Biological treatment in ankylosing spondylitis in the Nordic countries during 2010-2016: a collaboration between five biological registries.

OBJECTIVES: Large-scale observational cohorts may be used to study the effectiveness and rare side effects of biological disease-modifying anti-rheumatic drugs (bDMARDs) in ankylosing spondylitis (AS), but may be hampered by differences in baseline characteristics and disease activity across countries. We aimed to explore the research infrastructure in the five Nordic countries regarding bDMARD treatment in AS. METHOD: This observational cohort study was based on data from biological registries in Denmark (DANBIO), Sweden (SRQ/ARTIS), Finland (ROB-FIN), Norway (NOR-DMARD), and Iceland (ICEBIO). Data were collected for the years 2010-2016. Registry coverage, registry inventory (patient characteristics, disease activity measures), and national guidelines for bDMARD prescription in AS were described per country. Incident (first line) and prevalent bDMARD use per capita, country, and year were calculated. In AS patients who started first line bDMARDs during 2010-2016 (n = 4392), baseline characteristics and disease activity measures were retrieved. RESULTS: Registry coverage of bDMARD-treated patients ranged from 60% to 95%. All registries included extensive prospectively collected data at patient level. Guidelines regarding choice of first line drug and prescription patterns varied across countries. During the period 2010-2016 prevalent bDMARD use increased (p < 0.001), whereas incident use tended to decrease (p for trend < 0.004), with large national variations (e.g. 2016 incidence: Iceland 10.7/100 000, Finland 1.7/100 000). Baseline characteristics were similar regarding C-reactive protein, but differed for other variables, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (range 3.5-6.3) and Ankylosing Spondylitis Disease Activity Score (ASDAS) (2.7-3.8) (both p < 0.0001). CONCLUSION: Collaboration across the five Nordic biological registries regarding bDMARD use in AS is feasible but national differences in coverage, prescription patterns, and patient characteristics must be taken into account depending on the scientific question.

Septic arthritis in Iceland 1990-2002: increasing incidence due to iatrogenic infections.

OBJECTIVES: To assess the impact of increased number of diagnostic and therapeutic joint procedures on the incidence and type of septic arthritis (SA). METHODS: All cases of SA in Iceland from 1990-2002 were identified by thorough review of the available medical information. The results of synovial fluid cultures from every microbiology department in Iceland were checked and positive culture results reviewed, as well as patient charts with a discharge diagnosis of septic arthritis (International Statistical Classification of Diseases and Related Health Problems (ICD) code M009). RESULTS: A total of 253 cases of SA (69 children and 184 adults) were diagnosed in Iceland in 1990-2002, giving an average incidence of 7.1 cases/100,000 inhabitants. The incidence of SA increased from 4.2 cases/100,000 in 1990 to 11.0 cases/100,000 in 2002. This rise in SA was primarily observed in adults where the incidence rose by 0.61 cases/100,000 per year (p<0.001). SA was iatrogenic in 41.8% of adults and the number of iatrogenic infections increased from 2.8 cases/year in 1990-1994 to 9.0 cases/year in 1998-2002 (p<0.01). The annual number of arthroscopies increased from 430 in 1990-1994 to 2303 in 1998-2002 (p<0.001) and there was a correlation between the total usage of intra-articular drugs in Iceland and the incidence of SA (p<0.01). The frequency of post-arthroscopy SA was 0.14% and post-arthrocentesis SA 0.037%. CONCLUSIONS: The incidence of SA has increased in recent years due to an increased number of arthroscopies and joint injections. Although the frequency of SA per procedure has not changed, these results emphasise the importance of sterile technique and firm indications for joint procedures.

The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis.

OBJECTIVE: To study the effect of tobacco smoking and rheumatoid factor (RF) isotypes on disease activity and joint damage in early rheumatoid arthritis (RA). METHODS: One hundred early RA patients were followed prospectively for 2 yr. They were evaluated at recruitment and at 6 and 24 months. Sociodemographic information included smoking history, and radiographs of hands and feet were obtained. RF was monitored by IgM- and IgA-specific RF enzyme-linked immunosorbent assay and by agglutination, and serial measurements were also obtained for C-reactive protein. The influence of tobacco smoking and RF positivity on disease outcome was evaluated using multivariate analysis. Covariates for the regression analysis included sex, age, coffee consumption and IgA-RF positivity. RESULTS: A gradient of increase in disease activity was observed from never smokers to former smokers to current smokers during the 2 yr of observation, defined by number of swollen joints (SJC), tender joints (TJC) and visual analogue scale for pain (P<0.001, P=0.02 and P=0.005, respectively), but smoking status did not influence radiological progression. Ever smokers were more often IgA RF positive (P<0.05). IgA RF-positive patients had more active disease (SJC P=0.002, TJC P=0.01) and showed more radiological progression (P<0.0001) compared with IgA RF-negative patients. Of the RF-positive patients 22% had elevated IgM RF without IgA RF and these patients showed similar disease activity and radiological joint progression to the RF-negative patients. None of these associations were explained by possible confounders. CONCLUSION: Tobacco smoking has an adverse effect on patients with early RA and this is possibly immunologically mediated. IgM RF does not predict poorer prognosis in RA unless it is associated with a concomitant elevation of IgA RF.

Deficiency of complement-dependent prevention of immune precipitation in systemic sclerosis.

BACKGROUND: Previous studies have indicated that complement may be activated or inherently abnormal in systemic sclerosis (SSc), and it has been suggested that immune complex deposition plays a part in the microvascular damage of this disease. OBJECTIVE: To study several aspects of the complement system in 24 patients with SSc. METHODS: Complement dependent prevention of immune precipitation (PIP) was measured by a sensitive enzyme immunoassay, levels of C1q, C4, and C3 by rocket immunoelectrophoresis, C4 allotypes by high voltage agarose electrophoresis, and C4A, C4B, and C3d by an enzyme linked immunosorbent assay (ELISA). RESULTS: PIP was markedly decreased in the patients with SSc (p<0.001). Abnormal complement activation was detected in nine patients as raised levels of the complement split product C3d. However, a relation between low PIP and complement activation was not seen. PIP was significantly lower in patients who carried the C4A*Q0 allotype (p=0.03), and a strong correlation was found between PIP and C4A concentration (p<0.00001). The PIP defect may, at least in some patients, be associated with the initial phase of the disease. CONCLUSIONS: The results show a previously unrecognised functional defect of complement in SSc; the defect correlates with low levels of classical pathway components and, in particular, C4A.

Disease severity of 100 patients with systemic sclerosis over a period of 14 years: using a modified Medsger scale.

OBJECTIVE: To assess organ involvement according to a modified Medsger severity scale and its relation to outcome and prognosis in patients with systemic sclerosis. METHODS: One hundred consecutive patients observed in Lund with systemic sclerosis were followed up for a period of 14 years. The mean follow up time was 7.7 years. Initial assessment and an annual evaluation was performed for each patient, with a mean visit frequency of 5.6 per patient. RESULTS: Age at referral, high total skin score, truncal skin involvement, low vital capacity, low static lung compliance, low Cr-EDTA clearance, and ECG abnormalities at the initial assessment predict poor outcome. A severity scoring system for five organ systems indicates a slow progression of organ dysfunction after recruitment into the study. The female: male ratio was 2:1, the mean age at onset of symptoms was 42.3 (range 3-82), and the mean age at recruitment was 47.2 years (range 17-82). Thirty patients died during the follow up period at the mean age of 61.3 years (range 33-85). The causes of death were directly related to systemic sclerosis in at least 10 patients, infections in six, cancers in nine, and other causes in four patients. The standardised mortality ratio was 3.5 and 3.7 for men and women, respectively. CONCLUSION: A high severity score for function of vital organs was shown to predict shortened survival. In this study a severity score based on simple clinical assessment variables was able to predict poor outcome from extensive skin changes, ECG changes, and compromised lung and renal function. Organ dysfunction mainly became manifest during the first five years of the disease, whereafter organ function remained largely stable.

The inheritance of rheumatoid arthritis in Iceland.

OBJECTIVE: Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis. Although there is a large body of evidence suggesting that RA is immune mediated, the etiology remains unresolved. Twin studies have shown disease concordance rates of approximately 15% in monozygotic twins and 4% in dizygotic twins, while the estimated risk ratio for siblings of RA patients ranges from 5 to 8. Our goal was to use genealogic data from Iceland to further investigate the genetic component of RA. METHODS: Data were obtained from a population-based, computerized genealogy database that was developed to examine multigenerational relationships among individuals in the relatively homogeneous population of Iceland. Using an algorithm, the minimum founder test, we calculated the least number of founders required to account for a list of RA patients, and compared it with 1,000 sets of same-sized matched control groups. In addition, we estimated the kinship coefficient and risk ratios for relatives of the RA patients. RESULTS: Several familial clustering tests demonstrated that the RA patients were more related to each other than were the average control set of Icelanders. A significantly fewer number of founders was necessary to account for our patient list than for the random sets of matched controls (P < 0.001), and the average pairwise identity-by-descent sharing was greater among the patients than among the control sets (P < 0.001). In addition, there was an increased risk of RA in first- and second-degree relatives of the patients; e.g., for siblings, the risk ratio was 4.38 (95% confidence interval 3.26-5.67), and for uncles/aunts, the risk ratio was 1.95 (95% confidence interval 1.52-2.43). CONCLUSION: The familial component of RA is shown to extend beyond the nuclear family, thus providing stronger evidence for a significant genetic component to RA.

Low mannose binding lectin predicts poor prognosis in patients with early rheumatoid arthritis. A prospective study.

OBJECTIVE: To determine whether low mannose binding lectin (MBL) is associated with poor prognosis in rheumatoid arthritis (RA) and whether patients with RA have increased frequency of MBL deficiency. METHODS: Patients with recent onset symmetric polyarthritis (< 1 year, median 3 mo) were recruited if they had not been treated longer than 2 weeks with disease modifying drugs. They were reevaluated after 6 months and their disease activity and progression were correlated with their MBL concentration, rheumatoid factor (RF) isotypes, and C-reactive protein (CRP). Sixty-three female patients with advanced RA were also analyzed. RESULTS: Sixty-five patients with early arthritis fulfilled American College of Rheumatology criteria for RA and 52 were followed for 6 months or longer. Low MBL was associated with raised RF, IgA RF in particular (p = 0.02). and also with a combined elevation of IgM and IgA RF (p = 0.035). Patients with low MBL (lowest 25th percentile) showed less improvement after 6 months of treatment than patients in the highest MBL quartile. This applied to the Thompson joint score (p = 0.03) and grip strength (p = 0.004). Low MBL was also significantly associated with radiological joint erosions at recruitment and at 6 month followup (p = 0.039); and the group with advanced RA also showed a significant association between low MBL concentration and radiological damage (p = 0.036). However. neither patient group had increased frequency of MBL deficiency compared to healthy controls. CONCLUSION: Low MBL predicts poor prognosis in patients with early RA.

Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheumatoid arthritis.

The diagnostic value of measuring rheumatoid factor (RF) by agglutination or isotype-specific enzyme-linked immunosorbent assay (ELISA) was compared. The study included 70 patients with rheumatoid arthritis (RA) and 205 patients with various other rheumatic conditions. Of the RA patients, 74% were RF-positive by agglutination and 90% had one or more RF isotypes elevated by ELISA compared to 14% and 22%, respectively, of the other patients. Strikingly, 70% of the RF-positive RA patients had an elevation of two or more RF isotypes compared to only 16% of the other RF-positive patients (P < 0.0001). Furthermore, a combined elevation of IgM and IgA RF was found in 52% of the RF-positive RA patients, but only in two (4%) of the other RF-positive patients (P < 0.0001). It is concluded that a combined elevation of IgM and IgA RF is highly specific for RA and is very rarely found in rheumatic diseases other than RA. Isotype-specific RF assays are therefore diagnostically superior to agglutination tests. The detection of the RA-specific RF isotype pattern may be particularly helpful early in the course of RA even before the disease is fully differentiated.

Pneumoparotitis: a new diagnostic technique and a case report.

Pneumoparotitis is a rare cause of parotid gland swelling. We report a case of self-induced pneumoparotitis that resulted in subcutaneous emphysema and pneumomediastinum after an open biopsy of the parotid gland. We suggest a new method for diagnosing this condition. This is done by insufflation of the cheeks with contrast in the oral cavity. A reflux of air and contrast is subsequently demonstrated by a computed tomography scan of the area.

[The prevalence of fibromyalgia and chronic widespread musculoskeletal pain in Iceland.].

OBJECTIVE: To determine the prevalence of fibromyalgia and chronic widespread musculoskeletal pain (CWP) in Iceland in two demographic different areas. MATERIAL AND METHODS: Population based prevalence study on 1200 females and 1200 males 18-79 years old in South-West- and South-Iceland. Established musculoskeletal pain questionnaire and telephone screening of nonresponders was used. Tender point examination was done on the subjects with CWP and the diagnosis of fibromyalgia was made in accordance with the American College of Rheumatology (ACR) 1990 criteria. RESULTS: The prevalence of fibromyalgia in females based on 60.4% of the sample is 9.8%. The comparable prevalence in males based on 46.4% of the sample is 1.3%. The prevalence of CWP is 26.9% in females and 12.9% in males. A sharp increase in the prevalence of fibromyalgia and CWP in females is seen in the age group 31-40 compared with the age group 18-30. For female responders a statistical higher prevalence of CWP but not fibromyalgia is seen in South-West-Iceland, compared with South-Iceland. No regional differences were seen for males. CONCLUSION: The prevalence of fibromyalgia and CWP is very high in Iceland. A matter of special concern is the high prevalence in young females. Possible causes are long working hours and stressful living conditions.

Left ventricular myocardial perfusion and function in systemic sclerosis before and after diltiazem treatment.

To examine left ventricular (LV) myocardial perfusion and function, in systemic sclerosis. Myocardial perfusion was assessed at rest, during cold exposure, and at peak exercise in 10 patients with systemic sclerosis. Seven of the 10 patients were examined with Doppler echocardiography; before and after long-term diltiazem treatment. Compared with average resting values, isotope uptake was increased by 48% after exercise, compared with cold exposure the exercise value was increased by 35%. After 11 months of diltiazem treatment there was no change in myocardial uptake, compared with respective values before treatment. Doppler echocardiography showed an increase in LV end-diastolic diameter, fractional shortening, and left ventricular outflow tract velocity, after treatment. This indicates that long-term diltiazem treatment does not increase myocardial perfusion at rest, post-exercise, or during cold exposure. On the other hand diltiazem treatment may improve left ventricular performance.

Raised IgA rheumatoid factor (RF) but not IgM RF or IgG RF is associated with extra-articular manifestations in rheumatoid arthritis.

In rheumatoid arthritis (RA) seropositivity has been associated with poor prognosis including bone erosions and extra-articular manifestations. However, findings have been conflicting on the association between individual rheumatoid factor (RF) isotypes and extra-articular manifestations. In this study the occurrence of extra-articular manifestations was examined in the context of the RF isotype patterns rather than individual RF isotypes. IgM, IgG and IgA RF was measured by ELISA in 74 patients with RA and the findings correlated with the presence or absence of extra-articular manifestations. Of the IgA RF positive patients 80% had one or more extra-articular manifestations. In contrast, only 21% of patients with raised IgM and/or IgG RF but normal IgA RF had some extra-articular manifestations and 27% of the seronegative patients. It is concluded that the previously reported association between raised RF and extra-articular manifestations in RA can largely be attributed to the IgA RF isotype.

Systemic sclerosis in Iceland. A nationwide epidemiological study.

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

Functional study of the dermal microcirculation in systemic sclerosis.

To measure the effect of cooling on digital blood pressure we used a strain-gauge and photoplethysmograph, with an automatic cooling device. Eighteen patients were compared with 18 matched controls. Laser-doppler technique was used to measure the perfusion changes after heating a small area of the skin in 5 locations on the body, readings were given in perfusion units. Eighteen patients with systemic sclerosis were compared with 25 individuals with primary Raynaud's phenomenon and 30 healthy controls. Cooling to 10 degrees C caused a significant digital blood pressure drop of 58 mmHg in patients with systemic sclerosis and 61 mmHg in Raynaud's phenomenon, as compared with controls. The microcirculation in patients with systemic sclerosis responded in the same way to local heating as in the normal population, increasing the perfusion to the same extent. In conclusion, an unselected group of patients with systemic sclerosis have normal dermal microcirculatory response to heating in spite of severe cold intolerance.

Cineradiography identifies esophageal candidiasis in progressive systemic sclerosis.

Cineradiography of the esophagus showed signs of esophageal candidiasis in 11 out of 71 patients with progressive systemic sclerosis (PSS) - both in diffuse scleroderma and the CREST syndrome. Culture of esophageal brushings confirmed the presence of Candida albicans in eight of these 11 patients. Antimycotic treatment decreased the cineradiographic signs of candidiasis and the degree of dysphagia. Since impaired esophageal motility and treatment with immunosuppressive drugs may predispose to candida esophagitis, and since dysphagia will decrease after antimycotic treatment esophageal mycosis should always be sought in patients with PSS.

Clinical and serological features of severe vasculitis in rheumatoid arthritis: prognostic implications.

Sixteen patients with classic rheumatoid arthritis (RA) complicated by severe vasculitis were studied and compared with a matched control group of 16 RA patients without vasculitis. Seven of the patients with vasculitis died within 4 to 120 months (median 32 months) after developing vasculitic symptoms. Gangrene of digits and extremities, bowel ulcers or bowel perforation, or both, and cardiac involvement were more common among the patients who died than among those with a more favourable course. The present data suggest that large vessel vasculitis in RA is associated with high frequency of arteriosclerotic vascular disease. The serum concentrations of complement components C3 and C4 were lower, and concentrations of IgM rheumatoid factor, complement activating rheumatoid factor, and C1q binding immune complexes (C1q solid and C1q fluid phase assay) were significantly higher among vasculitic patients than in the control group. Laboratory data provided little prognostic information with regard to rheumatoid vasculitis, with the exception that IgM and IgG rheumatoid factors were significantly higher among patients with fatal course of disease than in those who achieved remission.