Irritable bowel syndrome and anti-GnRH antibodies in primary Sjögren’s

Irritable bowel syndrome and anti-GnRH antibodies in primary Sjögren’s
syndrome
Smoking, Low Level of Formal Education and Infrequent Alcohol Consumption Are
Independent Predictors of Rheumatoid Arthritis.
Thomas Mandl, Sabina Janciauskiene and Bodil Ohlsson.
Department of Clinical Sciences, Malmö University Hospital, Malmö, Sweden.
Ulf Bergström, Lennart Jacobsson, Jan-Åke Nilsson, Göran Berglund, Carl Turesson.
Malmö University Hospital, Malmö, Sweden.
Background: Patients with primary Sjögren’s syndrome (pSS) commonly report various gastrointestinal
complaints although the pathogenesis behind these is obscure. The gonadotropin-releasing hormone (GnRH) has
recently been found in half of the enteric nerves in the bowel wall and antibodies against GnRH have been
found in association with destruction of GnRH-containing neurons and gastrointestinal dysmotility. The aims of
the present study were to i) examine the prevalence of irritable bowel syndrome (IBS) and functional dyspepsia
(FD) according to the Rome III criteria and ii) to examine the prevalence of anti-GnRH antibodies and their
relation to IBS, in patients with pSS.
Methods: Forty-six consecutive patients with pSS (mean age 49 (range 25-60) years; 43 females) completed a
questionnaire on gastrointestinal complaints and were examined by an ELISA method for the presence of antiGnRH antibodies. Forty-six subjects (mean age 49 (range 25-60) years; 43 females), randomly selected from the
Swedish population registry, served as controls for the gastrointestinal complaints and 30 healthy controls
(mean age 38 (range 27-50) years, 30 females) were examined for the presence of anti-GnRH antibodies.
For comparison between groups Fisher’s exact test was used.
Results: IBS and FD were significantly more common in pSS patients in comparison to controls (39% vs. 9%;
p=0.001, and 65% vs. 39%; p=0.021 respectively). In addition, presence of anti-GnRH antibodies was
significantly more common in patients with pSS in comparison to controls (17% vs. 0%; p=0.019) (Table 1).
However, comparing pSS patients with and without anti-GnRH antibodies, no significant differences were
found with regard to prevalence of IBS or FD (Table 2).
Conclusion: IBS and FD were both more common in patients with pSS. In addition anti-GnRH antibodies were
found in 17% of patients with pSS while in none of controls. However, presence of such antibodies did not seem
to explain experienced gastrointestinal symptoms. The role for these antibodies in pSS thus remains to be
determined.
Purpose: Smoking and low level of formal education have been associated with
rheumatoid arthritis (RA), but their relative importance and the underlying mechanisms
are unknown. Previous studies have suggested that moderate alcohol consumption could
reduce the risk of RA. Our aim was to estimate the effect of smoking, level of education
and alcohol consumption on the future risk of RA.
Methods: Between 1991 and 1996, subjects (n=30447; 12121 men and 18326 women)
from a defined catchment area were included in a community based health survey.
Information on life style factors were obtained using a self-administered questionnaire.
From this population individuals who developed RA after inclusion were identified by
linking the health survey database to a community based RA register, the local patient
administrative register, the National Hospital Discharge Register and the National Cause
of Death Register. In a structured review of the medical records, patients were classified
according to the 1987 ACR criteria for RA, and the year of RA diagnosis was noted. Four
controls for every case, matched for sex, year of birth and year of screening, who were
alive and free of RA when the index person was diagnosed with RA, were selected from
the health survey database. Education was classified into five levels from elementary
school (≤ 8 years of school) to university degree. Three patterns of reported alcohol
consumption were registered: No alcohol within the last year; alcohol within the last year
but not the last month; and alcohol within the last month.
Results: One hundred and seventy two patients (36 men/136 women) were diagnosed
with RA and fulfilled the 1987 ACR criteria after inclusion in the health survey. Mean
age at diagnosis was 63 years. The median time from inclusion to RA diagnosis was 5
years (range 1–13). Current smoking at inclusion predicted RA (p=0.002). Individuals
with elementary school education only had an increased risk of RA compared to those
with a university degree (p=0.01). Individuals with reported infrequent alcohol intake
(within the last year, but not the last month) had an increased risk of RA odds ratio (OR)
3.45; 95 % confidence interval (CI) 1.91 - 6.29 compared to those reporting alcohol
intake within the last month, whereas there was no increased risk for those who had not
consumed alcohol within the last year (OR 1.13; 95% CI 0.58 -2.21). In multivariate
logistic regression, smoking (OR 2.23; CI 1.37- 3.65), low formal education (OR 2.25;
95% CI 1.02 - 4.93) and infrequent alcohol consumption (3.40; 95% CI 1.81 – 6.39) were
all significant predictors of RA.
Conclusion: Smoking and a low level of formal education are independent risk factors
for developing RA. This suggests that several different exposures related to
socioeconomics status are important for RA susceptibility. The role of alcohol
consumption must be further studied but these and other findings indicate that regular
drinking could have a protective effect.
Table 1.
Prevalence of irritable bowel syndrome and functional dyspepsia, according to the Rome III criteria, and
presence of anti-GnRH antibodies in pSS patients and controls.
pSS patients (n=46)
39%
65%
17%
Irritable bowel syndrome
Functional dyspepsia
Anti-GnRH antibodies
Controls (n=46 / 30)
9%
39%
0%
p-value
0.001
0.021
0.019
Table 2.
Number of patients seropositive (+) and seronegative (-) for anti-GnRH antibodies (ab) in pSS patients with (+)
and without (-) irritable bowel syndrome (IBS) and functional dyspepsia (FD) respectively. NS = Non
significant.
IBS +
IBS-
Anti-GnRH ab +
1
7
Anti-GnRH ab 17
21
p-value
NS
NS
FD+
5
25
FD-
3
13
Autonomic nervous dysfunction development in patients with primary Sjögren’s
syndrome – a 5 year follow-up.
Mandl T, Wollmer P, Ohlsson B.
Department of Clinical Sciences, Malmö, Malmö University Hospital, Malmö, Sweden
Purpose: To investigate autonomic nervous dysfunction development over a 5-year period in patients with
primary Sjögren’s syndrome (pSS).
Materials: 15 patients with pSS according to the American European Consensus Criteria (median age 61 (range
29-65) years, 14 females), without diabetes or other disease affecting autonomic nervous function, who had
previously been studied for autonomic nervous function, were included in the study. At baseline none were
taking any medication affecting autonomic nervous function but at follow-up two patients were taking
pilocarpine and one a betablocker, which however were seponated 24h prior to autonomic nervous function
testing. The controls consisted of previously investigated healthy individuals, i.e. 56 controls for the deepbreathing and orthostatic heart rate tests (median age 40 (range 16-59) years, 22 females), 80 controls for the
finger-skin blood flow test (median age 43 (range 19-81) years, 37 females), 238 controls for the orthostatic
blood pressure test (median age 60 (range 16-96), 106 females) as well as 200 population based controls for the
Autonomic Symptom Profile (ASP) questionnaire on autonomic nervous dysfunction symptoms (median age 45
(range 20-69) years, 100 females).
Methods: The patients were studied at baseline and after a median follow-up time of 5 years by 5 autonomic
nervous function tests (ANT), i.e. the deep-breathing test (expiration/inspiration (E/I)-ratio), the orthostatic
heart rate test (acceleration index (AI)), the finger-skin blood flow test (vasoconstrictory (VAC)-index), and the
orthostatic bloodpressure test (systolic and diastolic blood pressure (SBP & DBP)-ratios). The results were agecorrected and expressed as z-scores by comparison with three previously examined control groups. Patients also
filled out the ASP and these results were corrected according to age, gender, height and weight and were
expressed as z-scores, except for the gastroparesis and reflex syncope domains which were expressed as
rawscores. For comparison between groups the Mann-Whitney-U test was used and for in-group comparisons
the Wilcoxon matched-pairs signed-rank test.
Results: The E/I-ratio and SBP- & DBP-ratios were significantly decreased in pSS patients compared with
controls both at baseline and follow-up while the VAC-index only was significantly increased at follow-up. The
orthostatic intolerance, urinary dysfunction, gastroparesis, secretomotor, pupillomotor domains and the ASP
total score were all significantly increased in pSS patients compared with controls both at baseline and at
follow-up while the sleep disorder domain was only significantly increased in pSS patients compared to controls
at follow-up. When comparing ANT and ASP results in pSS patients between baseline and at 5 year follow-up,
the E/I-ratio and DBP-ratios were significantly decreased and the vasomototor domain score significantly
increased at follow-up (Table 1 and 2).
Conclusion: Both objective and subjective signs of a parasympathetic and a sympathetic dysfunction were
seen in pSS patients at baseline as well as after a 5 year follow-up. During the follow-up, the E/I-ratio, DBPratio and vasomotor domain score were found to significantly deteriorate.
Table 1 – Results of the autonomic nervous function tests in patients with primary Sjögren’s syndrome and controls. The autonomic nervous function
tests results were age-corrected and expressed as z-scores (SD). Results are presented as median (interquartile range).
* p<0.05 vs controls **p<0.01 vs controls *** p<0.001 vs controls.
E/I-ratio (SD)
AI (SD)
VAC-index (SD)
SBP-ratio (SD)
DBP-ratio (SD)
pSS patients
Baseline
-0.82 (-1.30, 0.07)*
-0.14 (-1.32, 0.33)
0.54 (-0.85, 1.61)
-0.96 (-1.96, -0.06)**
-0.76 (-1.05, -0.22)**
pSS patients
Year 5
-1.32 (-1.76, -0.67)**
0.15 (-0.94, 1.10)
0.39 (0.02, 1.48)*
-0.88 (-1.28, 0.64)*
-2.46 (-3.04, -1.64)***
Controls
-0.25 (-0.62, 0.60)
0.03 (-0.67, 0.65)
0.09 (-0.67, 0.62)
0.00 (-0.61, 0.70)
0.00 (-0.47, 0.54)
p-value pSS patients
Baseline vs Year 5
0.035
0.094
0.379
0.256
0.002
Table 2 – Results of the Autonomic Symptom Profile domains in patients with primary Sjögren’s syndrome and controls. Most domains were
corrected according to age, gender, height and weight and were expressed as z-scores (SD). However the gastroparesis and reflex syncope domains
were expressed as rawscores. Results are presented as median (interquartile range)
* p<0.05 vs controls **p<0.01 vs controls *** p<0.001 vs controls.
Orthostatic intolerance (SD)
Urinary dysfunction (SD)
pSS patients
Baseline
1.21 (-0.64, 2.46)*
0.29 (-0.49, 2.34)*
pSS patients
Year 5
1.25 (0.22, 2.54)**
0.12 (-0.45, 2.73)**
Controls
-0.39 (-0.78, 0.79)
-0.51 (-0.71, 0.32)
p-value pSS patients
Baseline vs Year 5
0.826
0.245
Gastroparesis
Autonomic diarrhea (SD)
Constipation (SD)
Secretomotor dysfunction (SD)
Pupillomotor dysfunction (SD)
Vasomotor dysfunction (SD)
Reflex syncope
Sleep disorder (SD)
Total score (SD)
0.75 (0.00, 1.50)*
0.62 (-0.51, 1.90)
0.45 (-0.54, 2.65)
2.30 (2.12, 4.66)***
1.57 (-0.24, 3.23)**
-0.45 (-0.56, 2.39)
0.00 (0.00, 0.00)
-0.42 (-0.83, 1.17)
1.92 (0.40, 3.32)***
0.00 (0.00, 1.50)*
0.65 (-0.52, 2.10)
1.05 (-0.54, 2.65)
4.25 (2.11, 5.07)***
1.73 (0.48, 3.07)***
-0.26 (-0.54, 2.71)
0.00 (0.00, 0.00)
0.44 (-0.16, 1.67)*
2.44 (0.90, 3.11)***
0.00 (0.00, 0.00)
-0.42 (-0.60, 0.68)
-0.30 (-0.52, -0.18)
-0.45 (-0.72, 0.52)
-0.42 (-0.71, 0.55)
-0.33 (-0.49, -0.20)
0.00 (0.00, 0.00)
-0.05 (-0.79, 0.35)
-0.21 (-0.82, 0.72)
0.608
0.875
0.861
0.975
0.875
0.022
0.317
0.221
0.510
Decreased Expression of the Endothelial Cell Activation Marker HLA-DQ in
Skeletal Muscle After Three Months of Adalimumab Treatment in Patients with
Rheumatoid Arthritis
Ulf Bergström1, Cecilia Grundtman2, Ingrid Lundberg2, Lennart TH Jacobsson1, Käth
Nilsson1, Carl Turesson1
1
Sektionen för Reumatologi, Universitetssjukhuset MAS, Malmö, 2Enheten för
Reumatologi, Inst för Medicin, Karolinska Universitetssjukhuset i Solna, Karolinska
Institutet
Background: Treatment with tumor necrosis factor (TNF) inhibitors for severe rheumatoid arthritis (RA) has
been associated with a decreased risk of cardiovascular (CV) disease in observational studies.Previous findings
indicate that systemic endothelial expression of HLA-DQ and interleukin-1α (IL-1α) is increased in patients
with severe extra-articular RA, indicating that they may be markers of systemic inflammation and increased CV
risk.
Method: Fourteen patients with active RA [11 females,3 males; mean age 63.7 years; median (M) disease
duration 9 years, interquartile range (IQR) 2.6-11.6; 11 (78 %) RF positive] were started on treatment with
adalimumab 40 mg subcutaneously every two weeks. Eight patients were on methotrexate (mean dose 18.75
mg/week, range 10-25).None of the patients had clinical signs of myopathy. A structured clinical evaluation was
performed and muscle biopsies were taken from the tibial anterior muscle at inclusion and after 3 months
treatment.IL-1α, HLA-DQ,and CD31 expression was investigated by immunohistochemistry. Quantification
was based on the total tissue area and performed using blinded digital computerized image analysis.
Results: Disease activity decreased (DAS28 mean 5.6 vs 4.1; p=0.007) from baseline to the 3 month evaluation.
A good or moderate EULAR response was seen in 8/14 patients. Muscle biopsies from 11 patients (6
responders/5 non-responders) were available for evaluation. There were no major inflammatory infiltrates
within the skeletal muscle. HLA-DQ was mainly expressed in endothelial cells in capillaries, whereas IL-1α
was mainly seen in larger vessels. Staining for HLA-DQ decreased significantly after treatment (M 0.073 %,
IQR 0.027-0.121 vs M 0.023%, IQR 0.009-0.040; p=0.041). There was a similar trend for IL-1α (mean
difference 0.049 %; 95 % confidence interval -0.069-0.168). Capillary density, measured as the proportion of
CD31 positive area, also tended to be reduced after adalimumab treatment. Decreased expression of IL-1α was
seen in EULAR good/moderate responders, but not in non-responders (mean difference 0.114% vs 0.028%).HLA-DQ expression decreased in both groups (median difference 0.046 % vs 0.036 %).
Conclusion: Treatment with adalimumab was associated with decreased expression of endothelial markers
associated with systemic inflammation in RA.Our findings could indicate reduced systemic endothelial
activation in patients treated with anti-TNF drugs, which may contribute to a lower risk of CV co-morbidity.
Anti-TNF therapy in RA and risk of Acute Myocardial Infarction (AMI), Stroke
and any Cardiovascular (CVD) events up to 7 years after treatment start
Anti-TNF therapy and risk of death up to 8 years after treatment start. Results from
the Swedish Biologics Register (ARTIS)
Lennart TH Jacobsson, Solbritt Rantapää-Dahlqvist, Jan-Åke Nilsson, Lotta Ljung, Johan
Askling.
Malmö University Hospital, Umeå University Hospital and Karolinska University
Hospital, Sweden.
LTH Jacobsson, S-B Rantapaa-Dahlqvist, and J Askling for the Swedish ARTIS group
Purpose: Rheumatoid arthritis (RA) and markers of inflammation are associated with cardiovascular disease.
Anti-TNF therapy in RA decrease inflammation and experimental data and clinical observational data suggest
that such treatment may decrease the risk for cardiovascular events.The aim of these analyses was to assess
long-term risks in anti-TNF treated patients for development of CVD events.
Methods: A national cohort of RA patients 1998-2005 (n=67,208) was identified using data from the three
national registers of hospital admission, outpatient visits, and early RA, respectively. Subjects starting anti-TNF
therapy during this period were identified through linkage with the Swedish Biologics Register (ARTIS)
(n=5299). For each such subject, four matched control subjects (total n controls=21,084) was randomly selected
from the national RA cohort. Analyses were adjusted for disease duration, co-morbidities (pervious
hospitalization due to CVD, diabetes, COPD), marital status, hospital stays, and joint surgery at entry to the
study).
The outcomes were defined as the first hospitalisation during follow up with a main diagnosis (ICD10) of any
CVD, AMI or stroke. Patients were censored at death, emigration or the end of the study period Dec 31st 2006.
Relative risks associated with anti-TNF therapy were estimated using Cox regression.Using Cox-regression
within the group of anti-TNF treated subjects, we also investigated the role of EULAR response to anti-TNF on
the risk of developing any CVD, AMI, and stroke, adjusting for age, sex, co-morbidities (see above), antirheumatic medication, HAQ and DAS28.
Results: Overall, 2778 CVD events, 492 AMI, and 338 strokes occurred during follow-up. Comparing antiTNF treated to their matched controls, the adjusted RRs overall, for males, and for females, respectively, for
CVD were 0.90 (0.78-1.03), 1.02 (0.81-1.29), and 0.82 (0.69-0.98). For AMI, the corresponding RRs were 1.02
(0.78-1.32), 1.17 (0.80-1.72), and 0.92 (0.65-01.32). For stroke, the corresponding RRs were 0.76 (0.55 - 1.05),
1.51 (0.80 - 1.72), and 0.68 (0.41 - 1.12).
Comparing good EULAR responders to non-responders, the adjusted RR were 1.03 (0.62 - 1.05) for any CVD
event, 0.86 (0.53 - 1.39) for AMI, and 0.81 (0.62 - 1.05) for stroke.
Conclusions: Anti-TNF therapy was not a risk factor for CVD overall, although there were indications of a
lower occurrence of CVD, AMI and stroke among women treated with anti-TNF. Response to anti-TNF therapy
did not emerge as a strong predictor of overall CVD risk, although a non-significant tendency towards a lower
risk of stroke among responders was noted. A definite answer to these issues would likely require evaluation in
the setting of a randomised controlled trial.
Background: RA is associated with an increased morbidity and mortality from various co-morbidities,
cardiovascular in particular. Anti-TNF therapy in RA has been shown to decrease inflammation and structural
damage, but has also been shown to increase the risk for infectious co-morbidites and suggested to decrease the
risk for cardiovascular events.. The long-term net effects of anti-TNF therapy on survival have been little
studied.
Objectives: The aim of this study was therefore to assess long-term outcomes in RA treated with anti-TNF
therapy, as measured by all-cause mortality.
Methods: A national cohort of RA patients 1998-2006 (n=67,150) was identified using data from the three
national registers of hospital admission, outpatient visits, and early RA, respectively. Through linkage to the
Swedish Biologics Register (ARTIS) we identified those subjects that started anti-TNF therapy 1998 through
2006 (n=6,403). Vital status and deaths 1998 through March 1st 2007 were captured through linkage with the
Population and Death Registers, respectively. The relative risk of death following treatment with anti-TNF was
compared to the general population mortality rates using standardised mortality ratios (SMR), and to the
mortality among anti-TNF naïve patients with RA in our RA cohort using Cox regression stratified for sex, age,
county, and adjusted for (time-dependent) four co-morbidities, marital status, hospital stays, and joint surgery.
Anti-TNF was assessed (time-dependent) as ever since first start, by time since first start, and separately within
each of the three RA-source cohorts.
Results: Compared to the general population mortality, the 392 deaths that occurred among the 6,403 patients
treated with anti-TNF corresponded to an overall SMR=1.57 (1.42 – 1.73). Compared to the 18,528 deaths that
occurred among the anti-TNF naïve patients with RA, the 392 deaths in the anti-TNF treated group
corresponded to a relative risk of 0.85 (0.77-0.95) which, when stratified by time since treatment was
0.56 (0.41-0.74), 0.85 (0.67-1.07), 0.83 (0.65-1.06), 1.06 (0.83-1.45), 0.79 (0.59-1.07), and 0.73 (0.57-0.93), <1
yr, 1-2, 2-3, 3-4, 4-5, 5+ yrs since first anti-TNF start, respectively. Subset analyses restricted to RA-patients
only identified in the inpatient register (RR=0.77, 0.69-0.87), and outpatient register (RR=0.83, 0.70-0.98),
revealed essentially similar results. Analyses within the Early RA Register (n=5463, 392 deaths, biologics
exposure 14%) revealed no increased mortality following anti-TNF treatment (RR=1.12, 0.70-1.78).
Conclusion: Patients with RA treated with anti-TNF are at higher risk of death compared to the general
population, but at lower risk of death than patients with RA not selected for anti-TNF treatment. This reduced
risk is likely to harbour several effects. These include channelling bias (especially during the first year of
treatment) and a possible protective effect (especially after 4 years of treatment), of which the latter could be
related to the effects of improved RA disease control.
Breast-feeding, but not oral contraceptives, is associated with a reduced risk of
rheumatoid arthritis.
Decrease of Hip Replacement Surgery in Patients with Rheumatoid Arthritis Results From a Well Defined Population in Southern Sweden
Mitra Pikwer1, Ulf Bergström1, Jan-Åke Nilsson1, Lennart Jacobsson1, Göran Berglund2,
Carl Turesson1.
1
Department of Rheumatology, Malmö University Hospital, Malmö, Sweden.
2
Department of Medicine, Malmö University Hospital, Malmö, Sweden.
Korosh Hekmat1, Lennart TH Jacobsson1, Jan-Åke Nilsson1, Ingemar F. Petersson2, Otto
Robertsson2, Göran Garellick3 and Carl Turesson1, 1Section of Rheumatology,
Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden,
2
Orthopedics, Department of Clinical Sciences, Lund, Lund University, Lund, Sweden,
3
Department of Orthopaedics, Swedish Hip Arthroplasty Register, Institute of Clinical
Sciences at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Background: Suggested predictors of rheumatoid arthritis (RA) include environmental and genetic factors. A
number of studies with conflicting results regarding the influence of hormonal factors on RA have been
published.
Methods: Between 1991-1996, 28 098 subjects (17035 women) were included in a community based health
survey. Information on oral contraceptive (OC) use, hormonal replacement therapy (HRT) use, parity, breastfeeding history and life style factors was obtained using a self administered questionnaire. This population was
linked to a community based RA register, the local patient administrative register, the National Hospital
Discharge Register and the National Cause of Death Register. The medical records were subjected to a
structured review, and all females with RA diagnosis after inclusion in the health survey, were included in our
case-control study. Four female controls for every case, matched according to age and year of screening, who
were alive and free of RA when the index person was diagnosed with RA, were selected from the health survey
population. Potential predictors were examined in logistic regression models. Patients were stratified by breastfeeding history as follows: never, total breast-feeding 1-12 months, total breast-feeding ≥ 13 months.
Results: 136 women with incident RA were compared to 544 controls. The mean age at RA onset was 63.3
years with a median duration of 5.5 years (range 1-13 years) from enrolment in the health study to RA onset.
Longer history of breast-feeding was associated with a reduced risk of RA [odds ratio (OR) : 0.46; 95%
confidence interval (CI) 0.24-0.91 for women with ≥13 months of breast-feeding, and OR 0.74; 95 % CI 0.451.20 for those with 1-12 months, compared to those who never breast-fed]. The protective effect of longer
breast-feeding remained significant when adjusting for parity and either smoking or level of education in
multivariate models. Parity, OC and HRT use did not have any significant effect on the risk of RA. However,
the number of women with a history of HRT use at screening was small (n=228; 44 cases), limiting the power
of the present study to address this issue.
Conclusion: Breast-feeding was associated with a dose dependent reduction of the risk of RA. Potential
explanations include long term modulation of immune or neuroendocrine pathways. Our results do not support
any major effect of OC or HRT use on RA susceptibility.
Purpose: Major joint arthroplasty is used effectively in many patients with severe rheumatoid arthritis. The aim
of modern pharmacologic treatment is to prevent joint destruction and reduce the need for orthopedic surgery.
The purpose of our study was to investigate trends in the incidence of primary total hip and knee replacements
in a well defined sample of patients with RA.
Method: Patients were recruited from a community based register established in 1997, which includes patients
from a single University Clinic and collaborating private practitioners. Prevalent cases of RA in 1997 and
incident cases 1997-2007 were included. Based on a structured review of the medical records, patients were
classified according to the 1987 American College of Rheumatology criteria, and the year of RA diagnosis was
noted. The incidence of major joint arthroplasty was estimated based on linkage of this cohort with the Swedish
National Hip Arthroplasty (through December 2006) and the Swedish Knee Arthroplasty Register (through
October 2007). During the study period, indications for joint replacement in Sweden were based on objective
clinical and radiographic findings and were relatively stable across different clinics, although minor changes
over time can not be excluded. Patients with a registered hip or knee arthroplasty before 1997 or before RA
diagnosis were excluded. The incidence rate for the period at and just after the time of the introduction of TNF
inhibitors (1998-2001) was compared to the period when biologics were part of the established treatment for
severe RA (2002-2006 for hip replacements and 2002-2007 for knee replacements).
Results: There were 2164 patients in the cohort (1545 women, 619 men; mean age at diagnosis 51 years).
During the study period, a primary hip arthroplasty was registered for 115 patients and a primary knee
arthroplasty for 85 patients. The incidence of primary hip arthroplasties decreased from the period 1998-2001
[12.6/1000 person-years(pyr)] to 2002-2006 (6.6/1000 pyr) [rate ratio (RR) 0.52; 95% confidence interval (CI)
0.35-0.76 for 2002-2006 vs. 1998-2001] There was a trend towards an increase of the incidence of primary
knee arthroplasty (4.8/1000 pyr 1998-2001 vs. 6.8/1000 pyr 2002-2007 – RR 1.43; 95% CI 0.89-2.31).
Conclusion: Our investigation shows a significant decrease in hip replacement surgery in patients with RA after
2001. Possible explanations include an effect on joint damage from more aggressive treatment with DMARDs
and biologics. The trend towards an increase of knee arthroplasty may be due to changing indications for
surgery. Alternatively, destruction of hip and knee joints in RA may be partly due to distinct mechanisms.
Circulating autoantibodies and increased cartilage turnover before the clinical onset
of rheumatoid arthritis
C. Turesson*1, U. Bergström1, L. T. H. Jacobsson1, L. Truedsson2, G. Berglund3, T.
Saxne4
1Department of Rheumatology, Malmö University Hospital, Malmö, 2Department of
Laboratory Medicine, Lund University Hospital, Lund, 3Department of Medicine, Malmö
University Hospital, Malmö, 4Department of Rheumatology, Lund University Hospital,
Lund, Sweden
Background: Previous studies indicate that autoantibodies may be detected in individuals who develop
rheumatoid arthritis (RA) years before onset. COMP is a marker of cartilage turnover, and has been associated
with progressive joint damage in patients with RA.
Objectives: Our purpose was to investigate circulating autoantibodies and serum COMP levels in samples
collected before the onset of RA.
Methods: Between 1991 and 1996, subjects (n=30447; 12121 men and 18326 women) from a defined
catchment area were included in a community based health survey. From this population, individuals who
developed RA after inclusion were identified by linking the health survey database to a community based RA
register and to local and national patient administrative registers. One control for each case, matched for sex,
year of birth and year of screening, who was alive and free of RA when the index person was diagnosed with
RA, was selected from the health survey. Antibodies to cyclic citrullinated peptides (anti-CCP) and to mutated
citrullinated vimentin (anti-MCV) and IgM rheumatoid factor (IgM RF) were determined by ELISA. Serum
COMP was measured with a sandwich ELISA (AnaMar Medical, Lund, Sweden). Based on previous studies, 12
U/L was used as a cut off for elevated COMP.
Results: One hundred and seventy two patients (36 men/136 women, mean age at RA diagnosis 63 years, 67 %
RF positive at diagnosis or later) were diagnosed with RA after inclusion in the health survey. The median time
from inclusion to RA onset was 5 years (range 1-13). Samples were available from 169 cases and 168 controls.
Pre-RA cases were more likely to be anti-CCP positive (>20 U/mL; 21.9 % vs 0.6 %; p<0.001), anti-MCV
positive (>20 U/mL; 29.6 % vs 3.0 %; p<0.001) and IgM RF positive (>20 IU/mL; 18.9 % vs 2.4 %; p<0.001)
than controls, with similar patterns among men and women when studied separately. The median (M) antibody
levels with interquartile ranges for positive cases were 82 U/mL (36-170) for anti-CCP, 130 U/mL (57-410) for
anti-MCV and 75 IU/mL (35-222) for IgM RF. All three antibodies were detected up to 10 years before disease
onset. The proportion of anti-CCP positives among pre-RA cases included 2-9 years before disease onset was 20
% compared to 53 % among those included 1-2 years before disease onset. COMP was measured in 83
individuals who developed RA 1-5 years after inclusion and the corresponding matched controls. Overall, serum
COMP levels were similar in cases and controls (M 10.1 vs. 10.2 U/L). Cases who developed RA 1-2 years
from inclusion (n=33) had higher COMP levels than the corresponding controls (M 11.7 U/L vs M 10.2 U/L;
p=0.20), and elevated COMP (>12 U/L) was more frequent among cases in this subset (36 % vs 19 %; p=0.11).
Among pre-RA cases included 1-2 years before disease onset, elevated COMP was seen in a greater proportion
of anti-CCP negatives compared to anti-CCP positives (50% vs 15%; p=0.04).
Conclusion: Anti-CCP, anti-MCV and IgM RF can be detected up to 10 years before clinical onset of RA in
subsets of patients of both sexes. Increased cartilage turnover, measured by COMP, and circulating RA specific
antibodies may be distinct processes in the pre-clinical phase of RA.
Plasma concentrations of Gas6 and sAxl correlate with disease activity and
glomerulonephritis in Systemic Lupus Erythematosus
Ekman C1, Jönsen A2, Sturfelt G2, Bengtsson AA2, Dahlbäck B1
Department of Laboratory Medicine, Division of Clinical Chemistry; 2Department of
Clinical Sciences, Section of Rheumatology; Lund University
1
Background: Systemic lupus erythematosus is an autoimmune disease affecting many different organ systems,
characterized by a multitude of autoantibodies and dysregulation of inflammation.
Methods: We have recently developed immunological methods to quantify the vitamin-K dependent protein
Gas6 and its soluble receptor sAxl in human plasma. In this study, we have investigated samples from 96 SLE
patients and correlated findings with clinical disease activity measured with the SLE Disease Activity Index
(SLEDAI) and laboratory findings.
Results: Higher concentrations of Gas6 and sAxl correlated with increased SLE disease activity (r=0.48,
p<0.001 and r=0.39, p=0.001 respectively). In particular, both Gas6 and sAxl increased during active
glomerulonephritis (p<0.001 for both). Furthermore, Gas6 and sAxl concentrations correlated with presence of
anti-dsDNA antibodies (p<0.001 for both) and leukopenia (p<0.001 and p=0.002 respectively). Additionally,
Gas6 and sAxl concentrations, correlated with higher erythrocyte sedimentation rate (r=0.43, p<0.001 and
r=0.48, p<0.001 respectively), higher serum concentrations of C-reactive protein (r=0.30, p=0.004 and r=0.31,
p=0.002 respectively) and inversely to serum concentration of hemoglobin (r=-0.48, p<0.001 and r=-0.51,
p<0.001 respectively).
Conclusions: These findings suggest a role for Gas6 and sAxl in the pathogenesis of SLE and possibly as
biomarkers of disease activity.
C1q inhibits immune complex induced IFNα production in plasmacytoid dendritic
cells – a novel link between C1q deficiency and SLE pathogenesis
Christian Looda,b, Birgitta Gullstrandb, Lennart Truedssonb, Anders I. Olinc, Gunnar V.
Almd, Lars Rönnblome, Gunnar Sturfelta, Maija-Leena Elorantae and Anders A.
Bengtssona.
a
Department of Laboratory Medicine, Section of Microbiology, Immunology and
Glycobiology, Lund University, Lund, Sweden. bDepartment of Clinical Sciences,
Section of Rheumatology, Lund University Hospital, Lund, Sweden. cDepartment of
Clinical Sciences, Section of Infection Medicine, Lund University, Lund, Sweden.
d
Department of Biomedical Sciences and Veterinary Public Health, Swedish University
of Agricultural Sciences, Uppsala, Sweden. eDepartment of Medical Sciences, Uppsala
University, Uppsala, Sweden.
Objective: C1q deficiency is the strongest risk factor known for the development of systemic lupus
erythematosus (SLE) since almost all humans with a genetic deficiency of C1q develop this disease. Low C1q
serum concentration is also a typical finding in SLE during flares, emphasizing the involvement of C1q in SLE
pathogenesis. Recent studies have revealed that C1q has a regulatory function on Toll-like receptor induced
cytokine production. We therefore investigated if C1q could regulate the interferon-alpha (IFNα) production.
Methods: Peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) were
stimulated with three known interferogenic stimuli and cultured with physiological concentrations of C1q. The
IFNα production was determined by an immunoassay.
Results: C1q significantly inhibited the IFNα production induced by RNA-containing immune complexes (ICs)
(p<0.04), Herpes simplex virus (HSV) (p<0.02) and CpG DNA (p<0.001) by PBMCs. C1q could also inhibit
the IFNα production from purified PDCs when stimulated with ICs (p<0.002) or CpG DNA (p<0.04) but
increased the HSV-induced IFNα production (p<0.001). The regulatory role of C1q was not specific for IFNα,
but was also seen for IL-6, IL-8 and TNFα. We could demonstrate binding of C1q to PDCs both by BIAcore
and flow cytometry and also intracellular detection of the two C1q binding proteins gC1qR and cC1qR.
Conclusion: Our findings contribute to the understanding of why C1q deficiency is such a strong risk factor for
SLE and suggest an explanation for the up-regulation of the type I IFN system seen in SLE patients.
Type I IFN-regulated gene and protein expression in platelets are correlated with
platelet function and are strongly associated with cardiovascular disease in systemic
lupus erythematosus
Christian Looda,b, Stefan Amistenc, Birgitta Gullstranda, Andreas Jönsenb, Maria Allhornd
Lennart Truedssona, Gunnar Sturfeltb, David Erlingec and Anders A Bengtssonb
a
Department of Laboratory Medicine, Section of Microbiology, Immunology and
Glycobiology, Lund University, Lund, Sweden. bDepartment of Clinical Sciences,
Section of Rheumatology, Lund University Hospital, Lund, Sweden. cDepartment of
Cardiology, Lund University, Lund, Sweden. dDepartment of Clinical Sciences, Section
of Infection Medicine, Lund University, Lund, Sweden.
Patients with systemic lupus erythematosus (SLE) have a marked increased risk to develop cardiovascular
disease and venous thrombosis. Neither traditional nor disease specific risk factors can fully explain this
comorbidity. We therefore undertook a study to investigate platelet mRNA and protein expression as well as
corresponding platelet functions in SLE patients and matched healthy controls. We found that platelets from
SLE patients have a type I IFN mRNA signature as well as an increased expression of type I IFN-regulated
proteins such as PRKRA, IFITM1 and CD69 (p<0.0001). The megakaryocytic cell-line MEG-01 increased the
expression of CD69 and IFITM1 upon IFNα stimulation, which could be compatible with IFNα interacting with
megakaryocytes in vivo. Most importantly, patients with a previous history of cardiovascular disease or venous
thrombosis had increased expression of type I IFN-regulated proteins as well as more activated platelets as
compared to patients without a previous history of cardiovascular disease or venous thrombosis. Furthermore,
SLE patients had increased complement deposition (p<0.0001), exposure of phosphatidylserine (p=0.03), and
increased percentage of platelet-monocyte complexes (p=0.0004), demonstrating increased platelet activation.
We suggest that interferogenic immune complexes (ICs) stimulate production of IFNα which could up-regulate
the megakaryocytic type I IFN-regulated genes and proteins and affect the platelet activation. Altogether, our
findings show that SLE patients have more activated platelets and increased expression of type I IFN-regulated
proteins which may contribute to the development of cardiovascular disease and venous thrombosis in SLE.
CLIFT determined anti-DNA antibodies have low diagnostic value for SLE in
unselected patients with early rheumatic disorder.
Preliminary results from “The Scandinavian anti-DNA study”.
Auto-antibodies against histones support phagocytosis of necrotic material by
polymorphonuclear leukocytes in the presence of serum. The LE cell phenomenon
revisited.
M. Compagno1, S. Jacobsen2, O.P. Rekvig3, L. Truedsson4, N. Heegaard5, H. Nossent6, A.
Jönsen1, O. Nived1, G. Sturfelt1, A. Wiik5, A.A. Bengtsson1
1
Department of Rheumatology, University Hospital, Lund, Sweden. 2Department of
Rheumatology, University Hospital at Rigshospitalet, Copenhagen, Denmark.
3
Department of Biochemistry, Institute of Medical Biology, Tromsö, Norway.
4
Department of Clinical Microbiology and Immunology, University Hospital, Lund,
Sweden. 5Department of Clinical Biochemistry and Immunology, Statens Serum Institut,
Copenhagen, Denmark. 6Department of Rheumatology, University Hospital, Tromsö,
Norway
Birgitta Gullstrand1, Helena Tyden2, Gunnar Sturfelt2, Lennart Truedsson1, and Anders A.
Bengtsson2.
Background: An abnormal level of anti-DNA antibodies presently represents a criterion for SLE classification,
and it is generally assumed that a positive anti-DNA test is a rare finding in cohorts of non-SLE patients.
Previous studies have shown that different assays to detect anti-DNA antibodies have different specificities for
SLE. Crithidia luciliae immunofluorescence test (CLIFT) has been suggested as one of the most specific assays.
Objectives: The Scandinavian anti-DNA study is a multicenter project in progress in Sweden (Lund), Norway
(Tromsø) and Denmark (Copenhagen) aiming at investigating the diagnostic value and clinical associations of
anti-DNA antibodies measured with various assays. In this particular part of the project, we investigated the
diagnostic value of CLIFT-positive anti-DNA antibodies for SLE in an unselected group of patients suspected to
have incipient rheumatic disease.
Patients and methods: A total of 1073 unselected patients with first appearance of rheumatologic symptoms
have been recruited to the study. A preliminary ANA screening was performed. The serum of all ANA positive
patients (n=314) and an equally sized matched ANA negative control group was tested for anti-DNA antibodies
with CLIFT (dilution 1:10 - ImmunoConcept) at the Department of Clinical Microbiology and Immunology in
Lund. All 628 patients had a diagnostic work-up performed by clinicians who made diagnosis unaware of the
serology results.
Results: Eighty-seven (13.8%) of the 628 patients were CLIFT positive. Two thirds of them (n=58) belonged to
the ANA-positive group and the rest (n=29) to the ANA-negative group.
A clinical diagnosis of SLE was made in 65 (10.3%) out of the 628 recruited patients, but only 23 of them were
CLIFT positive, hereof 21 ANA positive and 2 ANA negative.
Among the 64 CLIFT positive patients without SLE, 15 had another connective tissue disease, 13 had a chronic
inflammatory joint disease, 6 inflammatory systemic diseases, 12 arthralgia, 3 dermatological disorders, 7 a
non-rheumatic disorder, 8 had no diagnosis because of unspecific symptoms and signs. The positive predictive
value of CLIFT for a diagnosis of SLE in this cohort was 0.35.
Table 1. Clinical diagnosis in 87 CLIFT + patients
SLE
Other connective tissue disease
Chronic inflammatory joint disease
13
Arthralgia/pain
Inflammatory systemic disease
Dermatological disorder
Non-rheumatic disorder
Unspecific symptoms (no diagnosis)
8
23
15
12
6
3
7
Conclusion: In an unselected group of patients referred to the participating rheumatology clinics, positive
CLIFT had surprisingly low specificity for a diagnosis of SLE. Positive CLIFT was detected in many other
conditions. In the present study, ANA performed poorly as a screening test for anti-DNA, since nearly one out
of ten ANA negative patients was CLIFT positive.
1
Birgitta Gullstrand, BSc, Lennart Truedsson, MD, PhD, Department of Laboratory
Medicine, Section of Microbiology, Immunology and Glycobiology; 2Helena Tyden,
MD, Gunnar Sturfelt, MD, PhD, Anders A. Bengtsson, MD, PhD, Department of Clinical
Sciences, Section of Rheumatology, Lund University, Lund, Sweden.
The LE cell phenomenon, presence of polymorphonuclear leukocytes (PMN) containing phagocytised nuclear
material, was the first described laboratory finding associated with systemic lupus erythematosus (SLE). The
engulfed material contains auto-antibodies against histones, which are major SLE auto-antigens, and the LE cell
phenomenon is believed to reflect key pathogenetic events.
Our aim was to develop methods for detection of anti-histone antibodies and phagocytosis by PMN of necrotic
material in the presence of serum.
Serum samples from 19 SLE patients, consecutively collected over several years, and serum from 100 healthy
controls (NHS) were used. Antibodies to histone 1 (H1) and to a histone mix (1, 2, 3 and 4) (H) were detected
by ELISA. A flow cytometry phagocytosis assay (PA) was developed to measure uptake of necrotic material by
PMN in the presence of serum.
High antibody concentrations were associated with high levels in PA (H1-PA p<0.0001, r=0.628; H-PA
p<0.0001, r=0.715), and only seen in serum from SLE patients. Thus, our findings confirm previous reports and
suggest that measurement of the anti-histone auto-antibodies could be useful in SLE as a marker for
apoptosis/necrosis resulting in circulating necrotic cell material contributing to the autoimmune process in this
disease.
Charlson co-morbidity index is associated with mortality in systemic lupus
erythematosus
Systemic Lupus and Cardiac Risk Factors. A study of Patient record documentation
and compliance
Jönsen A1,2, Clarke AE1,3, Joseph L1, Belisle P1, Bengtsson AA2, Bernatsky S1,4, Nived
O2, Sturfelt G2, Pineau CA4
1
Division of Clinical Epidemiology, McGill University Health Centre, Montreal, Canada,
2
Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund,
Sweden. 3Division of Clinical Immunology/Allergy, McGill University Health Centre,
Montreal, Canada. 4Division of Rheumatology, McGill University Health Centre,
Montreal, Canada
Christin Bengtsson1, Anders A. Bengtsson1, Sol-Britt Rantapää-Dahlqvist2, Gunnar
Sturfelt1, Andreas Jönsen1 and Ola Nived1, 1Inst of Clinical sciences, Lund, Sweden,
2
University Hospital, Umeå, Sweden
Objectives: To investigate whether co-morbidity as assessed by the Charlson co-morbidity index (CCI) is
associated with mortality in the long term follow-up of systemic lupus erythematosus (SLE) patients.
Patients and Methods: Data from 499 SLE patients attending the Lupus Clinic at the McGill University Health
Center, Montreal, Canada and 170 SLE patients from the Department of Rheumatology at Lund University
Hospital, Sweden were collected from available databases. These patients constitute long term follow-up
cohorts. In the Montreal cohort, data on the CCI was obtained prospectively for patients still active in follow-up
in 2006 and 2007 (56%) and was then verified through chart review. For the other patients (44%), data were
retrieved through retrospective chart review only. In the Lund cohort, data on the CCI was obtained through
retrospective chart review. Additionally, data for disease activity over time, Systemic Lupus International
Collaborating Clinics/American College of Rheumatology Damage Index (SDI), smoking, education, antiphospholipid syndrome (APS) as well as demographic data were also retrieved. Variables were then entered into
a Cox proportional hazards survival model. The Montreal and Lund cohorts were analyzed separately.
Results: Eighty-one deaths were recorded in the Montreal cohort while the corresponding number for the Lund
cohort was 46. The median follow-up time was 13 years in both cohorts. The CCI and age at diagnosis were
associated with mortality in the Montreal cohort (CCI: HR = 1.56 per unit increase in the CCI, 95%CI 1.172.07; age: 1.04 per year increase in age, 95%CI 1.00-1.09). Age at diagnosis and CCI also showed an
independent association with mortality in the Lund cohort (CCI: HR 1.32, 95%CI 1.09-1.60; age: HR 1.09,
95%CI 1.05-1.12).
Furthermore, the SDI was associated with mortality in the Lund cohort (HR 1.36 per unit increase in the SDI,
95%CI 1.15-1.60), while the estimate in the Montreal cohort was HR 1.20 (95%CI 0.98-1.47). We did not find a
strong association between gender, ethnicity, disease activity, APS and mortality in either cohort, or for
smoking and education level in the Montreal cohort.
Conclusions: The presence of substantial co-morbidity in SLE is widely recognized. In this study, co-morbidity
as measured by the CCI, a validated co-morbidity index, was associated with decreased survival independent of
age, lupus disease activity and SDI. Including the CCI in studies of prognostic factors in SLE may be of
importance and the CCI may also be of value in the prognostic assessment of individual patients.
Purpose: Knowing that SLE patients are at greater risk for developing cardiovascular disease (CVD) and that
traditional cardiac risk factors (CR) are associated with this comorbidity, we found it of importance to study
patients knowledge of CR. We also wanted to analyze how we in every day clinic document information and
advice about CR. Finally we were interested in compliance to received instructions about medication and
improved lifestyle according to CR.
Method: This study was performed at four hospitals. All patients that fulfilled ≥4 ACR criteria, were asked to
participate and fill in a cardiovascular health questionnaire (CHQ). The CHQ was blinded to the investigator
that read the medical record and noted the documented CR. After this the results of the questionnaires were
recorded into the same database. The CHQ is adapted from the National Health and Nutrition Examination
Survey I Epidemiological Follow up Study and reveals the patients opinion of possible CR impact on
developing CVD. The CHQ also asks about the patients knowledge of CR, if a physician has advised lifestyle or
medication changes and if the patient has followed this advice. Compliance was based on subject´s responses, if
they had followed their physicians advice.
(By permission of Dr Karen Costenbader). Kappa statistics was used to compare patients record with CHQ and
to evaluate compliance.
Results: Altogether 210 out of 291 (72%) SLE patients completed the CHQ. The mean age of the patients were
55 years. High cholesterol, smoking and hypertension were known by the patients as very important risk factors
and nobody considered hypertension, smoking and overweight as not important for developing CVD. The
agreement between documentation and patients report was moderate for hypertension, overweight and
hypercholesterolemia (kappa 0.60-0.42), for diabetes substantial (kappa 0.66) but for physical inactivity and
smoking below fair (kappa 0.02, 0.05).
Patients compliance to information that they had received regarding medication and dietary changes (the latter
in patients with hypercholesterolemia and diabetes) was substantial (kappa 0.58-1.0). For lifestyle changes,
though, in patients with hypertension and overweight the compliance was fair to moderate (kappa 0.13-0.47).
Conclusion: All three CR fields investigated in this CHQ study (awareness, documentation and compliance),
could be improved. This opens up for discussions of the best ways to accomplish this in every day clinic.
Observational study of outcome, related to predictors and therapy for all biopsied
SLE patients with glomerulonephritis in one unit between 1986 and 2004, also
comparing the WHO and ISN classifications.
Ståhl-Hallengren Christina, Alm Per*, Bengtsson Anders, Jönsen Andreas, Sturfelt
Gunnar, Nived Ola.
Department of Rheumatology and Dpt of Pathology*, University Hospital, Lund,
Sweden.
Objective: To study possible predictors for end stage renal disease (ESRD) or reduced glomerular filtration rate
(GFR) in lupus nephritis with the aid of ACR renal response
criteria , and to compare the WHO with the new ISN lupus nephritis classification.
Method: All 53 biopsy verified cases of lupus nephritis in the local catchment area between the years 1986 and
2004 were identified and GFR, serum-creatinine, proteinuria, hematuria, SLEDAI-2K, renal variables and
complement were retrieved at biopsy, after 6, 12 months and at latest visit. Information about given therapy
was also extracted both from medical records and our local prospective SLE registry. Two cases were lost to
follow up and in one case the biopsy was unsatisfactory, why 50 cases remained. All renal biopsies were
reevaluated with the new ISN classification. Outcome was defined by the ACR renal response criteria.
Results: Mean follow up time was 9 years (2-24 y), complete renal response was achieved in 11 cases, partial
renal response in 32 cases, ESRD in 5 cases and nephritic syndrome in one case. The final GFR correlated with
the age at biopsy (p<0.01), with the ISN classification (p<0.05) and especially the presence of interstitial
manifestations (p<0.01), also with the decrease of proteinuria (p<0.01) and serum-creatinine (p<0.05) after six
months of treatment. The outcome also correlated with the nefrological components of SLEDAI 2K after 6
months of therapy (p<0.01, positive predictive value 56%). The WHO classification did not correlate with
outcome. The local practice was to give azathioprin as induction therapy during the first part of this
observational study and was then changed to individually designed pulse cyclophosphamid during the second
half. Both therapies seem to work, but the renal function at follow up showed a trend towards worse outcome in
the azathioprin treated patients despite younger age at biopsy, but with a little longer follow up time. .
Conclusions: A good outcome is correlated with the response to treatment after 6 months and the ISN
classification might add useful information for prediction. Since this is not a randomized study data do not allow
conclusions about effectiveness of different therapies.
A Phase I, Dose Escalation Study to Evaluate the Tolerability of ABR-215757 in
patients with Systemic Lupus Erythematosus (SLE)
Bengtsson A.A.1, Sturfelt G.1, Rönnblom L.2, van Vollenhoven R.F.3, Wallén Öhman
M.4, Tuvesson H.4, Lando P.4, Edman K.4, Liberg D.4, Källberg E.5, Olsson A.4,
Leanderson T.5
1
Dept of Rheumatology, Lund University, Lund, Sweden; 2Dept of Medical Sciences,
Uppsala University, Uppsala, Sweden; 3Dept of Rheumatology, Karolinska University
Hospital, Stockholm, Sweden; 4Active Biotech, Lund, Sweden; 5Div of Immunology,
Lund University, Lund, Sweden
Background: ABR-215757 is a small molecule compound intended for chronic oral treatment of SLE and
belongs to the quinoline 3-carboxamides, a group of immunomodulators interacting with S100A9. These
compounds cause reduction of autoreactive T cell proliferation without general immune suppression. ABR215757 effectively inhibits disease in MRLlpr/lpr mice, an experimental model for SLE. Multiple disease
parameters including serological disease markers and histopathological manifestations are affected by ABR215757. A previous clinical Phase I dose escalation study in healthy volunteers demonstrated tolerability of
ABR-215757 at doses up to at least 3.0 mg/day. The aim of the present study was to establish the maximum
tolerable dose (MTD) and to determine the tolerability of ABR-215757 in patients.
Methods: This was a randomized, double-blind, placebo-controlled, multi centre study. The patients received
escalating doses (1.5, 3.0, 4.5 and 6.0 mg/day) of ABR-215757 (3 patients/group) or placebo (one patient/group)
in addition to standard maintenance treatment. The primary endpoint was to determine MTD defined as the
highest dose where not more than 1 patient out of 6 experienced dose limiting toxicity (DLT). Safety
assessments involved analysis of haematology and clinical chemistry, ECG measurements and recording of
adverse events (AEs). In addition, the effect on interferon-inducible gene expression was studied.
Results: The most frequently reported AEs considered as possibly/probably related to study drug were
arthralgia, myalgia. The majority of the AEs were mild or moderate and transient. At 4.5 mg and higher some
AEs of severe intensity were reported. Eight serious adverse events (SAEs) considered as possibly/probably
related were reported, all of them in the 4.5 or 6.0 mg dose groups. No specific pattern of changes in ECG
measurements was observed. Further, ABR-215757 treatment induced significant changes of the gene profile
including decreased expression of a number of IFN regulated genes.
Conclusion: The MTD of ABR-215757 in SLE patients was concluded to be 4.5 mg/day, and safety data
support treatment with ABR-215757 up to at least 3 mg/day in future clinical studies. Furthermore, the results
indicated that ABR-215757 could normalize pathways central in the pathogenesis of SLE.
Faecal-Calprotectin as a Biomarker in Systemic Sclerosis
Employment status and risk factors for work disability in systemic sclerosis (SSc).
Kristofer Andréasson (1), Agneta Scheja (1), Tore Saxne (1), Bodil Ohlsson (2), Roger
Hesselstrand (1)
1) Department of Clinical Sciences, Lund, Section of Rheumatology, Lund University
2) Department of Clinical Sciences, Malmö, Section of Gastroenterology and
Hepatology, Lund University.
Sandqvist G, Hesselstrand R, Scheja A
Dept of Rheumatology, Lund University Hospital, Lund, Sweden
In systemic sclerosis (SSc), involvement of the gastrointestinal (GI) tract is frequent and its assessment distal to
the oesophagus complicated in clinical practice. Faecal calprotectin (F-calprotectin), also known as S100A9/A8,
is a validated biomarker in inflammatory bowel disease. In this study we analysed F-calprotectin to explore the
mechanisms of GI involvement in SSc and to test its potential as a biomarker of GI involvement in SSc.
The study comprised 77 consecutive SSc patients (65 female, 12 men). Mean disease duration, defined as years
from first non Raynaud manifestation, was 9 (S.D.=7) years. Levels of calprotectin in stool and plasma were
measured with ELISA (Bühlmann laboratories AG, Switzerland). F-calprotectin >50 µg/ml was considered
pathologically increased. P-calprotectin was compared with the median (0.83 µg/ml) for healthy controls.
Patients were subjected to a clinical, radiological and biochemical examination and their medical records
studied. Statistical correlations were done with parametric tests using the logarithm of F-calprotectin and Pcalprotectin.
A majority of the patients had increased levels of F-calprotectin (median 125; interquartile range (IQR) 45-213
µg/ml). A significant relationship was noted between patients’ reported proton pump inhibitor-usage and Fcalprotectin (r=0.50; p<0.001) and the number of medications prescribed for GI dysfunction (r=0.34; p=0.002).
Patients with radiological evidence of oesophageal dysfunction had higher levels of F-calprotectin than those
without (mean 141 vs 60 µg/ml; p=0.015). F-calprotectin correlated with the estimated pulmonary arterial
pressure (PAP; r=0.47; p<0.001), presence of diastolic dysfunction (p=0.006), but not with finger arterial
pressure or nailfold capillary density. There was a weak relationship between F-calprotectin and vital capacity
(r=-0.25; p=0.027) but no correlation with skin involvement or NSAID-usage. P-calprotectin was higher than
previously reported in healthy controls (median 1.5; IQR 0.7-1.9 µg/ml), correlated with other markers of
systemic inflammation, e.g. orosomucoid (r= 0.58; p<0.001), but did not show any significant relationship with
F-calprotectin (r=0.22; p=0.061).
Patients with SSc have increased levels of calprotectin in faeces, which suggests presence of an inflammatory
process in the GI tract. F-calprotectin correlates with clinically relevant GI manifestations and may prove to be a
useful non-invasive marker of GI involvement in SSc.
Background. The balance of activities of daily life is markedly influenced by employment status. Long periods
of absence from work are often accompanied by loss of life roles and have negative consequences for the
individual and society. Working ability is a multifactorial phenomenon, depending on individual resources and
demands of work.
Objective. To investigate employment status in SSc and to identify risk factors, individual and work related, for
work disability.
Methods. Fifty-seven (of 76 invited consecutive) patients (53 female/4 male) with SSc (47 lcSSc / 10 dcSSc),
age median 58 (IQ-range 47 – 62) years and disease duration 14 (9 – 19) years were included in the study. The
patients were assessed regarding sociodemographic characteristics (age, education, marital status, children at
home, employment status), disease manifestations [skin score, DLCO, perceived symptoms as Raynuad’s,
shortness of breath, fatigue, stiffness, pain, ulcers/scars, hand function (VAS)] work ability [Work ability index1
(WAI)], empowerment in a workplace (Psychological empowerment instrument2), study specific questions
about social support at home, adaptations at the workplace, and access to helpful colleagues, ADL capacity and
satisfaction [the scleroderma Functional Score3 (FS), Satisfaction with Daily Occupations4 (SDO)].
Results Sixteen (28.1%) patients worked without any sickness benefit, 20 (35.1%) were partial on sick leave
and partial working Twenty-one (36.8%) were on full-time sick leave or disability pension since median 8 (5.5 –
16.5) years after disease onset. The patients with full-time sickness benefit were significantly older at the
disease onset (p<0.05) than patients without, or with partial sickness benefit. No other significant difference
concerning sociodemographic or objective disease manifestations was found. Six patients had received
disability pension more than10 years before the study and are excluded in the analysis of risk factors for work
disability. The professions were; office clerks, teachers, various forms of nursing, child care workers, shop
assistants, cleaners and mechanics. The WAI was median 31.5 points out of 49, 13 patients (26.5%) had good or
excellent WAI (> 36), 15 (30.6%) had less good (28-36), and 21 (42.9%) had bad WAI.(<28). Working ability
was correlated to fatigue, pain, stiffness, hand function, social support, empowerment competence, ADLcapacity and satisfaction with daily activities (p<0.001). No correlation between WAI and sociodemographic
variables or objective measures of organ manifestations was found. Significant differences between the groups
were found in: fatigue, pain, hand function, empowerment competence and satisfaction with daily activities
(p<0.001), and ulcers, stiffness, empowerment impact, and possibility to adapt the work (p<0.01). No
differences were found concerning sociodemographic variables or objective measures of organ manifestations.
Conclusions. Work disability is major problem in SSc. Impaired hand function, pain, fatigue, difficulties to
adapt the work, and insufficient impact and belief to possess the skills, are prominent risk factors.
References. 1. Tuomi K et al. Finnish Institute of Occupational Health, Helsinki, 1998.
2. Hochwälder J, Bergsten Brucefors A. Scand J Psychol. 2005, 3. Silman A et al J Rheumatol 1998, 4. Eklund
M Scand J Occup Ther 2004.
Influenza vaccination status in patients with chronic arthritis. Room for
improvement
Early changes in bone mineral density of the hand predicts up to 20 years
radiological outcome in prospectively monitored rheumatoid arthritis patients
Meliha C. Kapetanovic, Tore Saxne, Carmen Roseman, Pierre Geborek
Department of Clinical Sciences, Lund, Section of Rheumatology, Lund University
Elisabet Lindqvist, Carmen Roseman, Jacob Algulin*, Tore Saxne and Pierre Geborek
Lund University Hospital, Lund, Sweden, *Sectra, Linköping, Sweden.
Objective. To study influenza vaccination status in patients with chronic arthritis (RA or spondylarthropathy)
regularly followed at Dept of Rheumatology, Lund University Hospital, Sweden.
Methods. Altogether, 430 patients participating in an ongoing study on pneumoccocal vaccination were
included. Information on influenza vaccination status during the last 12 months was collected by direct
questioning using a structured protocol. Based on diagnosis and treatment the patients were divided into 6
groups.
Treatments groups (number, % female, mean age ±SD (years), mean dis duration ±SD (years)) were:
1
RA patients on methotrexate (MTX)and/or other DMARDs (n=83; 78% female, 62 ±14¸ 12±10)
2
RA patients on biologics as monotherapy (n=62; 85% female; 61± 4; 20±11)
3
RA patients on biologics+ MTX and/or other DMARDs (n=92; 78% female; 60±14; 17±12)
4
Spondylarthropathy patients on biologics as monotherapy (n=58; 38% female; 51±10; 17±11 )
5
Spondylarthropathy patients on biologics +MTX (n= 55; 51% female; 52±12; 13±1
6
Spondylarthropathy patients on NSAIDs (n=80; 46% female; 51±13; 15±17)
Results. In total, 97 of 350 patients (28%) treated with methotrexate and/or biologics were vaccinated against
influenza. Number (%)vaccinated in different treatment groups were: 25 (30%) group 1; 23 (37%) group 2; 19
(21%) group3; 14 (24%) group 4; 16 (29%) group 5 and 11 (14%) group 6.
Conclusion. Influenza vaccination coverage among patients with chronic arthritis at our out-patient
rheumatology unit is low. Despite belonging to the recommended target group for vaccination only 28% of
patients with RA and spondylartropathy with active treatment received influenza vaccination. Annual
vaccination against influenza should be encouraged among patients with chronic arthritis.
Background: Bone mineral density (BMD) in the hand, as evaluated by digital X-ray radiogrammetry (DXR)
of the II-IV metacarpal bones, has been suggested to be a good predictor for joint damage in rheumatoid arthritis
(RA).
Objective: To investigate if DXR-BMD loss early in the disease predicts development of joint damage in RA
patients followed for up to 20 years.
Methods: 183 patients (116 women and 67 men) with early RA (mean disease duration 1 year) included 19851989 were followed prospectively at the Department of Rheumatology in Lund. Clinical and functional
measures were assessed at least yearly. Development of joint damage was evaluated according to the Larsen
score on radiographs of hands and feet taken years 0-5, 10, 15 and 20. BMD was evaluated by DXR (Sectra,
Linköping, Sweden) on the digitized hand X-rays also used for scoring radiographic joint damage. Early DXRBMD progression rate (bone loss) per year was calculated from the first 2 available radiograms taken on
average 10 months apart (SD 4.8).
Results: DXR-BMD at baseline was possible to obtain from radiographs from 149 patients and the bone loss for
the first year was calculated for these patients. Mean DXR-BMD loss during the first year was -0.018 (SD
0,025). DXR-BMD was stratification according to median. Patients with marked bone loss, i.e. above the
median for the group, had significantly worse progression of joint damage at all examinations during the 20year period.
Conclusion: Early DXR-BMD progression rate predicted development of joint damage evaluated according to
Larsen already at year one and further onwards up to 20 years in this cohort of early RA patients.
Clinical phenotype and sex predict termination of anti-TNF therapy in Ankylosing
Spondylitis
Adherence to therapy of etanercept and infliximab during first anti-TNF treatment
course in rheumatoid arthritis patients
Lars Erik Kristensen*, Johan Karlsson*, Martin Englund**, Ingemar F Petersson**, Tore
Saxne*, and Pierre Geborek*. * Dept of Rheumatology, Lund University Hospital, Lund
Sweden. **Southern Sweden Musculoskeletal Research Center, Dept of Orthopedics,
Lund University Hospital, Lund, Sweden
Lars Erik Kristensen, Pierre Geborek, and Tore Saxne for the South Swedish Arthritis
Treatment Group
Department of Rheumatology, Lund University Hospital, S-221 85 Lund, Sweden
Objective: TNF blocking agents are effective for treatment of ankylosing spondylitis (AS). However,
information on predictors of favourable treatment outcome is still limited.
We have studied clinical characteristics as possible predictors for premature termination of TNF blocking agents
in biologic naïve AS patients treated in clinical practice.
Material and Methods: Patients in southern Sweden with active AS, starting biologic therapy for the first time
between October 1999 and December 2008 (n=230), were included in a structured clinical follow up over 2
years. Patients with clinical spondylitis had not responded to at least 2 NSAIDs whereas patients who also had
peripheral arthritis (n=113) had also failed at least one conventional DMARD treatment course. Mean age (SD)
at inclusion was 43 (12) years with a disease duration prior to treatment of 16 (12) years. Information on
diagnosis, peripheral arthritis, disease duration, previous and ongoing DMARDs, treatment start and termination
as well as cause of withdrawal were prospectively collected. Cox proportional hazard models were used to
investigate predictors for premature treatment termination. The covariates tested for were sex, clinical
phenotype, age, disease duration, patient global health evaluation (VAS global), and type of TNF blocking
treatment all entered in the same model.
Results: The table shows hazard ratios, 95% confidence intervals, and level of significance for the predictors
studied.
Covariates
Hazard ratio
95% CI
p-value
Male vs. female
0.39
0.22-0.68
<0.01
Peripheral arthritis vs.
0.54
0.31-0.94
0.03
spondylitis only
Age, yr
1.02
0.99-1.05
0.13
Disease duration, yr 0.99
0.96-1.02
0.32
VAS global
1.00
0.99-1.02
0.84
Adalimumab vs.
0.83
0.36-1.88
0.65
infliximab
Etanercept vs.
0.61
0.33-1.14
0.12
infliximab
Conclusion: Significant predictors for premature treatment termination were female sex and isolated axial
spondarthritis. Age, disease duration, patient global health evaluation, and type of anti-TNF therapy did not
predict treatment termination in this study.
Background: The South Swedish Arthritis Treatment Group has followed patients receiving anti-TNF
treatments for the last 6 years. Thus long-term differences in adherence to therapy can be studied.
Objective: To compare the long-term adherence to therapy of etanercept and infliximab in biologic naïve
rheumatoid arthritis patients treated in clinical practice. To study the impact of concomitant methotrexate
(MTX) therapy.
Material and Methods: Patients with active rheumatoid arthritis, not responding to at least 2 DMARDs
including MTX starting biologic therapy for the first time, were included in a structured clinical follow up
protocol. The patients were treated in southern Sweden serving a population of about 1.3 million. Information
on diagnosis, disease duration, previous and ongoing DMARDs, treatment start and termination as well as cause
of withdrawal were prospectively collected during the period March 1999 to December 2004. Levels of
significance were calculated with life-table techniques using log-rank statistics.
Results: 249 patients received etanercept without concomitant MTX whereas 179 patients also received MTX.
The corresponding numbers for infliximab were 197 and 501 respectively. At treatment start mean age was 55
years, disease duration 12 years, and 79% of the patients were female. Etanercept and infliximab treatments
were observed for a maximum of 6 years (68 and 69 months respectively). Data for adherence to therapy as well
as proportion of patients withdrawing from treatment due to adverse events and treatment failure is shown in
table.
Table shows the adherence to therapy for infliximab and etanercept at fixed follow up times.
Remaining on therapy
3 months
6 months
12 months
%
%
%
level of sign
Etanercept
92.7
83.2
77.9
*p<0.001, **p<0.01
Infliximab
83.6
73.0
53.5
**p<0.001
Etanercept + MTX
98.3
92.1
90.4
*p<0.001
Infliximab + MTX
88.8
82.9
69.9
Withdrawal from therapy due to adverse events
%
%
%
Etanercept
5.4
10.2
13.6
*p<0.001, **p<0.01
Infliximab
14.3
22.1
37.7
**p<0.001
Etanercept + MTX
1.1
1.7
1.7
*P<0.001
Infliximab + MTX
8.3
11.9
20.2
*level of significans versus the corresponding infliximab group
**level of significance versus the same main treatment plus concomitant methotrexate
Therapy
24 months
%
36 months
%
72.5
68.7
35.0
27.9
87.6
85.4
57.0
51.8
%
17.0
%
20.5
52.9
57.3
3.6
5.4
29.0
31.6
Conclusion: Infliximab and etanercept both show a significantly higher level of adherence to therapy when
used in combination with methotrexate in biologic naïve rheumatoid arthritis patients. This is mainly because of
significantly fewer withdrawals due to adverse events.
Patients treated with etanercept show a significantly higher level of adherence to therapy when compared to
infliximab. This difference is seen both in patients receiving concomitant methotrexate as well as in those
treated without methotrexate.
Utility-based Outcomes Made Easy: The Number Needed Per QALY Gained
(NNQ). Observational Study of TNF Blockade in Inflammatory Arthritis.
A. Gülfe1, L. Kristensen1, I. F. Petersson2, L. T. H. Jacobsson3, T. Saxne1, P. Geborek1
1
Dept of Clinical Sciences, Section for Rheumatology, Lund University, Lund, 2South
Sweden Musculoskeletal Research Centre, Dept of Orthopedics, University Hospital,
Lund, 3Dept of Clinical Sciences, Section for Rheumatology, Lund University, Malmö,
Sweden
Background: Funding agencies or tax payers incur great costs due to new treatment modalities in arthritis care.
The outcome measures used are not always intuitive for the clinician or easy to understand for the layman.
Objectives: 1. To develop a simple, utility based outcome measure, the NNQ (number needed to gain 1 quality
adjusted life year, QALY) that can assist judging to what extent a therapeutic intervention may be worth while;
2. To apply it in a cohort of patients with established rheumatoid arthritis (RA), psoriatic arthritis (PsA) or
spondarthritis (SpA) treated with TNF blockers in a “real life”, clinical setting.
Methods: Patients: 1st and 2nd anti-TNF treatment courses for RA, PsA and SpA patients having utility data at
baseline and at least once more during 12 months were retrieved from the South Swedish Arthritis Treatment
Group (SSATG) registry of patients receiving biologic drugs. Patients were enrolled 2002-2006.
NNQ: Utility is a measure of health related quality of life (0=death, 1=perfect health) often derived from
preference based, generic instruments, e g EuroQoL-5-dimensions, EQ-5D. Economic models utilize quality
adjusted life years (QALYs); a year spent in perfect health yields 1 QALY, a year in a state with utility 0.5
yields 0.5 QALY, etc. The number needed to gain 1 QALY, NNQ, is the number of patients one has to subject
to an intervention to gain 1 QALY. We obtained mean QALY gain as the mean utility gain from baseline over 1
year. By inverting this value, one gets the NNQ.
Results: There were 1001 eligible 1st anti-TNF courses for RA, 241 for PsA and 255 for SpA. The NNQ for 1st
and 2nd courses are given in Table 1. NNQ was calculated based on mean QALY gain for all courses assuming
1 year duration of therapy (not time corrected – LOCF approach) and on each course contributing QALYs only
for the actual time on treatment (time corrected).
Table. NNQ (mean[95% CI]) for anti-TNF treatment of RA, PsA and SpA.
Not time corrected RA
1st course
2nd course
Time corrected
1st course
2nd course
PsA
4.5 (4.1-5.0)
6.4 (5.3-7.9)
SpA
4.5 (3.8-5.6)
4.2 (3.2-6.2)
4.1 (3.6-4.9)
4.3 (3.2-6.8)
4.7 (4.3-5.2)
6.7 (5.7-8.2)
4.8 (4.0-5.9)
4.7 (3.6-6.9)
4.4 (3.8-5.3)
4.5 (3.3-6.8)
Conclusion: NNQ was easy to calculate and relate to the “real world” clinical situation. Correcting for actual
time on treatment increases NNQ somewhat, as expected, due to lower QALY gain for courses <1 year. EQ-5D
was found to perform well across 3 different diagnoses. In our setting, NNQ in RA was found to be higher in
2nd than in 1st anti-TNF courses, maybe due to selection of treatment resistant patients. By contrast, NNQ was
about the same in 1st and 2nd anti-TNF treatment of PsA and SpA. The latter finding must be interpreted
cautiously because of limited cohort size.
What Aspects Do Outcome Measures Used in Team Rehabilitation Really Measure?
Sofia Hagel¹, Elisabet Lindqvist¹, Ingemar F Petersson², Ann Bremander³. ¹Dept of
Rheumatology, Lund University Hospital, Lund; ²Orthopaedics, Clinical Sciences,
University Hospital, Lund; ³Research and Development Centre, Spenshult Hospital for
Rheumatic Diseases, Halmstad, Sweden
Background: Data on rehabilitation outcome is scarce. We wanted to study the ability of well used and validated outcome measures for patients with
chronic inflammatory arthritis to cover the ICF domains (the WHO International Classification of Functioning), and the agreement and sensitivity to
change among the included measures.
Methods: HRQoL was measured by the NHP, the EQ5D and the SF-36. Physical function was evaluated with the HAQ, aerobic capacity (VO2max),
shoulder functioning test, grip strength, and the SOFI test. The outcome measures were classified according to the ICF and Spearman correlations (rs)
were performed within the same ICF domain and in groups of HRQoL and physical function. Standardized response mean (SRM) was used to
calculate responsiveness.
Analyses were based on results from 216 patients participating in a multidisciplinary daycare rehabilitation program for 18 days, 149 (122 females)
with peripheral arthritis median age 54 years (IQR 18), and 67 (31 females) with spondylarthritides (SpA) median age 44 years (IQR 21). Evaluations
of agreement and sensitivity to change were performed at inclusion, after 18 days and after 12 months.
Results: The ICF domains body function, activity and participation were all covered by SF 36, EQ5D and NHP. All other instruments covered only
one domain, while none covered ICF environmental. EQ5D showed correlations of rs<0.3, with the other HRQoL instruments (baseline and change
values). Correlations between NHP and SF36 subscales measuring similar aspects was the highest for SF36 MH and NHP emotion rs >0.7. Aerobic
capacity had correlations of rs<0.2, at all time points, with all other outcome measures on observed physical function, for all included patients.
Aerobic capacity also had an SRM of 0.8 or higher at all time points for all patients while the SRM for HRQoL instruments was 0.4 or lower.
Conclusion: ICF environmental aspects were not covered by commonly used rehabilitation outcome instruments. For accurate comparison between
studies HRQoL needs to be evaluated with the very same instrument, due to poor agreement between the different outcome measures. Aerobic
capacity, when appropriate, should accompany other measures on the ICF domain body function, since it showed low correlations to all other
outcome measures, indicating that it captures a different aspect, yet with a high SRM. The results of this study emphasis the need of consensus on a
core set of outcome instruments to make comparison among rehabilitation programmes possible.
The Prevalence of Psoriasis and Psoriatic Arthritis in Sweden – a Health Care
Register Study
Sofia Löfvendahl, Elke Theander, Åke Svensson, Martin Englund, Aleksandra
Turkiewicz, Ingemar F Petersson
Purpose: The occurrence of psoriasis and psoriatic arthritis (PsA) leading to health care contacts is not well
described before. The aim of this study is to estimate the prevalence of psoriasis and PsA in Sweden.
Method: In the Skåne Health Care Register (SHCR) (covering 1.2 million people or 1/8 of the Swedish pop.)
full coverage on individual data on age, sex, health care provider, date of visit, ICD-10 diagnosis codes are
continuously registered for both in- and outpatient care. We identified all individuals (no age restriction) with at
least one clinic visit to a physician (both primary care and specialized care) between Jan. 1, 2001 and Dec. 31,
2007 having received any of the following psoriasis diagnoses (ICD-10 codes): psoriasis vulgaris (L40.0),
generalized pustular psoriasis (L40.1), guttate psoriasis (L40.4), arthropathic psoriasis (L40.5), other psoriasis
(L40.8) and psoriasis unspecified (L40.9). By cross-referencing with personal identification numbers from the
Population Register (total pop. in southern Sweden Dec. 31, 2007= 1 199 357) those individuals identified in
SHCR as deceased or relocated out of the county by Dec. 31, 2007 were excluded. For the individuals
diagnosed with psoriasis between Jan. 1, 2001 and Dec. 31, 2007 we identified the number of patients with any
of the following PsA diagnoses (ICD-10 codes): distal interphalangeal psoriatic arthropathy (M07.0), arthritis
mutilans (M07.1), psoriatic spondylitis (L40.2), other psoriatic arthropaties (M07.3) and juvenile arthritis in
psoriasis (M09.0). Those diagnosed using ICD-10 diagnosis code L40.5 or a combination of a psoriasis and a
PsA diagnosis code were defined as having PsA. Prevalence estimate by Dec. 31, 2007 was calculated for
psoriasis and PsA. The prevalence estimates were adjusted for the uncertainty generated by the loss of patients
only seen by private practitioners for their psoriasis or PsA (appr. 15%).
Results: 13716 individuals had sought health care, been diagnosed with psoriasis and were still alive and
residents in the region by the end of 2007. The prevalence of diagnosed psoriasis in residents of southern
Sweden (all ages) was 1.35% (95% CI 1.32, 1.37). Out of the individuals diagnosed with psoriasis, 2491(18.2%)
were identified as having PsA. This indicates a prevalence of diagnosed PsA in residents of southern Sweden of
0.24% (95% CI 0.23, 0.25) by the end of 2007. Among those diagnosed with PsA 1163 (46.7%) were diagnosed
using ICD-10 diagnosis code L40.5 and 1328 (53.3%) were diagnosed with a combination of a psoriasis and a
PsA diagnosis code.
Conclusion: Using register data of true health care consumption gives more relevant prevalence estimates of
psoriasis and PsA. We found that at least one fifth of all individuals diagnosed with psoriasis also had health
care contacts for diagnosed PsA.