Hepascore predicts liver outcomes and all-cause mortality in long-term methotrexate users: A retrospective cohort study.

BACKGROUND AND AIM: Methotrexate (MTX) is routinely used for immunological disorders, and its long-term use is associated with hepatotoxicity. The aim of this study was to investigate whether a serum liver fibrosis test (Hepascore) predicted the risk of adverse liver-related outcomes and mortality. METHODS: A total of 92 patients in Western Australia who had a long-term MTX intake history,from 2004 to 2016, were recruited and followed up from the first Hepascore to death or end of the study. Clinical data, all deaths, and liver-related outcomes (liver-related death and decompensation) were obtained from hospital, PathWest, and WA Data Linkage Unit databases. RESULTS: Nine deaths and four adverse liver-related outcomes occurred during the follow up of 354 person-years. The 5-year survival was 86.1%. The liver-related outcome free survival was 95.6%. Baseline Hepascore ≥0.84 was associated with advanced fibrosis on liver biopsy (P = 0.025). A baseline Hepascore ≥0.84 was significantly associated with higher risks for adverse liver-related outcomes (P < 0.001) and all-cause mortality (P = 0.001). Cox regression demonstrated that only baseline Hepascore ≥0.84 was independently associated with the increased risk of all-cause mortality (7.91 [1.52-41.29], P = 0.014). Moreover, any Hepascore ≥0.84 found during follow up was independently associated with the increased risk of all-cause mortality (86.18 [4.03-1844.83], P = 0.007). CONCLUSIONS: This study demonstrated the potential importance of Hepascore monitoring in long-term MTX users. Patients with a Hepascore higher than 0.84 at any stage had increased mortality, but further studies are required to confirm this finding.

Epidemiology of spondyloarthritis: a review.

The classification of Spondyloarthritis (SpA) has been revised with the introduction of the ASAS classification criteria. Although this has best been described in ankylosing spondylitis and psoriatic arthritis, there are population studies evaluating the epidemiology of the different subgroups of SpA. In this paper, we present data on the incidence and prevalence of the subgroups of SpA in different populations, and point to data indicating how the introduction of new classification criteria, with the altered perception of the SpA entity, might impact on the epidemiology.

Sustained hypogammaglobulinemia under rituximab maintenance therapy could increase the risk for serious infections: a report of two cases.

We report two patients with granulomatosis with polyangiitis in remission with rituximab maintenance therapy with sustained hypogammaglobulinemia. Both patients had serious infections and were admitted to the intensive therapy unit. The patients had at least low IgM levels prior to the initiation of rituximab. They received cyclophosphamide and prednisolone at induction and at maintenance. They had lung affection, low level of both IgM and IgG and a cumulative dose of rituximab over 7 g at the time of the severe infection. Our patients have features similar to common variable immunodeficiency patients, and therefore prolonged very low levels of immunoglobulins could heighten the risk for severe infections.

Diagnostic value of antibodies against mutated citrullinated vimentin for rheumatoid arthritis.

OBJECTIVES: To compare the diagnostic efficiency of anti-MCV, anti-CCP2 and RF detection for patients with RA. METHODS: Cross-sectional study of patients with established rheumatic disease: rheumatoid arthritis (RA; n=75), psoriatic arthritis (PsA; n=25), 27 patients with ankylosing spondylitis (AS; n=27) and connective tissue disease (CTD; n=17). Anti-CCP2, anti-MCV and RF were detected by enzyme-linked immunosorbent assays on stored serum according to the manufacturer's instructions. RESULTS: IgM-RF had the highest sensitivity, but the positive likelihood ratio is just 1.43. The detection of anti-MCV has a higher sensitivity for RA (76%), a specificity similar to anti-CCP2 (96%) resulting in the lowest negative likelihood ratio (0.25). Anti-MCV levels correlate well with anti-CCP2 levels (R=0.74; p<0.01). The mean level of anti-MCV is significantly higher in RA than in other subgroups (395 U/ml versus 14.4 U/ml, χ2=61.0; p<0.001) and in each other subgroup (Mann-Whitney-Wilcoxon: U=239, p<0.001 for RA and PsA; U=215, p<0.001 for RA and AS; U=192, p<0.001 for RA and CTD). Among RA patients, anti-CCP2 levels have a dichotomous distribution whereas anti-MCV levels have a homogeneous distribution. CONCLUSIONS: Anti-MCV could be a better test for diagnosing RA than anti-CCP2.

Dramatic response to IL1-RA treatment in longstanding multidrug resistant Schnitzler's syndrome: a case report and literature review.

We report a case of longstanding multidrug resistant Schnitzler's syndrome that finally went into clinical remission upon treatment with anakinra and review the literature concerning IL1-RA treatment for Schnitzler's syndrome. A now 71-year-old patient presenting with recurring episodes of urticaria and fever and secondary weight loss for the past 16 years as well as arthralgia, hearing loss. The patient has anemia, leucocytosis with neutrophilia, thrombocytosis, elevated C-reactive protein and erythrocyte sedimentation rate, lymphadenopathy and a monoclonal IgM kappa band that later became oligoclonal with two IgM kappa bands and one IgM lambda band. The patient was treated with moderate effect with combination of prednisolone, azathioprine, and colchicine. In March 2009, anakinra 100 mg daily sc was added during a disease flare. Within 24 h after the first injection, both the urticaria and the fever disappeared and have not recurred. For the past 6 months, the patient has been in clinical and biochemical remission. Colchicine has been stopped while the azathioprine and prednisolone doses are being reduced. Twenty-four patients with Schnitzler's syndrome, including three patients with a variant of Schnitzler's syndrome and three patients with a Schnitzler-like syndrome, have been successfully treated with anakinra. Nevertheless, seven out of seven patients, that either interrupted or used anakinra every other day, had relapse of their symptoms within 24-48 h; anakinra was restarted in all patients with the same clinical efficiency. The current case history and the literature review already suggest an important role for IL-1 as a mediator in the pathophysiology of Schnitzler's syndrome.

Inflammatory cell infiltrates in vessels with different susceptibility to atherosclerosis in rheumatic and non-rheumatic patients: a controlled study of biopsy specimens obtained at coronary artery surgery.

BACKGROUND: The main aim of the present study was to compare the occurrence of inflammatory cell infiltrates in the aorta, a vessel with a high occurrence of atherosclerosis, with that in the saphenous vein (SV) and internal mammary artery (IMA), which are protected from atherosclerosis. METHODS AND RESULTS: Samples from the aorta, SV, and IMA of 65 patients with inflammatory rheumatic diseases (IRD) and from 51 control patients undergoing coronary artery bypass graft surgery were examined for the presence and location of inflammatory cell infiltrates and atherosclerotic lesions. Mononuclear cell infiltrates (MCIs) in the media or adventitia were observed in 2% IMAs, 17% SVs, and 35% aortic specimens (SV vs IMA: p=0.006; SV vs aorta: p=0.001). Atherosclerotic lesions were present in none IMA, 3% SVs and 18% aortic specimens. IRD and smoking increased the odds of MCI in the aorta (odds ratio (OR)=3.6, 95% confidence interval (CI): 1.6-8.5 and OR=4.0, 95% CI: 1.5-10.9), but not in the SV or IMA. CONCLUSIONS: The occurrence of medial and adventitial MCI in the aorta, SV, and IMA paralleled each vessel's susceptibility to atherosclerosis: it was highest in the aorta and lowest in IMA. Local vascular inflammation may be involved in atherogenesis, and influence the patency of vascular grafts.

Inflammatory rheumatic disease and smoking are predictors of aortic inflammation: a controlled study of biopsy specimens obtained at coronary artery surgery.

OBJECTIVE: Several inflammatory rheumatic diseases are associated with accelerated atherosclerosis. Atherosclerosis may result from systemic and/or local vascular inflammation. The aim of this study was to evaluate the occurrence of chronic inflammatory infiltrates in the aortas of patients with and those without inflammatory rheumatic disease who had undergone coronary artery bypass graft (CABG) surgery, and to assess the relationship between the infiltrates and other factors thought to play a role in atherosclerosis, such as smoking. METHODS: Aortic specimens routinely removed during CABG surgery in 66 consecutive patients with inflammatory rheumatic disease and 51 control patients without inflammatory rheumatic disease were examined by light microscopy for the occurrence, location, and severity of chronic inflammatory infiltrates and atherosclerotic lesions. RESULTS: Mononuclear cell infiltrates in the inner adventitia (apart from those localized along the epicardium) were more frequent in the group of patients with inflammatory rheumatic disease (47% versus 20%; P = 0.002, odds ratio [OR] OR 3.6, 95% confidence interval [95% CI] 1.6-8.5), and the extent of these infiltrates was greater. Multivariate analyses revealed that the occurrence of mononuclear cell infiltrates was associated with inflammatory rheumatic disease (OR 2.99, P = 0.020) and current smoking (OR 3.93, P = 0.012), and they were observed in 6 of 7 patients with a history of aortic aneurysm. Inflammatory infiltrates in the media were seen only in patients with inflammatory rheumatic disease. The frequency of atherosclerotic lesions, inflammation within the plaques, and epicardial inflammatory infiltrates in the 2 groups was equal. CONCLUSION: Among aortic samples collected during CABG surgery, those obtained from patients with inflammatory rheumatic disease had more pronounced chronic inflammatory infiltration in the media and inner adventitia than those obtained from control patients. Current smoking was an independent predictor of chronic inner adventitial infiltrates. The infiltrates may represent an inflammatory process that promotes atherosclerosis and formation of aneurysms.

[Systemic lupus erythematosus and pregnancy]. / Systemisk lupus erythematosus og svangerskap.

BACKGROUND: Systemic lupus erythematosus (SLE) often starts in women of fertile age. Due to the unpredictable nature of the disease and the increased risk of the disease flaring up during pregnancy, women with SLE have previously often been advised to avoid pregnancy. This summary reviews current insights in pregnancy management of women with SLE. METHOD: Search in the Medline database (period 1980-2005) using keywords: SLE, lupus nephritis, antiphospholipid antibody, neonatal lupus and pregnancy. RESULTS: Previous studies of pregnant women with SLE have had different designs, sample sizes, selections of patients, definitions and measures of outcome. Women with previous pregnancy losses, an ongoing active disease with nephritis or hypertension and positive antiphospholipid antibodies, have an increased risk of pregnancy loss. The most favourable pregnancy outcomes are achieved when conception takes place during a remission of the disease. INTERPRETATION: There are few absolute contraindications for pregnancies in women with SLE. Women with SLE may experience uncomplicated pregnancies, but they need to plan their pregnancies as the risk for complications is increased. Best results are achieved through the cooperation of rheumatologists, gynaecologists and nephrologists. Glucocorticosteroids, hydroxychlorocine, azathioprine and anticoagulation may be used during pregnancy.

Quantitative salivary gland scintigraphy can distinguish patients with primary Sjøgren's syndrome during the evaluation of sicca symptoms.

Abnormal findings on salivary gland scintigraphy (SGS) are part of the classification criteria for Sjøgren's syndrome (SS), but SGS is operator dependent and poorly standardised. We studied the use of quantitative data on the uptake, concentration and excretion of the four major salivary glands in the evaluation of sicca patients. During an initial clinical evaluation for sicca symptoms (mean duration, 51 months), 24 subjects were classified as either SS (n = 8) or isolated sicca (IS; n = 16). SGS was then performed after i.v. injection of 200 MBq pertecnetat. Digitalised quantitative data on time-to-peak uptake (Tmax), peak tracer distribution (C%) and stimulated excretion (E%) were calculated from time-activity curves and compared between groups and controls (n = 8) and correlated to clinical data. Statistical analysis was performed with non-parametric tests. SS patients had longer Tmax in both parotic glands (18.1 min; p < 0.01)) and both submandibular glands (mean 13.7 min, p < 0.05); whereas Tmax in IS patients was similar as in controls in both parotic (10.4 min; p > 0.2) and submandibular glands (9.4 min; p > 0.4). C% was significantly lower in the parotic glands of both the SS and the IS group compared to the controls (p < 0.01). E% was significantly reduced in SS patients (16.3% for parotic and 17.4% for submandibular glands; p < 0.01); whereas in the IS patients, excretion (32, 2% for parotic and 26, 9% for submandibular glands) was similar from all glands as in the control groups (35, 2% for parotic and 27, 8% for submandibular glands). No correlation was found between these SGS results and age, focus score, erythrocyte sedimentation rate, serum creatinin or immunoglobulin levels. No IS patient progressed to full-blown pSS during the 4 years of follow-up. Quantitative SGS data are useful and objective tools to distinguish patients with SS.

Damage accumulation in systemic lupus erythematosus and its relation to disease activity and mortality.

OBJECTIVE: To describe damage accrual and the interconnections between disease activity measures, damage accrual, and death in a Nordic lupus cohort. METHODS: Longitudinal study in the population-based Tromso lupus cohort. Disease activity [SLE Disease Activity Index (SLEDAI)] and disease damage [by Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI)] were recorded for each visit. Weighted average SLEDAI scores (WAS) were calculated to correct for variable observation times. Development of damage (SDI > 0), severe damage (SDI >or= 3), and death were used as separate endpoints. Univariate nonparametric analysis identified and hazard ratios (HR) by Cox regression techniques confirmed the independence of predictors for each outcome. RESULTS: Through 11.9 years of followup, 72 patients (46%) remained free of damage, 51 (32%) developed moderate damage, and 35 (22%) developed severe damage. SDI scores were higher in 37 nonsurvivors (23.4%; SDI 2.1) than in survivors (SDI 0.9; p < 0.05). Damage accrual was linear throughout the first decade of disease. The only independent predictor for SDI >/= 3 was a WAS score > 3 (hazard ratio 2.34; 95% CI 1.1-4.9). Age > 40 years at diagnosis (HR 5.6, 95% CI 2.4-12.7) and WAS > 3 (HR 2.4, 95% CI 1.2-4.9) were significant predictors for death. CONCLUSION: Damage accrual in SLE occurred in 54% of patients in a linear fashion over the first decade of disease. Global disease activity was the main determinant of damage accrual. Accrued damage was not an independent risk factor for death, which was predicted by age > 40 years and WAS > 3.

Critical comparative analyses of anti-alpha-actinin and glomerulus-bound antibodies in human and murine lupus nephritis.

OBJECTIVE: Although anti-double-stranded DNA (anti-dsDNA) antibodies are important in lupus nephritis, the question regarding which glomerular structures (alpha-actinin, nucleosomes, or others) are recognized by nephritogenic anti-dsDNA antibodies is still controversial. In this study, we determined which glomerular structures are recognized by monoclonal and in vivo-bound nephritogenic antibodies. METHODS: Western blotting was used to analyze the ability of nephritogenic anti-dsDNA antibodies to recognize glomerular and nucleosomal structures. Sera from patients with lupus nephritis, sera from random antinuclear antibody-positive patients, and paired antibodies from sera and kidney eluates from nephritic (NZB x NZW)F(1) mice were analyzed for activity against proteins identified by monoclonal nephritogenic antibodies, and against alpha-actinin, dsDNA, nucleosomes, histone H1, heparan sulfate, DNase I, and type IV collagen. Immunoelectron microscopy was used to determine the glomerular localization of alpha-actinin and in vivo-bound autoantibodies in nephritic (NZB x NZW)F1 mouse kidneys. RESULTS: Anti-alpha-actinin antibodies were observed in human and murine lupus nephritis sera and in sera from patients without systemic lupus erythematosus and were not detected in kidney eluates from nephritic mice. Antibodies to dsDNA and histone H1 were detected in all eluates. Western blot analyses revealed that nephritogenic anti-dsDNA antibodies recognized a 32-kd band, identified as histone H1. Competitive enzyme-linked immunosorbent assay demonstrated that nephritogenic monoclonal antibodies, and dominant antibodies eluted from nephritic kidneys, cross-reacted with dsDNA and H1. This cross-reactive anti-H1 specificity was largely absent in sera from those mice. Immunoelectron microscopic analysis of nephritic (NZB x NZW)F1 mouse kidneys revealed that antibodies eluted from kidneys, but not anti-alpha-actinin antibodies, bound to distinct nephritis-associated electron-dense structures linked to glomerular basement membranes. CONCLUSION: Cross-reactive anti-dsDNA/anti-histone H1 antibodies, but not anti-alpha-actinin antibodies, are central among those deposited in nephritic glomeruli.

Prior anti-dsDNA antibody status does not predict later disease manifestations in systemic lupus erythematosus.

OBJECTIVES: To determine if the past presence of anti-double-strand (ds)DNA antibody (Ab) will predict subsequent disease activity in patients with systemic lupus erythematosus (SLE). METHODS: A longitudinal study of clinical and serological disease manifestations registered during 2,412 patient months of follow-up in a well-defined lupus cohort. Organ-specific disease manifestations, the modified SLE disease activity index (M-SLEDAI) score, disease flares (M-SLEDAI increase > or =3) and predictive value of anti-dsDNA Ab testing [by enzyme-linked immunoabsorbent assay (ELISA) and Crithidia luciliae immunofluorescence (CLIFT) assays] were related to past anti-dsDNA Ab status. RESULTS: Anti-dsDNA Ab was previously demonstrated in 54 (57%) patients (group 1), while they were not earlier detected in 40 (43%) patients (group 2). The number of patients experiencing flares (46 vs 25%, p<0.01), the total number of flares (75 vs 17, p<0,001) as well as overall (60 vs 24 per 100 patient years, p<0,001) and organ-specific flare rate were higher in group 1. After adjustment for control frequency, group 1 remained at a higher risk for renal flares [odds ratio (OR) 2.4; confidence interval (CI) 1.5-4.1], and group 2 was at a higher risk for skin flares (OR 0.7; CI 0.5-0.8). While anti-dsDNA Ab testing overall was performed slightly more often in group 1 (OR 1.45; CI 1.0-4.6), anti-dsDNA Ab testing during flares was similar in both groups. CONCLUSION: The past presence of anti-dsDNA Ab identified patients with an increased risk of subsequent renal flares. However, as a new onset of anti-dsDNA Abs occurred late in the disease course, prior anti-dsDNA status was not adequate to predict disease flares.

Incidence and prevalence of ankylosing spondylitis in Northern Norway.

OBJECTIVE: To determine the incidence and prevalence of ankylosing spondylitis (AS) over a prolonged period in the 2 northernmost counties of Norway, where HLA-B27 has a high prevalence in the population. METHODS: We conducted a cohort study of all patients registered with a diagnosis of AS between 1960 and 1993 at the University Hospital of Northern Norway, which is the sole rheumatology department serving these counties. We registered demographics, year of disease onset (clinical disease), and year of diagnosis (radiograph confirmation) for all patients. The date of onset of clinical disease in patients with AS was used in the calculation of incidence rates. Annual incidence and point/period prevalence rates were expressed per 100,000 adults. Primary AS was defined as AS in the absence of psoriasis or inflammatory bowel disease (IBD). RESULTS: A total of 534 patients (75.1% male, mean age at clinical diagnosis 24.2 years, 93.0% HLA-B27 positive) had a confirmed diagnosis of AS (by the modified New York criteria). Median time from disease onset to radiologic confirmation was 8.0 years. Annual incidence of primary AS (n = 417) was 7.26, while estimated point prevalence rose from 0.036% in 1970 to 0.10% in 1980 and to 0.21% in 1990 with a period prevalence of 0.26%. AS was secondary to psoriasis or IBD in 117 patients (18.1%), with a diagnostic delay similar to that in primary AS. Annual incidence (14.1) and period prevalence in 1982-1993 (0.41%) were significantly higher in the town of Tromsø than in the surrounding rural region (5.21 and 0.22%, respectively). Mortality in patients with AS was low. CONCLUSION: The incidence of AS was relatively stable in the northern part of Norway over a 34-year period. Incidence and prevalence are higher than reported in similar studies from Finland and Minnesota, possibly due to a higher population prevalence of HLA-B27.

Is closer linkage between systemic lupus erythematosus and anti-double-stranded DNA antibodies a desirable and attainable goal?

The anti-double-stranded DNA (anti-dsDNA) antibody test incorporated in the 1982 revised American College of Rheumatology criteria for the classification of systemic lupus erythematosus needs updating to reflect current insights and technical achievements, including allowance for the presence of nonpathogenic anti-dsDNA antibodies. As we need to develop at least some measure of pathogenicity of anti-dsDNA antibodies, we propose that initial anti-dsDNA antibody screening is done by sensitive ELISA and supplemented by more stringent assays. Simultaneously the relevance of anti-dsDNA antibody presence needs to be restricted to clinical manifestations, thought to be caused by anti-dsDNA antibody and within an appropriate time frame.

[Treatment with etanercept in chronic polyarthritis]. / Behandling med etanercept ved kronisk polyartritt.

BACKGROUND: In randomised trials, treatment with anti-tumour necrosis factor alpha drugs has been shown to be efficacious for patients with rheumatoid arthritis. We analysed the effectiveness and toxicity of etanercept treatment in our day-to-day rheumatology practice at the University Hospital of Northern Norway. MATERIAL AND METHODS: Patients with active polyarthritis who had failed at least three different disease-modifying anti-rheumatic drugs including methotrexate and/or combination therapy were consecutively included in an open study when they started etanercept therapy (25 mg twice per week subcutaneously). During follow up we noted the number of swollen and tender joints, took visual analogue scores (0-100 millimetre) for pain and global well-being, administered the Modified Health Assessment Questionnaire, performed laboratory tests, and took note of side effects. RESULTS: Between April 1999 and July 2001, etanercept treatment was initiated in 71 patients. An ACR-20 response (20% improvement according to American College of Radiology criteria) occurred in 57% of patients after one month of treatment and in 70 % after three months, ACR-50 response in 24% and 42%, and ACR-70 response in 6% and 20%. While half of all patients reported side effects, only five patients (7%) discontinued treatment because of them. INTERPRETATION: Etanercept is effective therapy for many patients with severe chronic polyarthritis in clinical practice. Short-term side effects occur more frequently than reported and seem less frequent with concomitant methotrexate therapy. Long-term side effects are still unknown and require close monitoring.