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.

Increased ferritin response in adult Still's disease: specificity and relationship to outcome.

BACKGROUND: The disproportionate ferritin response encountered in some patients with adult Still's disease (ASD) may reflect a fundamental aspect in the pathophysiology of ASD. METHODS: An observational case-control study of 22 ASD patients followed for 63 months. Baseline laboratory data were compared with age- and gender-matched controls with new-onset rheumatoid arthritis (RA). Serum levels of ferritin and C-reactive protein (CRP) and the ferritin/CRP ratio were related to clinical outcome in ASD through nonparametric statistical analyses. RESULTS: Compared to RA patients, haemoglobin levels were lower (11.8 vs. 13.5 g/dL; p = 0.009) and leucocyte counts (17.1 vs. 8.6 10(9)/mL; p<0.001), erythrocyte sedimentation rate (ESR) (84 vs. 38 mm; p = 0.001), CRP (154 vs. 27 mg/L; p<0.001), aspartate aminotransferase (ASAT) (52 vs. 23 U/l; p = 0.004), serum ferritin (8750 vs. 62 microg/L; p<0.001) and ferritin/CRP ratios (9.7 vs. 1.7; p<0.001) were higher in ASD patients at baseline. Six patients (27%) achieved sustained remission (monocyclic disease), while 16 patients (73%) developed chronic disease (progressive in 27%, relapsing/remitting in 46%). The levels of ESR and CRP or other baseline variables were not associated with outcome. However, baseline serum ferritin was significantly higher in ASD patients with chronic disease (p = 0.04), while a cut-off of five times the normal upper level (NUL) was 100% sensitive and 60% specific for predicting chronic disease. CONCLUSION: An exaggerated ferritin response with levels>5 times the NUL and high ferritin/CRP ratios is useful for distinguishing between ASD and RA patients. Ferritin levels>5 times the NUL are also associated with a chronic disease course.

Anti-dsDNA antibodies and disease classification in antinuclear antibody positive patients: the role of analytical diversity.

BACKGROUND: The presence of "anti-DNA antibodies in abnormal titres" is a well established criterion for SLE classification, but there is no agreement on the performance of this test. OBJECTIVE: To study the correlation between clinical findings and five different solid and solution phase anti-DNA antibody assays. METHODS: 158 consecutively collected ANA positive sera were studied in a double blind fashion. Anti-DNA antibodies were determined by different solid phase assays (ssDNA-, dsDNA- specific ELISA, EliA anti-dsDNA assay, Crithidia luciliae assay), and by an experimental solution phase anti-DNA assay using biotinylated pUC18 plasmid, human, calf thymus, and E coli DNA. Antibody affinity was determined by surface plasmon resonance. Clinical data were obtained independently of the laboratory analyses and later related to the anti-dsDNA findings. RESULTS: Anti-dsDNA antibodies were most frequently detected by ELISA, but were not specific for SLE as they were present in up to 30% of other disease groups. Those detected by the Crithidia luciliae assay were predictive for SLE, while antibodies binding in solution phase ELISA using the pUC18 correlated strongly with the Crithidia luciliae assay. Surface plasmon resonance analysis showed that antibody binding to pUC18 was not due to higher relative affinity for dsDNA in general, but apparently to specificity for that plasmid DNA. Serum samples from three patients with lupus nephritis were positive in both pUC18 solution phase and Crithidia luciliae assays. CONCLUSIONS: Assay principle selection is decisive for the detection of clinically significant anti-DNA antibodies. Revision of the anti-DNA antibody criterion in the SLE classification may be needed.

Fibrosing alveolitis predating microscopic polyangiitis.

A 65 year old male was diagnosed with "cryptogenic fibrosing alveolitis (CFA)" and treated successfully with Prednisone. In the year following Prednisone-tapering he presented with livedo reticularis, segmental pauci-immune glomerulonephritis and necrotizing vasculitis of the peripheral nerves, increased pulmonary fibrosis, and the presence of p-ANCA antibodies. Aggressive immunosuppressive treatment of this microscopic polyangiitis (MPA) was successful and also resulted in stabilization of the pulmonary fibrosis. This case illustrates that MPA may present itself monosymptomatic as CFA.

Systemic lupus erythematosus VII: frequency and impact of secondary Sjøgren's syndrome.

BACKGROUND: The prognosis of patients with systemic lupus erythematosus (SLE) largely depends on the severity of cumulative organ damage during the course of the disease. While Sjøgren's syndrome (SS) predominantly affects exocrine glands, a considerable number of patients develop visceral organ damage. Thus, the occurrence of a secondary SS (2(o)SS) in SLE patients, may result in more extensive organ damage and thereby adversely affect prognosis. PATIENTS/METHODS: 138 patients meeting the 1982 American College of Rheumatology (ACR) classification criteria for SLE were prospectively studied over a mean period of ninety months. 2(o)SS was diagnosed according to the 1993 European Study Group criteria and complication rates and prognosis were compared between patients with and without SS. RESULTS: 27 patients (19%) developed SS after a mean period of 48 months. There was a gradual increase in SS prevalence over time after SLE-onset. 2(o)SS patients were older (mean age 41 vs 35 years, P = 0.03), had less renal disease (19% vs 38%, P = 0.04), more thrombocytopenia (26% vs 9%, P = 0.05) and similar serological profiles (including anti-SSa) as patients without SS. Overall mortality was lower in patients with SS (4% vs 13.5%, P = 0.01), while lifetable analysis showed improved survival estimates for 2 SS patients with borderline statistical significance (P = 0.06). CONCLUSIONS: 2(o)SS develops in about one-fifth of SLE patients in a time-dependent fashion: these patients are older, have less renal involvement and their prognosis is at least as good as for those remaining free of SS.

SLICC/ACR Damage Index in Afro-Caribbean patients with systemic lupus erythematosus: changes in and relationship to disease activity, corticosteroid therapy, and prognosis.

OBJECTIVE: To apply the recently described Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI) in a well defined cohort of patients with systemic lupus erythematosus (SLE) and to study its association with disease activity, corticosteroid therapy, and prognosis. METHODS: We conducted a record review of 90 patients with SLE followed at a single center for a mean period of 6 years with periodic evaluations of SLE Disease Activity Index (SLEDAI), cumulative damage according to SLICC/ACR-DI, and therapy. Overall disease activity during the disease course was calculated as weighted averages of SLEDAI (WAS). RESULTS: Mean SLICC/ACR-DI was 0.6 six months after diagnosis and increased to 2.4 at last assessment. Thirteen patients (14%) remained free of accumulated damage at last visit. Index scores showed significant correlations with WAS scores and the number of disease exacerbations (SLEDAI > 10), but not with age, mean daily, or cumulative corticosteroid dosage. High WAS scores were independently associated with poorer survival, but SLICC/ACR-DI scores were not. CONCLUSION: SLICC/ACR-DI scores correlate with overall disease activity, but not with length or intensity of corticosteroid therapy. While easily applicable, its prognostic value is subordinate to that of persistent disease activity.

[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.

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.

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.