Glycoprotein YKL-40: A potential biomarker of disease activity in rheumatoid arthritis during intensive treatment with csDMARDs and infliximab. Evidence from the randomised controlled NEO-RACo trial.

OBJECTIVE: YKL-40, a chitinase-like glycoprotein associated with inflammation and tissue remodeling, is produced by joint tissues and recognized as a candidate auto-antigen in rheumatoid arthritis (RA). In the present study, we investigated YKL-40 as a potential biomarker of disease activity in patients with early RA at baseline and during intensive treatment aiming for early remission. METHODS: Ninety-nine patients with early DMARD-naïve RA participated in the NEO-RACo study. For the first four weeks, the patients were treated with the combination of sulphasalazine, methotrexate, hydroxychloroquine and low dose prednisolone (FIN-RACo DMARD combination), and subsequently randomized to receive placebo or infliximab added on the treatment for further 22 weeks. Disease activity was evaluated using the 28-joint disease activity score and plasma YKL-40 concentrations were measured by immunoassay. RESULTS: At the baseline, plasma YKL-40 concentration was 57 ± 37 (mean ± SD) ng/ml. YKL-40 was significantly associated with the disease activity score, interleukin-6 and erythrocyte sedimentation rate both at the baseline and during the 26 weeks' treatment. The csDMARD combination decreased YKL-40 levels already during the first four weeks of treatment, and there was no further reduction when the tumour necrosis factor-α antagonist infliximab was added on the combination treatment. CONCLUSIONS: High YKL-40 levels were found to be associated with disease activity in early DMARD-naïve RA and during intensive treat-to-target therapy. The present results suggest YKL-40 as a useful biomarker of disease activity in RA to be used to steer treatment towards remission.

Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1.

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 5-year follow-up results of a randomised clinical trial, the NEO-RACo trial.

OBJECTIVE: To study whether adding initial infliximab to remission-targeted initial combination-DMARD treatment improves the long-term outcomes in patients with early rheumatoid arthritis (RA). METHODS: Ninety-nine patients with early, DMARD-naïve RA were treated with a triple combination of DMARDs, starting with methotrexate (max 25 mg/week), sulfasalazine (max 2 g/day), hydroxychloroquine (35 mg/kg/week), and with prednisolone (7.5 mg/day), and randomised to double blindly receive either infliximab (3 mg/kg; FIN-RACo+INFL) or placebo (FIN-RACo+PLA) infusions during the first 6 months. After 2 years the treatment strategies became unrestricted, but the treatment goal was strict ACR remission. At 5 years the clinical and radiographic outcomes were assessed. RESULTS: Ninety-one patients (92%) were followed up to 5 years, 45 in the FIN-RACo+INFL and 46 in the FIN-RACo+PLA groups. At 5 years, the respective proportions of patients in strict ACR and in disease activity score 28 remissions in the FIN-RACo+INFL and FIN-RACo+PLA groups were 60% (95% CI 44% to 74%) and 61% (95% CI 45% to 75%) (p=0.87), and 84% (95% CI 71% to 94%) and 89% (95% CI 76% to 96%) (p=0.51). The corresponding mean (SD) total Sharp/van der Heijde scores at 5 years were 4.3 (7.6), and 5.3 (7.3), while the respective mean Sharp/van der Heijde scores changes from baseline to 5 years were 1.6 (95% CI 0.0 to 3.4) and 3.7 (95% CI 2.2 to 5.8) (p=0.13). CONCLUSIONS: In early RA, targeted treatment with a combination of traditional DMARDs and prednisolone induces remission and minimises radiographic progression in most patients up to 5 years; adding initial infliximab for 6 months does not improve these outcomes.

Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci.

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

Impaired postural control is associated with worse scores of the Health Assessment Questionnaire disability index among women with rheumatoid arthritis.

OBJECTIVE: To explore the relationship between functional status and different domains of postural control, and to make recommendations about the use of postural control tests in clinical practice among women with rheumatoid arthritis. SUBJECTS: A total of 91 women with rheumatoid arthritis and 110 controls. The patients were grouped according to the total score of the Health Assessment Questionnaire (HAQ):HAQ1 = 0 (good, n = 21); HAQ2 = 0.1 to < 1 (impaired, n = 44);HAQ3 = 1­3 (severely impaired, n = 26). METHODS: Postural control tests: timed one-leg stance test(OLST), timed up and go test (TUG), and posturography tests on a force-plate. RESULTS: A poorer performance in the OLST and TUG tests was associated with higher, i.e. worse, HAQ scores. The results of the force-plate measurements were more complex.The results for healthy controls provided some clarifying information,but did not alter the main results. CONCLUSION: It is recommended that both OLST and TUG tests are included in the postural control assessment design for patients with arthritis. It seems that the force-plate measurements are not as good for screening postural control impairments associated with functional disability, but they may still have their use in, for example, monitoring the effect of intervention or rehabilitation.

Subaxial cervical vertebrae in patients with juvenile idiopathic arthritis--something special?

OBJECTIVES: To describe the main dimensions of the cervical vertebrae and spinal canal in two groups with juvenile idiopathic arthritis (JIA) and a non-inflammatory control group. METHODS: There were altogether 158 female patients in three different groups included in the study: a group with severe, complicated JIA (sJIA), a population based JIA group (pJIA), and fibromyalgia patients as a non-inflammatory control group (pFM). The patients' clinical records and cervical spine radiographs taken in adult age (>17 years) were evaluated. RESULTS: The patients with sJIA had the mean area of the 3rd-6th cervical vertebrae bodies and the average width and height of the 3rd-6th cervical vertebrae bodies significantly smaller than the patients in the pJIA and pFM groups. The mean value of the maximal difference between the successive vertebral body areas of each individual was significantly larger in the sJIA group than the other groups (p=0.047; the body height adjusted). There were no significant differences in the mean diameter of the sagittal spinal canal between study groups. CONCLUSIONS: Inflammatory changes of the cervical spine are common, and growth disturbances of cervical vertebrae in patients with JIA have been described previously. We found that patients with severe complicated JIA have a smaller cervical vertebral body size in general. They also have more differences in the sizes of their own vertebrae, representing growth disturbances of individual vertebral bodies. This is probably caused by the inflammatory disease and/or its more aggressive pharmacotherapy. The spinal canal diameter was only slightly smaller in the sJIA group. Thus the disturbed growth of the vertebral body in sJIA does not, in general, increase the risk of spinal canal compression.

Rheumatoid atlantoaxial subluxation can be prevented by intensive use of traditional disease modifying antirheumatic drugs.

OBJECTIVE: To evaluate the 5-year incidence of cervical spine disorders in patients with early rheumatoid arthritis (RA) treated by 2 different disease modifying antirheumatic drug (DMARD) strategies. METHODS: In a national, multicenter, prospective FIN-RACo-trial, a cohort of 199 patients with early, clinically active RA was randomly assigned to treatment with a combination of 3 DMARD and prednisolone (Combi group) or with a single DMARD (Single group) with or without prednisolone, aiming to induce remission. After 2 years, the DMARD therapy was unrestricted. Lateral view cervical spine radiographs during full flexion and extension were taken at the 5-year followup visits. The presence of anterior atlantoaxial subluxation (aAAS), atlantoaxial impaction (AAI), and subaxial subluxation (SAS) was assessed in the 149 patients with radiographs available (80 Single and 69 Combi). RESULTS: At the 5-year visits, aAAS, AAI, and SAS were found in 13 (9%), 6 (4%), and 9 (6%) patients, respectively. The corresponding Single/Combi group ratios were 11/2, 5/1, and 5/4. Of the baseline data, only poor physical function [Health Assessment Questionnaire (HAQ); p = 0.024] and Single treatment strategy (p = 0.019) were significantly associated with aAAS. Worse HAQ scores and Disease Activity Score 28 values were found in patients who developed aAAS during the 5-year followup. CONCLUSION: RA patients with sustained clinical disease activity and poor HAQ are at increased risk of developing aAAS. The development of aAAS during the first 5 years of RA was rare among the patients treated with a combination of DMARD for at least 2 years from the diagnosis. Intensive treatment with traditional DMARD prevents or retards the development of aAAS in patients with recent-onset RA.

Toll-like receptor 4 and CD14 polymorphisms in ankylosing spondylitis: evidence of a weak association in Finns.

OBJECTIVE: To investigate the association of CD14 and Toll-like receptor (TLR4) with ankylosing spondylitis (AS). METHODS: A promoter variant in CD14 and 2 coding polymorphisms in TLR4 were investigated in UK and Finnish families with AS and in a UK case-control study. A metaanalysis of published TLR4 and CD14 studies was performed. RESULTS: In the Finnish study the CD14-260bp T variant showed an association (p = 0.006), and the common 2-marker TLR4 haplotype showed a weak association (global p = 0.03), with AS. No associations were seen in the UK based studies or in the metaanalyses. CONCLUSION: CD14 and TLR4 showed an association with AS in the Finns only.

Serum antibodies against intact human collagen IX are elevated at onset of rheumatoid arthritis but are not related to development of erosions.

OBJECTIVE: To measure the presence of autoantibodies binding to intact human recombinant collagen IX and assess their usefulness as a diagnostic marker and an indicator of disease activity in rheumatoid arthritis (RA). METHODS: Recombinant human full-length collagen IX (rCIX) was produced in a baculovirus expression system and purified for use in ELISA developed to detect antibodies to native and denatured collagen IX. Fifty-three patients with recent-onset rheumatoid factor-seropositive RA were analyzed for the presence of rCIX antibodies of the IgG type at the time of initial diagnosis and after 3, 6, 12, and 24 months of followup. The RA sera were accompanied by 30 controls. Associations were determined between patients' antibody titers, development of erosions in the hands and feet, and various clinical and laboratory markers. RESULTS: Serum antibody levels among patients with RA at time of diagnosis were 1.78 times higher against native rCIX (p < 0.001) and 1.71 times higher against denatured rCIX (p < 0.001) than in the controls, and they remained high during the followup. No correlation was seen between antibody levels and clinical and laboratory findings. CONCLUSION: Our data show that patients with recent-onset RA have significantly elevated levels of autoantibodies to human rCIX. These autoantibodies were observed already at the early stages of the disease, which may reflect their diagnostic potential in RA.

Anti-TNF therapy in the treatment of ankylosing spondylitis: the Finnish experience.

Biological therapy for ankylosing spondylitis (AS) has led to improved disease control beyond that of conventional treatments. International recommendations encourage clinicians prescribing biological treatments to register patients in national registers to collect information on outcome and toxicity. Patients with AS (n = 229) from the Register of Biological Treatment in Finland (ROB-FIN) with severe disease of long duration were followed-up for up to 24 months. Due to an active disease, one or more concomitant disease-modifying antirheumatic drugs (DMARDs) were used by 86% at commencement of biological therapy. This add-on strategy with infliximab led to a rapid pain relief and improvement of patient's and physician's global assessments, C-reactive protein/erythrocyte sedimentation rate, and swollen and tender joint counts within 6 weeks. Concomitant use of NSAID and oral corticosteroid was reduced. Corresponding results were documented at 3 months with etanercept, which was more recently approved for the treatment of spondyloarthropathies. Seventy-nine percent of the patients were ASAS 20 responders. A subgroup of AS patients with only axial involvement (n = 46) responded correspondingly. The first biological drug was discontinued in only 7% due to lack of efficacy and in 6% due to adverse events. Anti-TNF agents, often used in combination with DMARDs, appeared to have persistent effectiveness and limited toxicity in a real-life clinical setting in a cohort of Finnish AS patients with severe disease and long disease duration.

A 30-year result of deforming arthritis in systemic lupus erythematosus.

Symmetric non-erosive polyarthritis is the most common clinical feature in systemic lupus erythematosus (SLE). We report on a 42-year follow-up of a 71-year-old woman who first had polyarthritis in 1963 at the age of 29 and continuously since 1975. SLE was diagnosed in 2000 at the age of 66 as anti-dsDNA (56 kIU/l), and antinuclear antibodies (1:2,560) turned positive. In 2005 hand and feet radiographs revealed severe Jaccoud's arthritis with subluxations but without erosions.

Evaluation of the MDHAQ in Finnish patients with RA [corrected].

OBJECTIVE: To study the characteristics of the Multidimensional Health Assessment Questionnaire (MDHAQ) in Finnish patients with rheumatoid arthritis. METHODS: The reliability of the questionnaire was tested by test-retest procedure. Construct validity was studied by factor analysis and convergent validity by calculating correlations between the Finnish MDHAQ (Finn-MDHAQ) scales and the Finnish Health Assessment Questionnaire (HAQ) and the Finnish Arthritis Impact Measurement Scales (Finn-AIMS2). Correlations between Finn-MDHAQ and measures of clinical characteristics, disease activity, and functional class were also measured. An item analysis was made of the Finn-MDHAQ scales Function (FN) and Psychological (PS). RESULTS: Internal consistency on the FN scale was 0.92 (95% lower limit 0.89) and 0.66 (0.56) on the PS scale. Reproducibility (95% CI) on FN was 0.93 (0.82 to 0.97) and on PS 0.84 (0.70 to 0.92). Factor analysis identified 2 factors, mobility of upper extremities and trunk, and mobility of lower extremities. Strong correlations were found between the FN scale and HAQ and physical subscales of Finn-AIMS2 and between PS and the psychological subscales of Finn-AIMS2. In item analysis corrected item correlation was high on the Finn-MDHAQ scales, except in one item on the PS scale. CONCLUSION: The Finn-MDHAQ is an applicable, reliable, and valid instrument for the part of the FN scale measuring functional ability in Finnish rheumatic patients. The incongruity in the PS scale structure that produced moderate internal consistency can be overcome with minor modifications.

Why Atlas, why not Heracles: reflections on the rheumatoid cervical spine.

Rheumatoid involvement of the 24 joints of the cervical spine leads to prominent changes in the occipito-atlanto-axial area. Eight different subtypes of such changes are recognized, depicted, and defined. The frequencies of these 8 subtypes in rheumatoid arthritis and other arthritides are tabulated. A central role in these disorders is played by a small-size, heavy-duty fitting piece or adapter, atlas, between the occiput and C2. The history of the fate of Atlas, who led the fight of godlike titans against the new gods of Olympos, is recapitulated. In particular, for a short moment Atlas was released from his heavy physical ordeal by another strongman, the heavy-weight wrestler of his times, Heracles. The reasons for the current nomenclature and answer to the question "Why Atlas, why not Heracles" are provided.

Cervical spine disorders in patients with rheumatoid arthritis and amyloidosis.

The aim of this radiographic study was to ascertain the extent of inflammatory cervical spine disorders in patients with rheumatoid arthritis (RA) complicated by secondary amyloidosis (SA). The study involved 147 patients with RA and SA, whose cervical spine radiographs were available. They were treated at the Rheumatism Foundation Hospital, Heinola, during the period 1989-2000 and had had RA for a mean of 24 years. The inflammatory abnormalities of the cervical spine were studied from radiographs taken at or after the diagnosis of SA during flexion and extension. One-hundred and eleven (76%) patients had subluxations, impaction or apophyseal joint ankylosis. Atlantoaxial impaction (AAI) was seen in 76 (52%) patients and anterior atlantoaxial subluxation (AAS) in 59 (40%). Apophyseal joint ankylosis was the third most frequent finding, seen in 34 (23%) cases. A combination of AAI and apophyseal joint ankylosis was noted in 26 (18%) patients. Eight (5%) patients had undergone surgery on the cervical spine. In conclusion, inflammatory and destructive changes are frequent in the cervical spine of patients with RA and SA. Characteristic changes are AAI and AAS. RA patients with SA have more severe disease than those in epidemiological studies when cervical spine disorders are concerned.