Correction to: Remarkable improvement in serum 25-hydroxyvitamin levels among hip fracture patients over a 12-year period: a prospective study in South-eastern Finland.

The presentation of Table 4 was unclear in the original publication. The article has now been corrected in this respect.

Remarkable improvement in serum 25-hydroxyvitamin levels among hip fracture patients over a 12-year period: a prospective study in South-eastern Finland.

Hypovitaminosis D is a problem among hip fracture patients. In a 1-year cohort study comprising 245 hip fracture patients (mean age of females 81 years and males 78 years) from south-eastern Finland, the mean 25-hydroxyvitamin D [S-25(OH)D] concentration was 73(SD 31) nmol/L. Vitamin D supplementation has been integrated into our current practice. INTRODUCTION: The objectives of this study are to verify vitamin D levels among hip fracture patients and to compare the results with a similar study conducted in the same two hospitals covering the same geographic area 12 years ago. METHODS: A prospective cohort comprising 245 Caucasian hip fracture patients was enrolled in the study in two acute hospitals in south-eastern Finland (61° N) over a 12-month period in 2015-2016. The S-25(OH)D was measured using 25-hydroxyvitamin D electrochemiluminescence binding assay. The S-25(OH)D concentrations were compared with the corresponding concentrations of a similar cohort analyzed in the same two hospitals 12 years ago. RESULTS: Of the 245 patients, 70% were women with a mean age of 81 (SD 10) years, while the men had a mean age of 78 (SD 12) years (p < 0.01). The total mean S-25(OH)D concentration was 73 (SD 31.3) nmol/L. Regional differences were found: 15% in hospital A and 36% in hospital B had a S-25(OH(D level < 50 nmol/L, and the mean S-25(OH)D level was 79.2 (SD 31.7) nmol/L in hospital A and 62.4 (SD 27.5) nmol/L in hospital B (p < 0.001). No differences were found in S-25(OH)D concentrations by either the place of residence or the time of year. Overall, the percentage of patients with a sufficient vitamin D level (> 50 nmol/L) was remarkably higher in 2015-2016 (77%) than in 2003-2004 (22%). CONCLUSION: Our results indicate that vitamin D supplementation has been widely integrated into our current practice. However, regional differences were found in the S-25(OH)D concentrations for which the reasons are unknown.

Agreement between clinical and radiological methods of diagnosing knee osteoarthritis.

OBJECTIVE: To determine the agreement between clinical diagnosis and different radiological grading scales of knee osteoarthritis (OA) in an epidemiological study. METHODS: Health 2000 Survey is an extensive population study focusing on major health problems in a representative sample of 8028 Finns over 30 years of age. In the survey, physicians diagnosed knee OA on the basis of physical status, symptoms, and medical history. A total of 130 participants (mean age 60 years, 68% female) were re-examined 1 year later (Kuopio OA 2000 Study) to determine the agreement between clinical and radiological diagnosis as well as between three different radiological grading scales (Kellgren and Lawrence, Ahlbäck, and Piperno). Weight-bearing knee radiographs were taken and graded by a radiologist in Kuopio University Hospital. The history of knee symptoms was obtained using the Western Ontario MacMaster (WOMAC) and Lequesne questionnaires. RESULTS: Knee OA was diagnosed clinically in 17.7% and radiologically in 24.6-30% of participants. The strength of agreement was moderate (kappa values 0.34-0.54) between the clinical and the radiological diagnosis and substantial (0.62-0.78) between the different radiological scales. Those subjects identified by any diagnostic method as having OA in either knee reported significantly more symptoms and disability than the other subjects. CONCLUSION: The agreement between the clinical diagnosis performed in a large population study and radiological grading scales was only moderate. By contrast, the agreement between different radiological scales was substantial.

Association of tumour necrosis factor a, b and c microsatellite polymorphisms with clinical disease activity and induction of remission in early rheumatoid arthritis.

OBJECTIVE: To study the associations of tumor necrosis factor (TNF) a, b and c microsatellite markers with 1) the clinical disease activity and 2) the induction of remissions in patients with early rheumatoid arthritis (RA) treated with two treatment strategies. METHODS: In the FIN-RACo (FINnish Rheumatoid Arthritis Combination therapy) trial of two years, 195 patients with recent-onset RA were randomly assigned to receive either a combination (COMBI) (sulphasalazine, methotrexate, hydroxychloroquine, and prednisolone) or a single (SINGLE) (initially sulphasalazine with or without prednisolone) disease modifying antirheumatic drug (DMARD) therapy. TNF a, b and c microsatellite and HLA-DRB1 typings were carried out in 165 (79 COMBI; 86 SINGLE) study completers. RESULTS: At baseline the 28 joint disease activity scores (DAS28) of the patients positive for TNFa2, a13 or b1 microsatellite markers were significantly higher than in the other patients. In the SINGLE patients the DAS28 improved comparably in patients with (n = 31) or without (n = 53) the TNFb1 marker (NS), while the DAS28 of the TNFb1-positive COMBI patients (n = 22) improved significantly more than that of the TNFb1-negative cases (n = 57) (p = 0.014). Respective 31.8% (7/22) and 28.1% (16/57) of the COMBI patients with or without TNFb1 allele achieved remission at one year. The corresponding figure in SINGLE patients were 0% (0/31) and 20.8% (11/53) (p = 0.006). At two years the remission frequencies in the TNFb1+/TNFb1- patients in the COMBI and SINGLE were 50.0%/38.6% and 9.7%/22.6%, respectively. CONCLUSION: Early TNFb1+ RA patients have more active disease but respond more favourably to COMBI treatment than the patients without this microsatellite allele. The finding may be of clinical relevance for the choice of DMARDs in early RA.

Sindbis viruses and other alphaviruses as cause of human arthritic disease.

Amongst the arthritis-causing arboviruses, i.e. those spread by insects, the alphavirus group is of special interest. These viruses occasionally cause vast outbreaks, such as O'nyong-nyong in Africa in 1959. In Fennoscandia, Sindbis-related Ockelbo, Pogosta, or Karelian fever viruses have been found to cause significant morbidity. The major symptoms in addition to joint inflammation are fever, fatigue, headache and rash. The joint symptoms may persist for weeks, even months. The diagnosis is based on the clinical picture and serology. The causative viruses are closely related but not identical. It appears that at least in Finland the Pogosta disease is more common than thought, and the symptoms may often be overlooked. Several factors related to the viruses, their hosts, and global environmental changes may affect the spread of these viruses. All over the world arbovirus-caused diseases have increased, because of global changes.

HLA-DR-DQ haplotypes and genotypes in Finnish patients with rheumatoid arthritis.

OBJECTIVES: To elucidate the contribution of HLA-DR-DQ haplotypes and their genotypic combinations to susceptibility to rheumatoid arthritis, and to evaluate the various models for HLA associated risk for the disease in a series of Finnish patients. METHODS: 322 Finnish patients with rheumatoid arthritis were typed for common north European HLA-DR-DQ haplotypes and compared with a series of 1244 artificial family based control haplotypes. RESULTS: The association of the so called shared epitope (SE) haplotypes (DRB1*0401, *0404, *0408, and *01) with rheumatoid arthritis was confirmed. The DRB1*0401 haplotypes carried a far stronger risk for the disease than the (DRB1*01/10)-(DQA1*01)-DQB1*0501 haplotypes. Seven protective HLA haplotypes--(DRB1*15)-(DQA1*01)-DQB1*0602; (DRB1*08)-(DQA1*04)-DQB1*04; (DRB1*11/12)-DQA1*05-DQB1*0301; (DRB1*1301)-(DQA1*01)-DQB1*0603; (DRB1*1302)-(DQA1*01)-DQB1*0604; (DRB1*07)-DQA1*0201-DQB1*0303; and (DRB1*16)- (DQA1*01)-DQB1*0502--were identified. In accordance with the reshaped shared epitope hypothesis, all the protective DRB1 alleles in these haplotypes share either isoleucine at position 67 or aspartic acid at position 70 in their third hypervariable region motif. However, differences in the disease risk of haplotypes carrying the same DR but different DQ alleles were also found: (DRB1*07)-DQA1*0201-DQB1*0303 was protective, while (DRB1*07)-DQA1*0201-DQB1*02 was neutral. The same haplotypes carried different risks for rheumatoid arthritis depending on their combination in genotypes. CONCLUSIONS: When assessing the influence of HLA genes on the susceptibility to rheumatoid arthritis, not only should the HLA-DR or -DQ alleles or haplotypes be unravelled but also the genotype. The effect of HLA class II region genes is more complicated than any of the existing hypotheses can explain.

Effect of a three month course of ciprofloxacin on the late prognosis of reactive arthritis.

BACKGROUND: The value of antibiotics in the treatment of reactive arthritis (ReA) is still controversial. OBJECTIVES: To analyse the long term outcome of patients with ReA, treated with a three month course of ciprofloxacin or placebo. METHODS: Patients who had had ReA and had participated in a double blind, placebo controlled trial on the effectiveness of ciprofloxacin 4-7 years earlier were invited to a clinical examination. Of the 71 patients who were included in the original study, 53 agreed to visit the clinic for an examination. Twenty six of 53 patients had originally received ciprofloxacin and 27 had belonged to the placebo group. Of these, 20 in the ciprofloxacin and 25 in the placebo group were HLA-B27 positive. RESULTS: 11/27 (41%) patients in the original placebo group had now developed chronic rheumatic disease, as compared with only 2/26 (8%) patients originally treated with ciprofloxacin (p=0.006). Two patients who originally had received placebo, none in the ciprofloxacin group had developed ankylosing spondylitis, and three patients in the original placebo group, none in the ciprofloxacin group had recurrent anterior uveitis. The same tendency was seen when several different measures were analysed. Of the patients with chronic spondyloarthropathy, 10 in the placebo and none in the ciprofloxacin group were HLA-B27 positive. CONCLUSION: Analysis 4-7 years after the initial ReA suggests that a three month course of antibiotics in the acute phase may have a beneficial effect on the long term prognosis.

Prevalence of Sindbis-related (Pogosta) virus infections in patients with arthritis.

OBJECTIVE: To determine the role of Pogosta virus as a triggering infection in non-specific arthritis. METHODS: Serum samples of 142 patients with acute arthritis were screened for the evidence of Pogosta virus infection. Serological tests for Chlamydia trachomatis, salmonella, parvovirus B19, and Borrelia burgdorferi were also carried out. As verified later, 78 of the patients had rheumatoid arthritis and 63 seronegative poly- or oligoarthritis, while one had systemic lupus erythematosus. RESULTS: In the early stage of the joint symptoms 4 patients with rheumatoid arthritis, 1 with seronegative polyarthritis and 1 with systemic lupus erythematosus had recent Pogosta virus infection. Four of them had probably had Pogosta disease at the time of the onset of arthritis. In 11 patients with a diagnosis of seronegative arthritis, serological evidence of preceding infection due to salmonella or Chlamydia trachomatis was found, strongly suggesting classical reactive arthritis in these cases. CONCLUSIONS: Our study suggests that also a Sindbis virus infection may be associated both to an acute joint inflammation as a part of Pogosta disease or chronic arthritis. At present, this possibility still needs further research.

The prevalence of antibodies against Sindbis-related (Pogosta) virus in different parts of Finland.

OBJECTIVE: To study the occurrence of Sindbis-related (Pogosta) disease in Finland by serological means. METHODS: A total of 2250 serum samples from five different areas were included in the study. Four hundred samples were collected from healthy blood donors and 1850 samples from patients who were suspected to have some viral infection. Antibodies of IgG and IgM classes against Pogosta virus were measured. RESULTS: Eleven per cent of 2250 samples were positive for IgG and 0.6% were positive for IgM class antibodies against Pogosta virus. The antibody prevalence in Finland was almost equally distributed, being highest in western Finland (17%) and lowest in southern and northern Finland (9%). Of all samples with IgG class antibodies, 25% were taken from children under 10 yr of age. CONCLUSIONS: The prevalence of antibodies against Pogosta virus was much higher than we expected. Additionally, they were detected from all locations studied and not only in eastern Finland, which has been thought to be the main endemic area for this disease. Pogosta disease has been considered to affect mainly middle-aged persons, but our results indicate a high prevalence also among children.

Acute disseminated encephalomyelitis following nephropathia epidemica.

Acute disseminated encephalomyelitis (ADEM) is an acute monophasic inflammatory and demyelinating disease of the central nervous system (CNS) occurring days to weeks after a virus infection or vaccination. Nephropathia epidemica (NE) is a haemorrhagic fever with renal syndrome caused by Puumala virus, with endemic regions in Europe, especially Scandinavia and Western Russia. We describe a case of severe nephropathia epidemica requiring dialysis, followed by severe CNS symptoms caused by ADEM. To our best knowledge this is the first case in the literature in which NE caused ADEM.

Reactive arthritis.

Reactive arthritis is a disease affecting mostly young adults. Owing to a greater general awareness the diagnosis has become more common during recent years. It is well established that ReA is caused by an infection, mostly in genetically susceptible individuals. The pathogenetic mechanisms are still poorly understood, and the treatment rests mainly on anti-inflammatory drugs or steroids. Vigorous and early treatment of the triggering infection may prevent the development of ReA but this is rarely possible in everyday clinical practice. Despite its name, the disease should be considered as a general disorder that affects not only the joints. The prognosis is not as good as earlier believed, and relapses or chronic development are not unusual.

Bacteria-Triggered reactive arthritis: implications for antibacterial treatment.

Reactive arthritis (ReA) is definitely caused by an infection. Several observations suggest that the triggering microbe may persist in the tissues of the patient for a prolonged time. The obvious conclusion is to consider antibacterial treatment. In two instances antibacterial agents are of definite value: in the primary and secondary prevention of rheumatic fever and for early eradication of Borrelia burgdorferi in order to prevent development of the arthritis associated with Lyme disease. Altogether, clinical and experimental data exist to indicate that if antibacterial treatment of ReA can be started very early during the pathogenetic process, the disease can be prevented or the prognosis improved. In fully developed ReA, the value of antibacterial agents is less certain. All available evidence indicates that short term antibacterial treatment has no effect on the prognosis and final outcome of ReA, and the results with long term administration of antibacterials are also overall poor. In some instances sulfasalazine appears useful, rather as a result of its antirheumatic effect or influence on an underlying inflammatory bowel disease than its action as an antibacterial agent. Tetracyclines have also been found to have an effect on ReA, but again, this is probably due to their anti-inflammatory action rather than any antibacterial effect.

HLA haplotype analysis in Finnish patients with rheumatoid arthritis.

OBJECTIVE: To further characterize the HLA gene products that play an important role in the pathogenesis of rheumatoid arthritis (RA). METHODS: One hundred thirty-four haplotypes from 67 Finnish RA patients and 77 control haplotypes were analyzed for HLA-DRB1 loci, associated alleles of the HLA-DQB1 locus, alleles of the type 2 transporter-associated antigen processing (TAP2) genes, and HLA-B27. In addition, a panel of microsatellite markers within the HLA class I and class III regions was studied. RESULTS: The frequency of HLA-DRB1*04 in the haplotypes of RA patients was found to be 34% (45 of 134) compared with 14% (10 of 72) in control haplotypes (P = 0.004). The frequency of HLA-DRB1*13 was decreased in RA haplotypes (4%, or 5 of 134) in contrast to control haplotypes (24%, or 17 of 72) (P = 0.000031). The decrease in DRB1*13 was not secondary to the increase in DRB1*04, since it was also found among DRB1*04-negative haplotypes (P < 0.001). The DRB1*13-associated DQB1*0604 allele was similarly decreased in RA haplotypes (P = 0.025). The TAP2I allele of I/J dimorphism was increased in RA patients (85%, or 114 of 134) as compared with controls (69%, or 49 of 71) (P = 0.011). Of the tumor necrosis factor (TNF) microsatellite alleles, TNFa6 and TNFb5 were found to be increased in RA haplotypes (for a6 27% versus 5% in controls [P = 0.00043], and for b5 43% versus 26% in controls [P = 0.037]). CONCLUSION: Both protection-associated and susceptibility-associated alleles can be found among HLA class II genes, and the results suggest that loci outside DR/DQ may contribute to the pathogenesis of RA.

Differences between female and male patients with familial rheumatoid arthritis.

OBJECTIVE: To determine whether there are genetic differences between female and male patients with familial rheumatoid arthritis (RA). METHODS: 45 men and 119 women from 78 families with RA who all had at least one first degree relative with RA were compared. HLA-DRB1 alleles were analysed, including DRB1*04 subtypes and associations of DRB1*04 haplotypes with DQB1*0301 or DQB1*0302 alleles, the age of the patients at disease onset, the presence of rheumatoid factor (RF), joint erosions, and rheumatoid nodules. RESULTS: HLA-DRB1*13 allele (the subtype allele of DR6, reported to be protective against the development of RA) was found in 14/119 (12%) of female but in none of the male patients (p=0.036). The HLA-DR4 allele was found slightly more often in men than women patients with familial RA (31/45 (69%) v 75/119 (63%), NS). Men were also more often RF positive than women (44/45 (98%) v 98/117 (84%); p=0.031). On the other hand, the mean age at onset of RA was significantly lower in the female group (40.4 years) than in men (46.6 years, p=0.0044). CONCLUSION: The results indicate that there is stronger genetic background in familial male than female patients with RA in the genetic susceptibility defined by the studied HLA antigens. However, the earlier age of onset of the disease in female group and the increased proportion of women with RA indicate that there are additional sex related predisposing factors enhanced in familial cases.

Bacterial PCR in the diagnosis of joint infection.

OBJECTIVES: To evaluate the value of broad range bacterial PCR in the diagnosis of joint infection and to find out if there are bacteria causing arthritis which are not cultivable by the present methods. METHODS: Polymerase chain reaction (PCR) with broad range bacterial primers and DNA sequencing (bacterial PCR) was used to analyse 154 synovial fluid (SF) samples from patients with different arthritic diseases. RESULTS: Bacterial DNA was detected in 18 SF samples, including samples from six patients with culture proven purulent arthritis, and from three patients with possible purulent arthritis. Three samples from patients with culture confirmed purulent arthritis remained negative in bacterial PCR. CONCLUSIONS: The results indicate that in the usual diagnostic laboratory setting bacterial PCR does not offer any obvious advantage over bacterial culture in the microbiological diagnosis of joint infection.

Increase in T-cell subsets of oral mucosa: a late immune response in patients with treated coeliac disease?

BACKGROUND AND AIMS: In coeliac disease, the gut involvement is gluten-dependent. Following the introduction of a gluten-free diet, inflammatory cell infiltration decreases in the small intestinal mucosa. Our hypothesis was that the oral mucosa might mirror the changes found in coeliac disease similarly to the mucosa of the small intestine. Thus, the number of inflammatory cells in the oral mucosa would decrease in patients with coeliac disease on a gluten-free diet. METHODS: The distribution CD45RO+ and CD3(+) T cells, T-cell subpopulations (CD4(+), CD8(+), T-cell receptor (TCR)alpha beta+ and TCR gamma delta+ cells) and HLA DR expression were studied in the buccal mucosa of 15 untreated and 44 gluten-free diet treated coeliac disease patients, and of 19 controls. All 15 patients with untreated coeliac disease were immunglobulin (Ig)A endomysial antibody positive and all 44 patients on gluten-free diet except one were endomysial antibody negative, as were all control subjects. RESULTS: Untreated coeliac disease patients did not differ from controls in the densities of CD45RO+ cells, CD3(+) cells or of T-cell subsets. In contrast, in treated coeliac disease patients, a significant increase in the numbers of mast cells, CD3(+) and CD4(+) lymphocytes was found in the lamina propria of oral mucosa as compared with patients with untreated coeliac disease and controls. The increase in CD3(+) T cells was in part owing to an increase in lymphocytes expressing no TCR. No differences were found in the expression of human leucocyte antigen (HLA) DR in the epithelium or in the lamina propria in the patient groups studied or in the controls. In treated coeliac disease patients only a few TCR gamma delta+ T cells were found intraepithelially and in the lamina propria, but these cells were not detected in the lamina propria of oral mucosa of patients with untreated coeliac disease or in the controls. CONCLUSIONS: The infiltration of T cells into oral mucosa was increased in treated coeliac disease patients in spite of adherence to a gluten-free diet. Because the CD3(+) T cell count was higher than those of the TCR alpha beta+ and TCR gamma delta+ T cells, there must be other cells involved, probably natural killer (NK) cells. The increase in T-cell subsets in the treated coeliac disease patients seems not to result from poor dietary compliance, but might occur as a late immune response in coeliac disease and reflect chronic immunologic stimulation followed by regeneration of memory T cells.

Prolonged arthritis associated with sindbis-related (Pogosta) virus infection.

OBJECTIVE: A follow-up study of musculoskeletal symptoms after Pogosta virus infection. METHODS: Twenty-six patients with earlier serologically confirmed Pogosta disease were examined. Ultrasonography of affected joints was performed in patients who had chronic musculoskeletal symptoms. Serum antibodies against Sindbis virus were determined. The patients were typed for HLA-DR and B27. Efforts were made using the polymerase chain reaction to demonstrate the virus. RESULTS: Only 50% of the patients were symptomless 2.5 yr after onset of Pogosta disease. Three patients had fibromyalgia, six had occasional arthralgia and two had chronic arthritis. CONCLUSIONS: The epidemiology of Pogosta disease is changing and practitioners should be better aware of it. Pogosta virus infection may lead to chronic musculoskeletal discomfort and arthritis.

Local challenge on oral mucosa with an alpha-gliadin related synthetic peptide in patients with celiac disease.

OBJECTIVE: Gluten-derived peptides (e.g., amino-acids 31-49 of alpha-gliadin) have been shown to cause changes typical of celiac disease in the gut. Gluten-derived peptides have mostly been used in in vitro studies. The easiest access to the gastrointestinal system may be the mouth. In the present study we were interested to see whether a synthetic peptide corresponding to amino-acids 31-49 of alpha-gliadin could induce inflammatory changes in the oral mucosa after a local challenge in celiac disease patients. METHODS: The challenge was made by injecting the peptide solution at a concentration of 10 microg/ml submucosally into the oral mucosa of 10 celiac disease patients after a gluten-free diet (GFD) and 12 healthy control subjects. B and CD45RO+ T cells, mast cells, CD3+, CD4+, CD8+ lymphocytes, and alphabeta and gammadelta T-cell receptor-bearing (TcR alphabeta, TcR gammadelta) lymphocytes were counted and HLA DR expression was determined. The expression of CD25 and Ki-67 antigen was also examined. RESULTS: The peptide significantly increased the total number of T cells in the lamina propria of the celiac disease patients. The expression of T-cell activation marker CD25 (IL-2 receptor), but not that of cell proliferation marker Ki-67, was also significantly increased in the lamina propria after peptide challenge. Such a reaction was not observed in the controls. The numbers of CD3+ and CD4+ T cells in the lamina propria were also increased in celiac disease patients after the challenge. The count of TcR gammadelta+ cells was very small in the oral mucosa in celiac disease and showed no increase when the oral mucosa was challenged with the peptide. The expression of HLA DR staining was enhanced after the submucosal peptide challenge in celiac disease; however, the difference was not statistically significant. CONCLUSIONS: The results show that in the celiac disease patients after the peptide challenge the oral mucosal lamina propria responds with a nonproliferative increase of lymphocytes. Thus, submucosal challenge with the peptide 31-49 can be used as an aid in the diagnosis of celiac disease. However, further studies with optimized methodology, including various concentrations of the peptide, adjuvants, other peptides, etc., are warranted, especially because the oral mucosa provides the easiest access to an in vivo peptide challenge in celiac disease.

BPI-ANCA is found in reactive arthritis caused by Yersinia and Salmonella infection and recognise exclusively the C-terminal part of the BPI molecule.

OBJECTIVE: To examine the prevalence, binding sites and functional interactions of antineutrophil cytoplasmic autoantibodies (ANCA) against the bactericidal/permeability increasing protein (BPI) in reactive arthritis (ReA). METHODS: Sera were analysed for the occurrence of ANCA by indirect immunofluorescence microscopy (IIF) and ELISA. Binding sites were determined using BPI, lipopolysaccharid binding protein (LBP), and fusion proteins of both proteins in ELISA. In addition, the effect of antibodies on the antibiotic activity of BPI was examined. RESULTS: BPI-ANCA was found in patients with Yersinia- and Salmonella-triggered ReA and directed against the C-terminal portion of BPI. Goat anti BPI antibodies recognising this part inhibited the antibiotic activity of BPI in vitro. CONCLUSION: BPI-ANCA was associated with ReA triggered by Salmonella and Yersinia infection. Directed against the C-terminal part of BPI, it can potentially inhibit its antibiotic activity and might be useful to identify patients with infectious bowel disease prone to extraintestinal sequelae.