The influence of ERAP1 gene variants on clinical phenotype in ankylosing spondylitis.

OBJECTIVES: Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene variants diminish the risk of developing ankylosing spondylitis (AS) through a reduction in ERAP1 activity. We investigated whether disease expression was altered in patients who developed AS despite the presence of two protective ERAP1 variants. METHOD: We conducted a cross-sectional and longitudinal cohort study of patients with established AS (n = 334, 90% B27+, mean age at study 45 years) for whom clinical data and biological samples were collected during a research visit. Genotyping for the single nucleotide polymorphisms (SNPs) rs27044 and rs30187 was performed on genomic DNA by reverse transcription polymerase chain reaction (RT-PCR) with interleukin (IL)-6 and tumour necrosis factor (TNF) levels determined by a sandwich enzyme-linked immunosorbent assay (ELISA). Associations between genotypes and haplotypes, clinical and serological findings were analysed using SNPstats. RESULTS: Both SNPs were in strong linkage disequilibrium and formed three common haplotypes (C/C 0.65, G/T 0.30, and C/T 0.04). Haplotype C/T carried a lower risk for uveitis [odds ratio (OR) 0.32, p = 0.03] and elevated C-reactive protein (CRP) levels (OR 0.26, p = 0.04). There was no effect of ERAP1 haplotypes on cytokine levels or major outcomes after 8 years of follow-up. CONCLUSIONS: The ERAP1 rs27044/rs30187 haplotype C/T is associated with lower risk of extraspinal disease and systemic inflammation in Nordic AS patients but has no impact on IL-6 or TNF levels.

APRIL levels strongly correlate with IL-17 in systemic lupus erythematosus.

INTRODUCTION: Activated self-reactive B cells play an important part in systemic lupus erythematosus (SLE). A proliferation-inducing ligand (APRIL) and B cell-activating factor (BAFF) are B-cell specific stimulators, but activate B cells through different receptors. We investigated the reciprocal association between serum APRIL (s-APRIL), serum BAFF (s-BAFF) and immunological and clinical findings in SLE patients. METHODS: A cross-sectional case-control study was performed in 100 SLE patients (87% female, age 49 years, disease duration 12 years). APRIL and BAFF levels were measured by sandwich ELISA, compared with healthy controls and correlated with autoantibody, cytokine (IL-6 and IL-17) and clinical findings through nonparametric and multivariate regression analyses. RESULTS: Both median s-APRIL (478 vs. 0 pg/ml, p = 0.01) and s-BAFF (1720 vs. 0.9 pg/ml, p < 0.001) were higher in SLE patients than controls. Increased s-BAFF was observed in 86% of patients, while s-APRIL was increased only in 17% (p < 0.01). S-APRIL correlated with s-BAFF in controls (p = 0.04), but not in SLE (p = 0.8). Increased s-APRIL was strongly and independently associated with IL-17 activation (p < 0.001), while increased s-BAFF levels were associated with anti-nucleosome antibody presence (p = 0.001). Disease activity and organ damage were associated with s-BAFF but not s-APRIL. CONCLUSIONS: While both s-BAFF and s-APRIL levels are elevated in SLE patients, they reflect different immunologic and clinical pathways. The strong association between s-APRIL and IL-17 activation supports a role for Th17 helper cells in B cell activation in SLE.

The distribution of HLA-B27 subtype in patients with ankylosing spondylitis in Northern Norway.

BACKGROUND: Although the high prevalence of human leucocyte antigen (HLA)-B27 and ankylosing spondylitis (AS) in Northern Norway is now well documented, data on the distribution of HLA-B27 subtypes and their potential impact on disease presentation and course are lacking. METHOD: We conducted a cross-sectional study of patients (n = 124) with established (modified New York criteria) AS participating in a longitudinal disease registry. Clinical data at the time of sample collection were recorded and genotyping for HLA-B27 was performed by low-resolution polymerase chain reaction (PCR) screening. Subtyping was then performed with sequence-specific primers (PCR-SSP) and direct exon 2 and 3 sequencing. The results were analysed with SCORE and Seqscape software. RESULTS: Four patients (3%) were HLA-B27 negative in all genetic analyses. In the remaining 120 HLA-B27-positive patients, HLA-B27*05 was present in 117 (98%) and HLA-B27*02 in three patients (2%). There was complete concordance between the screening and subtyping results. The three patients with HLA-B27*02 had no distinguishing clinical characteristics. CONCLUSIONS: HLA-B27*05 is the predominant subtype of HLA-B27 in Northern Norway. This supports the concept of a North-South gradient for HLA-B27 subtypes with little regional drive to adapt to environmental challenges. Low-resolution HLA-B27 PCR screening captures all relevant subtypes in this region.

Interleukin-6 promotes arthritis and joint deformation in patients with systemic lupus erythematosus.

The underlying mechanisms for the subsets of self-limiting, intermittent or chronic and deforming arthritis in systemic lupus erythematosus (SLE) are not well understood. We performed a cross-sectional analysis of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-8 and TNF-α) and joint status in 47 SLE patients (79% females, age 42 years, disease duration 8.6 years). All cytokines levels were significantly elevated in SLE patients compared with controls, but only IL-2 and IL-8 levels were higher than in patients with rheumatoid arthritis. SLE patients with ongoing synovitis (19%) and joint deformities (11%) had increased erythrocyte sedimentation rate (ESR), IL-6 and anti-dsDNA Ab levels. IL-6 levels correlated with ESR, anti-dsDNA Ab and haemoglobin, but not with C-reactive protein levels. Arthritis constitutes a considerable burden of disease in SLE over time, and joint deformations are associated with longstanding disease and arthritis flare rates. IL-6 is a potential biomarker and therapeutic target in the prevention of joint damage in SLE arthritis.

Epidemiological and clinical characteristics of psoriatic arthritis in northern Norway.

BACKGROUND: To determine the characteristics of psoriatic arthritis (PsA) in northern Norway, where the human leucocyte antigen HLA-B27 is prevalent. METHODS: An observational study of patients with ICD-9 CR codes for psoriatic arthropathy (696.0 and 713.3) and spondylarthritis (720) seen during a 19-year period at a single regional rheumatology department. In patients with confirmed PsA demographics, date of onset of arthritis and psoriasis, clinical presentation and subsequent disease course (including therapeutic measures) were recorded during a mean follow-up of 11.1 years. RESULTS: Arthritis was documented in 329/657 (50%) of patients with a diagnostic code for PsA. The mean annual incidence rate for PsA was 6.9/100 000 and the point prevalence was 130/100 000 (0.13%) adults. The male to female ratio was 1.4 and the mean age at onset of psoriasis was 27.8 years (SD 14.1), and 35 years (SD 11.8) at onset of arthritis. Arthritis preceded psoriasis in 13.8% of cases. Oligoarthritis was the most frequent subtype (48%), followed by polyarthritis (32%), spondylitis (9%), monoarthritis (7%), and classic distal interphalangeal (DIP) arthritis (2%). Erosive disease (56% of cases) occurred mainly with polyarthritis; arthritis mutilans occurred in six patients (2%). Surgical interventions were performed in 22% of patients. Disease activity fluctuated considerably over time. Mortality (4.3%) was increased in PsA patients with polyarthritis and secondary amyloidosis (n = 5). CONCLUSION: The prevalence of PsA and related spondylitis is not increased in northern Norway. PsA does, however, lead to a considerable burden of disease due to erosive disease development and surgical intervention.

Contemporary use of disease-modifying drugs in the management of patients with early rheumatoid arthritis in Norway.

OBJECTIVE: As treatment options for rheumatoid arthritis (RA) are rapidly expanding, we evaluated the current use of disease-modifying anti-rheumatic drugs (DMARDs) in the management of patients with early RA in Norway with particular attention to the influence of risk factors for a poor disease outcome on DMARD selection. METHODS: An observational multicentre study registering the type of therapy initiated in 820 DMARD-naive patients with early active RA [67% female, mean age 51 years, disease duration 4 months, 57% rheumatoid factor (RF) positive]. The impact of baseline risk factors associated with poor prognosis (disease activity parameters and biomarkers of inflammation) on DMARD selection was analysed through odds ratios (ORs) by multivariate logistic regression. RESULTS: Methotrexate (MTX) monotherapy was selected for 78% of patients. MTX was preferred over sulfasalazine (SSZ) monotherapy (19%), leflunomide monotherapy (2%), and combination therapy (2%) in female patients [OR 1.6, 95% confidence interval (CI) 1.1-2.5], age >50 years (OR 2.5, 95% CI 1.6-3.8), short disease duration (OR 2.7, 95% CI 1.4-5.0), 10 swollen joints (OR 2.2, 95% CI 1.2-4.0), and erosive disease (OR 1.8, 95% CI 1.1-3.2). Concurrent steroid therapy was started in 73% of patients, regardless of the type of DMARD therapy initiated. CONCLUSION: Monotherapy with MTX is currently the DMARD treatment of choice for early RA in Norway. Disease duration, age, swollen joint count, and erosive disease have considerable impact on DMARD selection in contrast to the presence of biomarkers. Few patients with early RA in Norway receive combination DMARD therapy, while the majority of patients receive corticosteroid bridging therapy.

Polymorphism in the 5' regulatory region of the B-lymphocyte activating factor gene is associated with the Ro/La autoantibody response and serum BAFF levels in primary Sjogren's syndrome.

OBJECTIVE: To investigate the association between haplotypes in the 5' regulatory region of the B-lymphocyte activating factor (BAFF) gene, disease susceptibility and serum BAFF (s-BAFF) levels in Caucasian primary SS (pSS) patients. METHODS: Case-control study in an established pSS cohort with PCR-RFLP genotyping for four SNPs (-2841 T-->C, -2704 T-->C, -2701 T-->A, -871 C-->T), which tag a haplotype block in the 5' regulatory region of the BAFF gene and s-BAFF determination by ELISA. RESULTS: s-BAFF levels were elevated in Ro/La-positive pSS patients (n = 85, 1770 pg/ml) compared with both Ro/La-negative pSS patients (n = 27, 1193 pg/ml) and controls (n = 59, 1171 pg/ml), P < 0.001. s-BAFF increased with diversification of the anti-Ro/La antibody response, but was not correlated with age, RF or immunoglobulin G levels. There were four common BAFF haplotypes. While the CTAT haplotype was associated with Ro/La-positive pSS [odds ratio (OR) 2.6; 95% CI 1.7, 4.1; P = 0.00004], the TTTT haplotype was associated with elevated s-BAFF in autoantibody-positive pSS (n = 85; 88% females; P = 0.008). The shared -871 T allele had no independent contribution to disease susceptibility or s-BAFF. CONCLUSIONS: Disease susceptibility for Ro/La-positive pSS is increased with the CTAT haplotype, but not associated with high s-BAFF levels. Elevated s-BAFF levels in pSS are associated with the TTTT haplotype and may be a secondary phenomenon in Ro/La-positive pSS. While both haplotypes carry the -871 T allele, this allele is not independently associated with disease susceptibility.

Incidence and course of symptomatic deep venous thrombosis of the lower extremities in a black Caribbean population.

During a 5-year period 131 patients with symptomatic deep venous thrombosis of the lower extremities (DVT) were identified in a black Caribbean population. Eighty-one patients (61%) had objective evidence (ascending venography), while in 39% the diagnosis was based on clinical findings only. The overall annual incidence rate for definite DVT was 11 per 100,000 person years; there was a steep increase with age in both sexes. Proximal DVT was present in 69% of patients. Swelling (92%), pain on palpation (89%) and tenderness (87%) were the most frequent symptoms, while immobilization (43%) and varicosities (42%) were the most frequent risk factors; DVT was rare during pregnancy (1 in 15,000 deliveries). Seventeen patients (21%) developed pulmonary embolism and five patients (6.2%) died during the hospital stay (four of fatal pulmonary embolism, one due to toxic epidermolysis after venography). We conclude, that symptomatic DVT of the lower extremities has a low incidence in this black Caribbean population, but is nonetheless associated with considerable morbidity and mortality due to pulmonary embolism.

Course and prognostic value of Systemic Lupus Erythematosus Disease Activity Index in black Caribbean patients.

The course and prognostic value of disease activity measured by the validated Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was investigated in 68 newly diagnosed black Caribbean cases. A high percentage of patients had clinical renal involvement (78%). Disease activity at onset was mild to moderate (SLEDAI < or = 10) in 36% of patients; about half never reached a higher SLEDAI score, whereas the other half advanced to higher disease activity (SLEDAI > 10). SLEDAI scores decreased significantly over time from diagnosis. Within 3 months after disease onset, 54% of patients reached their maximum SLEDAI scores. There were no differences in clinical features or survival between these patients and those with later (mean, 35 months) maximum disease activity, although the latter had more frequent disease flares. Overall survival was poor (91% and 56% at 1 and 5 years, respectively). High persistent disease activity (weighted average of SLEDAI scores > 10) was independently associated with decreased survival, whereas a high initial SLEDAI, a high maximum SLEDAI, and an increase number of flares were not. The main cause of death was infection, which often was associated with active disease (mean SLEDAI at death, 16 +/- 8.9). SLEDAI was a practical and reliable way of evaluating disease activity but was of limited prognostic value.

Cerebral arteriovenous malformations in The Netherlands Antilles. High prevalence of hereditary hemorrhagic telangiectasia-related single and multiple cerebral arteriovenous malformations.

Seventeen patients with symptomatic cerebral arteriovenous malformations (AVMs) were diagnosed between 1980 and 1990 in the Leeward Islands of the Netherlands Antilles. Five patients had multiple AVMs. The annual incidence of symptomatic AVMs was 1.1/100,000. The mean age of presentation was 35 years. In 6 patients cerebral AVMs were associated with hereditary hemorrhagic telangiectasia (HHT); 4 of these patients had multiple AVMs. We conclude that HHT is frequently encountered in Netherlands Antillians with symptomatic and multiple cerebral AVMs.

Longstanding isolated cerebral systemic lupus erythematosus in an 8-year-old black girl. Resemblance with multiple sclerosis.

We describe a 12-year-old girl with SLE who presented with longstanding isolated neurological symptoms resembling MS. The literature concerning the difficulties in diagnostic procedures in cerebral SLE are reviewed in comparison to MS.

Pure red-cell aplasia in systemic lupus erythematosus.

A woman with SLE of six years duration developed severe anaemia which was characterized by severe bone marrow erythroid hypoplasia; no deficiencies could be found to explain this finding. Antibodies against erythroid progenitors are a likely cause of this anaemia, which completely resolved after transfusion of packed red-cells.

Antinuclear antibody profiles in relation to specific disease manifestations of systemic lupus erythematosus.

UNLABELLED: The aim of the study was to investigate the prevalence of antinuclear and associated antibodies (anti-dsDNA, anticardiolipin, anti-RNP, anti-Sm, anti-SSA and anti-SSB) and/or combinations thereof in systemic lupus erythematosus (SLE) patients with respect to their diagnostic and pathogenetic significance. The prevalence of anti-dsDNA antibodies was strongly influenced by the selection criteria of the patient; the lowest prevalence was found in SLE patients with central nervous system (CNS) involvement; the highest prevalence in patients with nephritis. The results were also influenced by the different assays. Combinding different assays (Farr/PEG ratio) quantitative as well as qualitative differences could be shown between patients with nephritis (Farr/PEG ratio greater than or equal to 5) and with CNS involvement (Farr/PEG ratio less than 5). No difference in anticardiolipin antibody prevalence between the different SLE patient groups could be demonstrated. Regarding antibodies against RNP, Sm, SSA and SSB, the prevalence was found to be strongly influenced by the criteria used for patient selection. Only in CNS patients and association with anti-RNP and anti-SSB antibodies alone or in combination was found. In pleuropericarditis a weak association with RNP antibodies existed. IN CONCLUSION: studying the prevalence and possible pathogenetic significance of antibodies one should always consider patient selection criteria and the effect of the different assays used when analysing the results.

Panniculitis as the first manifestation of systemic lupus erythematosus: description of two cases.

Two patients are described in whom panniculitis proved to be the first symptom of the disease systemic lupus erythematosus (SLE). Histological examination of a painless solitary cutaneous lesion in the otherwise asymptomatic first patient showed a nonspecific nodular panniculitis; 1 yr later a definite diagnosis of SLE was made. In the second patient panniculitis had the clinical appearance of erythema nodosum and was one of several presenting symptoms of SLE. These patients were part of a group of 68 newly diagnosed patients with SLE, indicating a 3% prevalence of panniculitis in SLE. These cases illustrate that SLE should always be considered as an underlying disease in young female patients presenting with nodular panniculitis, which may mimic the clinical picture of erythema nodosum.

Pneumatosis intestinalis in mixed connective tissue disease.

Two young female patients with established mixed connective tissue disease (MCTD) are described, in whom the disease course was complicated by intestinal pseudo-obstruction and pneumoperitoneum due to pneumatosis intestinalis. Conservative management of this rare complication in MCTD, which included the use of high-flow normobaric oxygen by mask, led to a complete resolution of the abdominal symptoms in both patients.

Multiple myeloma in the Afro-Caribbean population of Curaçao.

To determine the incidence and course of multiple myeloma (MM) in the Afro-Caribbean population of Curaçao, we studied all MM patients discharged from the only hospital on the island during an 11-year period starting in 1980. As 50 patients fulfilled the diagnostic criteria for MM proposed by Durie, the average annual incidence (AI) of MM was estimated at 3.1/100,000 person years; AI was similar in males and females, but showed a steep increase with age in both sexes; 10% of all MM patients were < 40 years of age. At diagnosis 68% of patients were in Stage III, in 26% serum creatinine levels were > 20 mg/l, 36% had hypercalcaemia, and 50% had multiple bone lesions. Median survival was 20.5 months; Stage III myeloma and bone marrow plasma cell percentage > 50 were independent risk factors for poor survival. Infections were the immediate cause of death in 54% of the non-survivors. We conclude that the incidence rate of MM in the Afro-Caribbean population of Curaçao is one of the lowest reported in black populations; however, the presentation and course of MM follow the pattern seen in most other countries.

[Cerebrovascular accidents at a young age in Rendu-Osler-Weber disease; a survey in the Netherlands Antilles]. / Cerebrovasculaire accidenten op jonge leeftijd bij de ziekte van Rendu-Osler-Weber; een inventariserend onderzoek op de Nederlandse Antillen.

Thirty-two patients (17 men and 15 women) are presented in whom the diagnosis Rendu-Osler-Weber disease was established between 1980 and 1990 during hospitalisation in the Leeward Islands of the Netherlands Antilles. Among this group there were eight families, each of which contained two patients. Estimated point-prevalence rate in 1991 was 19.4/100,000, which is ten times higher than has been reported so far. Epistaxis, gastrointestinal blood loss and cerebrovascular accidents (CVA) were the main presenting symptoms. Mean age at diagnosis was 53.2 years. Arteriovenous fistulae in the lung developed in 11 patients (34%). Eleven patients experienced a total of 12 CVAs at a mean age of 48 years; four of these patients had an ischaemic CVA in the presence of pulmonary fistulae, while three patients had a haemorrhagic stroke in the presence of a cerebral arteriovenous malformation. Thus, cerebrovascular accidents at an early age are common complications in Rendu-Osler-Weber disease and warrant further investigation of this disease among inhabitants of the Leeward Islands of the Netherlands Antilles.

[AIDS on Curaçao: the first 6 years]. / AIDS op Curaçao: de eerste 6 jaren.

We present our experience with AIDS in Curaçao in the first 6 years after the introduction of a serologic HIV screening method. 71 cases of full-blown AIDS were diagnosed in the period 1-1-1986 to 12-31-1991 giving a mean incidence of 81 cases per million per year. Non-homosexual transmission was the predominant mode of spread of HIV with a low male-to-female ratio of 1.3:1. Kaposi's sarcoma, non-Hodgkin lymphoma and hairy leukoplakia were not found. Survival probability was 48% and 30% at 1 and 2 year after diagnosis respectively, with better survival for female patients. In view of the still rising HIV prevalence rate, the peak in AIDS incidence in Curaçao can be expected between 1993 and 1998 so that the AIDS epidemic will become a tremendous social and economic burden in the Dutch Antilles in the years to come.

[Low incidence of non-Hodgkin lymphoma but high seroprevalence of HTLV-I in Curaçao]. / Lage incidentie van non-Hodgkin-lymfoom, maar hoge seroprevalentie van HTLV-I op Curaçao.

OBJECTIVE: To determine whether the low incidence of non-Hodgkin's lymphoma (NHL) in Curaçao has changed in comparison with the increase in incidence in many western countries, and to investigate the role of the HTLV-I infection that is endemic in the Caribbean area. DESIGN: Retrospective. SETTING: Curaçao, Netherlands Antilles. METHOD: Retrospective file analysis in the only hospital in Curaçao. RESULTS: During the period 1987-1992, 31 patients had a histologically confirmed diagnosis of NHL resulting in an annual incidence rate of 4.9/100,000 adults. There was a strong age-related increase in NHL incidence rate (0.5 for patients < 30 years to 17.8 for patients > or = 70 years), with a male to female ratio of I. (In the western world the incidence is 12-14, in the seventies it was 4.5 in Curaçao.) Seven of 12 patients (58%) tested were seropositive for HTLV-I. Median survival was 6 months, despite conventional therapy. CONCLUSION: While HTLV-I infection can often be demonstrated in NHL patients in Curaçao, NHL incidence has remained low over the past 25 years.