLE according to age, sex and ethnicity. Adults (16 years and over) with SLE were identified from five different sources. Only patients fulfilling four or more of the updated 1997 American College of Rheumatology (ACR) criteria were included. The incidence was stable during the nine year study period, with a mean annual incidence rate of 3.0 per 100,000 at risk (95% confidence interval (CI) 2.4–3.5). Females exhibited a bimodal pattern in age specific incidence with the first peak at 16–29 years of age and the second at 50–59 years of age. The overall prevalence was 51.8 per 100,000 population (95% CI 45.2–58.4), with 91.0 (95% CI 78.8–103.1) for females and 10.7 (95% CI 6.4–15.0) for males. The prevalence proportions for European descendants were similar to those for Asians but statistically significant lower than those for individuals adopted from non-European countries. The findings indicate a higher prevalence in Norwegians compared to Caucasians in Denmark and England. The higher prevalence of SLE in foreign adopted individuals warrants further examination.

Differences between rheumatologists and other internists regarding diagnosis and treatment of systemic lupus erythematosus

OBJECTIVES To compare the diagnostics and treatment of SLE patients in the care of rheumatologists with patients in the care of other specialities within a geographically complete cohort. METHODS Nine different sources were used to identify SLE patients resident in Oslo between 1999 and 2008. Only SLE patients fulfilling four or more of the updated 1997 ACR criteria were included. Data were extracted from medical records. The patients were classified into three groups according to each patients responsible doctors speciality. RESULTS A total of 325 SLE patients were included in the study. Of these, 227 had solely been in the care of rheumatologists (rheumatology group), 34 had solely been in the care of nephrologists, haematologists or infectious disease specialists (non-rheumatology group) and 64 had been in the care of both rheumatologists and other specialists (multidisciplinary group). Even though patients in the non-rheumatology group and multidisciplinary group showed similar disease characteristics, patients in the non-rheumatology group were less often tested for aPLs (68 vs 94%; P = 0.001) and less often treated with HCQ (12 vs 78%; P < 0.001). CONCLUSIONS In contrast to rheumatologists, non-rheumatologists do not routinely test all SLE patients for aPLs, and rarely prescribe HCQ. These findings indicate that more communication between different specialists caring for SLE is needed, and highlights an area in need of agreement.

Disease activity during pregnancy and the first year postpartum in women with systemic lupus erythematosus

Disease activity measured by validated methods has been sparsely examined during and after pregnancy in women with systemic lupus erythematosus (SLE). The aim of this study was to describe the longitudinal course of disease activity during pregnancy and the first year postpartum using the Lupus Activity Index in Pregnancy (LAI‐P).

[Lupus-nephritis--diagnosis and treatment].

BACKGROUND Systemic lupus erythematosus (SLE) is an autoimmune, multiorgan disease that usually affects young women. The kidneys are affected (lupus nephritis) in close to one fifth of the patients. Over the past decade earlier diagnosis and improved treatment of lupus nephritis has resulted in substantial improvement of renal function and patient survival. Despite these advances, 10 - 15 % of SLE patients with lupus nephritis progress to end-stage renal disease, requiring dialysis or renal transplantation. The article outlines main principles for diagnosing and treating lupus nephritis, according to current practice at Oslo University Hospital. MATERIAL AND METHODS National and international guidelines (on treatment of lupus nephritis), literature identified through a non-systematic search in PubMed and our own clinical experience form the basis for the article. RESULTS In lupus nephritis, low-dose cyclophosphamide and corticosteroids are topical treatment for induction therapy, and mycophenolate mofetil is an alternative treatment. We recommend maintenance treatment with azathioprine or mycophenolate mofetil for at least two years. Treatment with rituximab may be considered in patients with refractory lupus nephritis. INTERPRETATION Subtypes and activity of the renal disease are decisive for choice of treatment.

Influence of disease activity and medications on offspring birth weight, pre-eclampsia and preterm birth in systemic lupus erythematosus: a population-based study

Objectives Exploring the associations between disease activity and medications with offspring birth weight, pre-eclampsia and preterm birth in systemic lupus erythematosus (SLE). Methods Data from the Medical Birth Registry of Norway (MBRN) were linked with data from RevNatus, a nationwide observational register recruiting women with inflammatory rheumatic diseases. Singleton births in women with SLE included in RevNatus 2006–2015 were cases (n=180). All other singleton births registered in MBRN during this time (n=498 849) served as population controls. Z-score for birth weight adjusted for gestational age and gender was calculated. Disease activity was assessed using Lupus Activity Index in Pregnancy. We compared z-scores for birth weight, pre-eclampsia and preterm birth in cases with inactive disease, cases with active disease and population controls. Results Z-scores for birth weight in offspring were lower in inactive (−0.64) and active (−0.53) diseases than population controls (−0.11). Inactive disease did not predict pre-eclampsia while active disease yielded OR 5.33 and OR 3.38 compared with population controls and inactive disease, respectively. Preterm birth occurred more often in inactive (OR 2.57) and active (OR 8.66) diseases compared with population controls, and in active compared with inactive disease (OR 3.36). Conclusions SLE has an increased odds for low birth weight and preterm birth, amplified by active disease. The odds for pre-eclampsia is elevated in active, but not inactive disease. This calls for tight follow-up targeting inactive disease before and throughout pregnancy.

Women with systemic lupus erythematosus get pregnant more easily than women with rheumatoid arthritis

Objectives To examine possible differences in the ability to get pregnant and time to pregnancy (TTP) in women with SLE and RA, and to study possible influencing factors. Methods Data from RevNatus, a Norwegian nationwide prospective observational register including women with inflammatory rheumatic diseases when planning pregnancy or after conception, was used. We compared rate of achieved pregnancy, the pregnancy outcomes live birth or pregnancy loss, and TTP between women with SLE (n = 53) and women with RA (n = 180). TTP was compared between the groups using Kaplan-Meier plots, and Cox proportional hazard regression was performed adjusting for maternal age, parity and medication use. RAND-36 was used to assess health-related quality of life (HRQoL) in women achieving and not achieving pregnancy. Results Women with SLE had a pregnancy ratio of 1.91 (95% CI: 1.27, 2.88, P = 0.002) compared with women with RA, and a substantially shorter median TTP (3.0 vs 7.0 months, P = 0.001). Higher maternal age, medication use and low HRQoL in the physical domains may influence the ability to achieve pregnancy and prolong TTP in women with RA. Women with SLE not achieving pregnancy had lower HRQoL scores than SLE-women achieving pregnancy, while women with RA had generally low scores in physical domains whether or not achieving pregnancy, indicating poor HRQoL. Conclusions In the studied cohort, women with SLE got pregnant more easily than women with RA.