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ObjectiveNeuropsychiatric events occur unpredictably in systemic lupus erythematosus (SLE) and most biomarker associations remain to be prospectively validated. This study examined a disease inception cohort of 1047 SLE patients to determine which autoantibodies at enrolment predicted subsequent neuropsychiatric events.MethodsPatients with a recent SLE diagnosis were assessed prospectively for up to 10 years for neuropsychiatric events using the American College of Rheumatology case definitions. Decision rules of graded stringency determined whether neuropsychiatric events were attributable to SLE. Associations between the first neuropsychiatric event and baseline autoantibodies (lupus anticoagulant (LA), anticardiolipin, anti-β2 glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor) were tested by Cox proportional hazards regression.ResultsDisease duration at enrolment was 5.4±4.2 months, follow-up was 3.6±2.6 years. Patients were 89.1% female with mean (±SD) age 35.2±13.7 years. 495/1047 (47.3%) developed one or more neuropsychiatric event (total 917 events). Neuropsychiatric events attributed to SLE were 15.4% (model A) and 28.2% (model B). At enrolment 21.9% of patients had LA, 13.4% anticardiolipin, 15.1% anti-β2 glycoprotein-I, 9.2% anti-ribosomal P and 13.7% anti-NR2 antibodies. LA at baseline was associated with subsequent intracranial thrombosis (total n=22) attributed to SLE (model B) (HR 2.54, 95% CI 1.08 to 5.94). Anti-ribosomal P antibody was associated with subsequent psychosis (total n=14) attributed to SLE (model B) (HR 3.92, 95% CI 1.23 to 12.5, p=0.02). Other autoantibodies did not predict neuropsychiatric events.ConclusionIn a prospective study of 1047 recently diagnosed SLE patients, LA and anti-ribosomal P antibodies are associated with an increased future risk of intracranial thrombosis and lupus psychosis, respectively.

The diagnostic value of measuring rheumatoid factor (RF) by agglutination or isotype-specific enzyme-linked immunosorbent assay (ELISA) was compared. The study included 70 patients with rheumatoid arthritis (RA) and 205 patients with various other rheumatic conditions. Of the RA patients, 74% were RF-positive by agglutination and 90% had one or more RF isotypes elevated by ELISA compared to 14% and 22%, respectively, of the other patients. Strikingly, 70% of the RF-positive RA patients had an elevation of two or more RF isotypes compared to only 16% of the other RF-positive patients (P

The Medical Outcomes Study Short Form 36 (SF-36) is recommended to assess quality of life (QOL) in systemic lupus erythematosus (SLE). The aim of the current study was to assess QOL over time in the first 5 years of a multicenter inception cohort of patients with SLE.An inception SLE cohort was assembled according to a standardized protocol between 2000 and 2012. In addition to clinical and laboratory assessments, patients completed the SF-36 at yearly intervals. Only patients who had ≥5 completed QOL questionnaires were included in these analyses. Generalized estimating equation models were run separately for each of the 8 subscales and for the physical and mental component summary scores, adjusting for repeated measures by patients.A total of 495 patients were included. The mean ± SD disease duration at the first visit was 5.3 ± 4.1 months. The mean ± SD age at enrollment was 35.8 ± 13.2 years. All 8 subscales and the 2 summary scores showed improvement in the first 2 years from enrollment. Between years 2 and 5, none of the subscales or summary scores showed any change. Minimum clinically important improvement was achieved by 35-56% of the patients and was influenced by demographic and disease factors.Unlike late-stage lupus, where QOL is stable over time, in patients with early disease, all subscales improve in early followup up to 2 years. Therefore, the SF-36 may be a sensitive outcome measure in early disease in patients with SLE.

The prevalence of lifetime psychiatric disorders was investigated among all known systemic lupus erythematosus (SLE) patients in Iceland. The participation rate was 81%. Over 49% of the subjects received a lifetime psychiatric diagnosis. The number of diagnoses per person was 2.3. The most common disorder among those with a disorder was phobia (560/0), followed by generalized anxiety (12%). Agoraphobia with and without panic, simple, social phobia, and alcohol abuse were found to be more common among the SLE patients in comparison with a population sample (p

Heritability studies have suggested an important role of genetic predisposition in the progression of joint destruction in rheumatoid arthritis (RA); the heritability is estimated at 45-58%. Several single-nucleotide polymorphisms (SNPs) have been identified as being associated with RA susceptibility. Our objective was to study the association of several of these loci with progression of joint destruction.We studied 1,750 RA patients in 4 independent data sets with 4,732 radiographs scored using the modified Sharp/van der Heijde method. Thirteen susceptibility SNPs that were not previously associated with joint destruction were tested in 596 Dutch RA patients. Subsequently, significant SNPs were studied in data sets of RA patients from North America and Iceland. Data were summarized in inverse-weighted variance meta-analyses. Further, the association with circulating protein levels was studied and the associated region was fine-mapped.In stage 1, 3 loci (AFF3, IL2RA, and BLK) were significantly associated with the rate of joint destruction and were further analyzed in the additional data sets. In the combined meta-analyses, the minor (C) allele of IL2RA (rs2104286) was associated with less progression of joint destruction (P = 7.2 × 10(-4) ). Furthermore, the IL2RA (rs2104286) protective genotype was associated with lower (0.85-fold [95% confidence interval 0.77-0.93], P = 1.4 × 10(-3) ) circulating levels of soluble interleukin-2 receptor α (sIL-2Rα). Additionally, lower sIL-2Rα levels were associated with a lower rate of joint destruction (P = 3.4 × 10(-3) ). The association of IL2RA with the rate of joint destruction was further localized to a 40-kb region encompassing the IL2RA intron 1 and the 5' region of IL2RA and RBM17.The present genetic and serologic data suggest that inherited altered genetic constitution at the IL2RA locus may predispose to a less destructive course of RA.

OBJECTIVES--To investigate the incidence, prevalence and clinical features of systemic sclerosis (SS) in Iceland. METHODS--All patients diagnosed with SS from 1975-90 were included. Retrieval for the study began in 1980 and was carried out by computerised search from registers of all hospitals and health care clinics and death registration files, and with personal communication with doctors in Iceland. RESULTS--Over a 16 year period from 1975-90, 15 new cases were found with an incidence of 0.7 and 0.05/100,000, for females and males at risk respectively, and 0.38 for both sexes. At the end of 1990 there were 18 patients alive with SS, 13 with limited and five with diffuse cutaneous involvement. The age standardised prevalence was 11.9 and 1.5/100,000 for females and males at risk respectively. The crude prevalence rate for both sexes was 7.1/100,000. There were five deaths, two patients died of SS related causes, one had SS renal disease. The relative risk of death was similar to that in the general population. The calculated five year survival rate was 100% and the 10 year survival rate 81%. No HLA antigen association was found. CONCLUSION--Compared with previous surveys this study shows a low incidence of systemic sclerosis and a high proportion of patients with limited cutaneous involvement.

Lindal E, Thorlacius S, Stefansson JG, Steinsson K. Pain and Pain Problems among Subjects with Systemic Lupus Erythematosus in Iceland. Scand J Rheumatol. 1993; 22: 10–13.This population study includes the majority of all systemic lupus erythematosus (SLE) patients in Iceland (n = 65). The study lists various self-rated pain descriptions both from a 54–item pain questionnaire and from the somatisation section of the Diagnostic Interview Schedule (DIS). Results show SLE patients to have significantly more joint and chest pain than does another patient group; to use analgesics more frequently; to have been in hospital more often during the past 10 years and to believe they know the reason for their pain. Also listed are factors that patients have found to increase and decrease SLE pain.

Objective To examine the accumulation of risk factors over 3 years in a multicenter, international inception cohort of patients with systemic lupus erythematosus (SLE). Methods The Systemic Lupus International Collaborating Clinics registry for atherosclerosis comprises 27 centers from 11 countries. An inception cohort of 935 patients with SLE was assembled, according to a standardized protocol, from 2000 to 2006 to study risk factors for atherosclerosis. Both classic and other coronary artery disease (CAD) risk factors were collected at entry and through 3 years of followup. Therapy was documented over the 3 years. The Framingham 10-year risk factor profile was calculated for each patient at year 1 and year 3. Results A total of 278 patients from the inception cohort were followed for 3 years and constituted the population for this study. At enrollment a substantial number of patients already demonstrated several risk factors for CAD, both classic and other. All risk factors increased from enrollment over the 3 years of followup. Treatment of hypertension and hypercholesterolemia also increased over 3 years, but less so for hypercholesterolemia. The Framingham 10-year CAD risk profile was higher in men than in women both at entry and at 3 years, and remained unchanged over the 3 years. Corticosteroid use increased only slightly over 3 years, but use of antimalarials and immunosuppressive agents increased to a greater extent. Conclusion Patients with SLE should be monitored for CAD risk factors from the time of diagnosis and appropriate treatment should be instituted early.

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis. Although there is a large body of evidence suggesting that RA is immune mediated, the etiology remains unresolved. Twin studies have shown disease concordance rates of approximately 15% in monozygotic twins and 4% in dizygotic twins, while the estimated risk ratio for siblings of RA patients ranges from 5 to 8. Our goal was to use genealogic data from Iceland to further investigate the genetic component of RA.Data were obtained from a population-based, computerized genealogy database that was developed to examine multigenerational relationships among individuals in the relatively homogeneous population of Iceland. Using an algorithm, the minimum founder test, we calculated the least number of founders required to account for a list of RA patients, and compared it with 1,000 sets of same-sized matched control groups. In addition, we estimated the kinship coefficient and risk ratios for relatives of the RA patients.Several familial clustering tests demonstrated that the RA patients were more related to each other than were the average control set of Icelanders. A significantly fewer number of founders was necessary to account for our patient list than for the random sets of matched controls (P0.001), and the average pairwise identity-by-descent sharing was greater among the patients than among the control sets (P0.001). In addition, there was an increased risk of RA in first- and second-degree relatives of the patients; e.g., for siblings, the risk ratio was 4.38 (95% confidence interval 3.26-5.67), and for uncles/aunts, the risk ratio was 1.95 (95% confidence interval 1.52-2.43).The familial component of RA is shown to extend beyond the nuclear family, thus providing stronger evidence for a significant genetic component to RA.

To study MHC haplotypes and C4AQ0 in Caucasian multicase systemic lupus erythematosus (SLE) families from Iceland.Eight families with 26 SLE patients, 98 non-SLE first-degree relatives, and a control group were studied. For statistical analysis one SLE patient and one first-degree relative were randomly chosen from each family. C4 allotyping was performed by protein electrophoresis, HLA typing of class I by the lymphocytotoxicity test, and typing of class II alleles with polymerase chain reaction with sequence specific primers.Six of the 8 families showed a high background of C4A protein deficiency (C4AQ0) and a significant increase was seen in C4AQ0 in the randomly chosen group of patients. A similar tendency that was statistically nonsignificant was seen in first-degree relatives. In the SLE patients C4AQ0 was found on several MHC haplotypes. Half the patients with C4A protein deficiency carry C4AQ0 on the classical C4A deletion haplotype B8-C4AQ0-C4B1-DR3 or variants of it, and the remaining C4A deficient patients on other non-DR3 carrying haplotypes. The transmission of C4AQ0 from parents to patients was in most cases through the family line, although in some instances it originates from outside the multicase SLE family through spouses married into the family.In these Caucasian multicase SLE families from Iceland, C4AQ0 shows weaker linkage disequilibrium with DR3 than reported in studies on other white populations, emphasizing the role of ethnicity. The common factor in the MHC haplotypes studied is C4AQ0, supporting a hypothesis that C4AQ0 may be an independent risk factor for SLE.

To investigate the association of C4AQ0 with increased incidence of systemic lupus erythematosus (SLE) or positive serology (28%) in an extended Icelandic family, and whether this can be explained by impaired complement function in handling immune complexes (IC).The ability of the classical pathway to opsonize nascent IC [alkaline phosphatase (AP)-anti-AP] and bind them to human erythrocytes was evaluated by the new ICRB assay. The capacity of erythrocytes from family members to bind nascent IC was also measured by a modification of the ICRB assay. IC levels were measured by complement consumption assay, C3d by a sandwich ELISA, factor B by immunoelectrophoresis, and the alternative pathway function by a hemolytic assay.Family members with homozygous or heterozygous C4AQ0 (47%) showed no impaired complement dependent opsonization of IC and binding to erythrocytes. Their factor B and alternative pathway function was normal. Fifty-six percent of the family members (n=18) had abnormally high IC levels, seemingly independent of C4AQ0. However, 6 of the 7 individuals with high IC levels and SLE symptoms had C4AQ0 compared to 2 of 11 symptom-free individuals with high IC levels.Our results suggest that the susceptibility for SLE in this family may result from 2 different defects, one leading to elevated IC levels, and another associated with C4AQ0 without detectable impairment in the complement dependent IC transport mechanism. Individuals with both abnormalities have increased susceptibility to SLE.

To analyze the relationship between lymphocyte subsets, different rheumatoid factor (RF) isotypes, and clinical features in patients with rheumatoid arthritis (RA).Patients with established RA (n = 95) were examined clinically and blood samples were collected for measurements of RF by ELISA and for analysis of lymphocyte subsets by flow cytometry.IgA RF positive patients had more severe disease and higher prevalence of extraarticular manifestations than the other patients. Patients with elevated IgA RF had a higher percentage of CD5+ B cells and of CD4+CD45RO+ T cells compared to the other patients with RA or controls. High percentage of CD4+CD45RO+ T cells was also significantly associated with extraarticular manifestations. Patients with the sicca syndrome had significantly higher ratio of CD5+ B cells than patients without or with other types of extraarticular manifestations.Different disease manifestations in RA may be associated not only with certain RF isotypes and RF isotype combinations but also with changes in lymphocyte subsets in the blood. The relative increase of CD4+CD45RO+ T cells in the blood of IgA RF positive patients with RA might reflect preferential recruitment of CD8+CD45RO+ T cells to inflammatory sites.

In an epidemiological survey of systemic lupus erythematosus (SLE) in Iceland several families with multiple cases were identified. In one family, 35 individuals (family members and spouses) in 3 generations were studied clinically, tested for autoantibody formation, and typed for HLA and toxicity complement phenotypes.Typing for HLA-A, B, C, DR, and DQ was performed by microlymphocytotoxic assay. In selected samples HLA-DR typing by polymerase chain reaction amplification with sequence specific primers was performed. C4 allotypes were defined by agarose gel protein electrophoresis followed by immunofixation with goat antisera.Five family members fulfilled 4 or more criteria for SLE. Additionally, 5 family members had clinical manifestations or positive serology but did not fulfill 4 ARA criteria. The mean age at onset of symptoms was 22 yrs (8-40). Other autoimmune diseases were not documented in family members. C4A null seemed to be highly associated with disease in this family. All except one patient with SLE and all those with clinical manifestations and positive serology had C4A null in the homozygous or heterozygous form. The individual with SLE and not carrying C4A null had both HLA haplotypes identical. It is noteworthy that there were 5 different C4A null bearing haplotypes involved, of which 3 originated from the spouses.Our results are consistent with the argument that C4A deficiency plays a role in the pathogenesis of SLE. There is, however, the possibility of an unidentified environmental or another genetic factor being involved.

To investigate the incidence and clinical and histopathologic features of giant cell (temporal) arteritis (GCA) in the Caucasian population of Iceland.All patients diagnosed between 1984 and 1990 were included. Case ascertainment for the study was done in 2 ways: 1) a computerized search from all hospitals and primary care clinics for the diagnosis of GCA, and 2) a review of all temporal artery biopsies performed during the 7-year period.One hundred thirty-three patients with GCA were identified. All fulfilled the 1990 American College of Rheumatology criteria for the classification of GCA. The incidence rate for the population 50 years and older was 27/100,000 (36/100,000 and 18/100,000 for women and men, respectively). Clinical findings included the following: mean age at diagnosis 72.5 years for women and 70.3 years for men, new headache 63.2%, abnormal temporal artery on palpation 43.6%, mean erythrocyte sedimentation rate 88 mm/hour, symptoms of polymyalgia rheumatica 48.1%, and visual disturbances 14.3%. A total of 744 patients underwent temporal artery biopsy during the 7-year period; 16.8% had a positive biopsy result. All 133 patients with the diagnosis of GCA underwent a temporal artery biopsy; 94% had a positive result. Histopathologic findings from the positive biopsies included a fragmented internal elastic lamina in 99.2%, giant cells in 65.6%, and fibrinoid necrosis in 12%.Compared with previous epidemiologic surveys, this study shows a high incidence of biopsy-proven GCA in Iceland.

Histological changes in biopsies from the placental and placental bed in 2 successive pregnancies of 2 women with systemic lupus erythematosus and antiphospholipid antibodies were studied. In one of the first 2 pregnancies vasculitis was found in the spiral arteries of the placental bed biopsy, while the other showed perivascular inflammatory infiltration and deciduitis. This was associated with poor pregnancy outcome and elevated antiphospholipid antibodies (aPL). In the subsequent 2 pregnancies prednisolone treatment was tailored to suppress the aPL titer with markedly decreased inflammatory changes and no evidence of vasculitis in the spiral arteries of the placental bed was found. This was associated with a normal pregnancy outcome. A causal relationship between aPL and inflammatory vascular changes in the placental bed as well as a beneficial effect of the corticosteroid treatment in those two women in suggested.

In a nationwide study the 1982 revised ARA criteria were applied for the classification of systemic lupus erythematosus (SLE). This unselected group of patients included all cases diagnosed and managed in hospitals, as well as outside hospitals in Iceland over the 10-year period from 1975 to 1984. Seventy-six new cases were found, with an incidence of 5.9 and 0.8/100,000 for females and males at risk, respectively. The mean age at diagnosis was 46.6 years. Twenty-five percent of the patients would have been missed had the study included hospital patients only. A clinical pattern different from previous studies was found as illustrated by a low incidence of kidney disease; nephritis was found in 20% of patients. Comparison with a former study on SLE in Iceland shows an actual increase in incidence over a period of 10 years. The 5 year survival was 84% and the 10 year survival 78%.

Radiological progression was evaluated in 15 patients with rheumatoid arthritis (RA) treated with methotrexate (MTX). Prior to MTX treatment, all the patients had failed on other slow-acting agents and all showed radiological deterioration. For each patient, three sets of radiographs of hands and wrists were evaluated: prior to MTX treatment while on other slow-acting agents, at the beginning of MTX treatment, and at the most recent evaluation on MTX. Two experienced radiologists evaluated the radiographs independently. The rate of radiological progression was calculated by dividing the change in radiological score by the number of months between sets of radiographs. The mean time from film set one to two (period one) was 29.4 months and from set two to three (period two) 32.5 months. The mean rate of radiological progression for period one was 0.576 and for period two, 0.381. Eight patients showed decline in radiological progression during MTX treatment.

We describe a patient with C2 deficiency and severe systemic lupus erythematosus (SLE) that did not respond to conventional therapy. Over a period of 45 months, she was given 22 cycles of plasma therapy. For 6-8 weeks after each plasma infusion, there was a full clinical remission of the SLE, and a brief restoration of hemolytic complement activity. However, there were more prolonged increases in the activities of the complement components that are believed to be more directly involved in the clearance of immune complexes. Because of the theoretical risk that the infused complement might enhance inflammatory tissue damage, there has been some reluctance to try plasma replacement therapy in SLE patients with complement deficiency. We have not observed any adverse effects with the long-term use of this treatment, and our experience indicates that this therapeutic approach can be beneficial.

We report a case of systemic lupus erythematosus (SLE) and recurrent infections associated with isolated Clq deficiency. A 17-year-old girl from Saudi Arabia was hospitalized with seizures, fever, arthralgia, hair loss, oral ulceration and skin rash. Clinical and laboratory findings fulfilled the ARA preliminary criteria for the classification of SLE. Nonlesional skin contained immunoglobulins and C3 at the dermal-epidermal junction. She did not have antibodies to DNA or low C3 or C4. Total serum hemolytic complement activity was absent due to a total selective absence of Clq. There was no circulating inhibitor of Clq activity. The published experience of isolated selective complete Clq deficiency associated with clinical disease is reviewed.

A systematic analysis of the efficacy of methotrexate (MTX) in severe rheumatoid arthritis (RA) was carried out. Twenty-one patients with severe classical RA resistant to conventional therapy were treated with 7.5 to 25 mg of oral or intramuscular MTX for 3-114 weeks (mean of 38 weeks). Eleven patients (52.4%) showed definite clinical improvement and a fall in sedimentation rate; some improvement was seen in 5 other patients (23.8%). Two patients were unresponsive. Three patients discontinued MTX, 1 because of acute hepatitis and the other 2 because of noncompliance and fear of toxicity. Abnormal liver function tests reversible with modification of therapy occurred frequently. Other side effects were minor. The results of this uncontrolled study indicate that MTX may be an effective drug for the treatment of severe RA. Double blind trials and longterm followup are needed prior to its widespread use in RA.