Mortality and causes of death across the systemic connective tissue diseases and the primary systemic vasculitides.

Objectives: Studies assessing relative mortality risks across the spectrum of systemic inflammatory rheumatic diseases are largely missing. In this study, we wanted to estimate standard mortality ratios (SMRs) and causes of death in an ethnically homogeneous cohort covering all major CTDs and primary systemic vasculitides (PSVs). Methods: We prospectively followed all incident CTD and PSV cases included in the Norwegian CTD and vasculitis registry (NOSVAR) between 1999 and 2015. Fifteen controls for each patient matched for sex and age were randomly drawn from the Norwegian National Population Registry. Causes of death were obtained from the National Cause of Death Register, death certificates and hospital charts. Results: The cohort included 2140 patients (1534 with CTD, 606 with PSV). During a mean follow-up time of 9 years, 279 of the patients (13%) died, compared with 2864 of 32 086 (9%) controls (P < 0.001). Ten years after diagnosis, the lowest survival was 60% in dcSSc, 73% in anti-synthetase syndrome (ASS) and 75% in lcSSc. In the CTD group, the highest SMRs were observed in dcSSc (SMR 5.8) and ASS (SMR 4.1). In the PSV group, Takayasu arteritis (SMR 2.5) and ANCA-associated vasculitis (SMR 1.5) had the highest SMRs. Major causes of death were cardiovascular disease (CTD 27%, PSV 28%), neoplasms (CTD 25%, PSV 27%), chronic respiratory disease (CTD 20%, PSV10%) and infections (CTD 9%, PSV 16%). Conclusion: We observed premature deaths across the spectrum of CTDs and PSVs, with highest SMRs in dcSSc and ASS. The overall mortality was highest in the CTD group.

[Medical prophylaxis and treatment of steroid induced osteoporosis]. / Medikamentell profylakse og behandling av steroidindusert osteoporose.

BACKGROUND: Glucocorticoid steroids are widely used as antiinflammatory and immunosuppressive medications and are well known to induce osteoporosis. MATERIAL AND METHODS: Randomised clinical trials and Cochrane reports on the use of calcium, vitamin D, bisphosphonates and hormones were reviewed and the results summarised. Additionally, national and some international recommendations were reviewed in order to propose recommendations for prophylaxis and treatment. The literature was identified by Medline searches. RESULTS AND INTERPRETATION: Calcium and vitamin D prevent bone loss in low-to-medium-dose glucocorticoid steroid therapy. Bisphosphonates maintain or modestly increase lumbar and hip bone mass. The fracture risk was not significantly reduced in the spine and the hip. The clinical randomised trials and Cochrane reports conclude that bisphosphonates as well as calcium and vitamin D taken together are effective and the drugs of choice in prevention and treatment.

[Pulmonary veno-occlusive disease in a patient with scleroderma and the CREST syndrome]. / Pulmonal venookklusiv sykdom ved sklerodermi og CREST-syndrom.

BACKGROUND: Pulmonary veno-occlusive disease is a rare and poorly understood condition that affects the postcapillary pulmonary vasculature, posing diagnostic problems and treatment dilemmas. MATERIALS AND METHODS: We present a patient with veno-occlusive disease and give a short review on the disease. RESULTS: The patient was a 54-year-old female with a history of the CREST variant of scleroderma. Admitted with dyspnoea, she was treated with epoprostenol in addition to oxygen, diuretics and warfarin. Epoprostenol improved her condition initially; her symptoms grew worse during further medical escalation. With an attempt to stop epoprostenol, however, she became even more dyspnoeic and tolerated best an intermediate dose. She died after three months of treatment with signs of progressive right heart failure. INTERPRETATION: Veno-occlusive disease may be difficult to diagnose and treat. Clinical signs of pulmonary hypertension without evidence of left ventricular failure may give rise to suspicion of the disease, and high-resolution CT of the lungs with relatively specific findings can be helpful. The prognosis is poor and lung transplantation is the only form of effective treatment. Vasodilators as a bridge to transplantation must be used with caution because of the risk of intolerance and development of pulmonary oedema.

[Combination therapy in rheumatoid arthritis]. / Kombinasjonsterapi ved revmatoid artritt.

BACKGROUND: During the last decade patients with active rheumatoid arthritis have been offered early and aggressive drug therapy in order to decrease the damaging effect of inflammation on cartilage and bone. Combination of two or more disease-modifying antirheumatic drugs has been used more frequently to achieve better efficacy than with monotherapy without increasing drug side effects. MATERIALS AND METHODS: We have studied available rheumatological literature to find the best documented drug combinations. RESULTS: The combination of methotrexate, sulfasalazine and hydroxychloroquine seems to be a well documented alternative, and so is the combination of methotrexate and cyclosporine. Modern biologic drugs like etanercept, infliximab and anakinra work best in combination with methotrexate. INTERPRETATION: The combination of two or more disease-modifying antirheumatic drugs can be a good alternative to monotherapy in the treatment of patients with active rheumatoid arthritis, either when monotherapy has failed or unacceptable side effects have occurred, or as a first choice in patients who need very early and aggressive therapy. Combination therapy should only be initiated by a rheumatologist, after informed consent. A safe clinical and chemical monitoring must be organized in cooperation with the patient and the primary physician.

Severe deficiency of 25-hydroxyvitamin D3 (25-OH-D3) is associated with high disease activity of rheumatoid arthritis.

This study aims to measure the serum level of 25-hydroxyvitamin D3 (25-OH-D3) in 302 patients with rheumatoid arthritis (RA), studying the association to disease activity. Three hundred two RA patients underwent clinical examination and serological analysis. 25-Hydroxyvitamin D3 was determined by high-performance liquid chromatography-tandem mass spectrometry. Vitamin D3 deficiency defined as serum levels of 25-hydroxyvitamin D3 below 50 nmol/l was detected in 101 RA patients (33.4 %). There was no significant correlation between the serum level of 25-hydroxyvitamin D3 and Disease Activity Score 28 (DAS28) (3w) score. In a subpopulation of RA patients with very low serum level of 25-OH-D3 (≤15 nmol/l) (n = 15), there were significant differences compared to patients with normal 25-OH-D3 (n = 200): higher percentage of patients with positive rheumatoid factor (100.0 versus 77.5 %; p = 0.05), higher CRP (28.7 versus 14.8 mg/l; p = 0.001), higher number of patients treated with at least three disease-modifying antirheumatic drugs (DMARDs) (40.0 versus 14.5 %; p = 0.02), higher number of patients with high disease activity DAS28 score of ≥5.1 (20.0 versus 4.5 %; p = 0.01), lower age (54.5 versus 64.0 years; p = 0.003) and shorter disease duration (5.1 versus 10.3 years; p = 0.06). Deficiency of 25-hydroxyvitamin D3 was detected in 33.4 % of the RA patients. A subpopulation of patients with severe deficiency of vitamin D3 serum level of ≤15 nmol/l was characterised by all being positive for rheumatoid factor, high percentage of patients with very high disease activity and high percentage of patients treated with at least three DMARDs.

A study of the prevalence of sicca symptoms and secondary Sjögren's syndrome in patients with rheumatoid arthritis, and its association to disease activity and treatment profile.

AIM: To examine the prevalence of sicca symptoms and secondary Sjögren's syndrome (sSS) in rheumatoid arthritis (RA) patients, and the impact of sSS on disease activity and treatment profile in RA patients. METHODS: Three hundred and seven RA patients responding positive to at least one of the questions in a questionnaire about sicca symptoms, were examined by Schirmer I test for tear production, and unstimulated whole saliva collection (USWC). Secondary Sjögren's syndrome was defined by at least one subjective sicca symptom, in addition to a positive Schirmer I test and positive USWC. RESULTS: Among the 307 RA patients, 86 (28%) responded positive to at least one question about sicca symptoms, and 11 patients were positive for both Schirmer I and USWC tests, giving a minimum prevalence of sSS at 3.6%. There were no differences in RA patients with and without sSS regarding age, sex, disease duration, disease activity score (DAS-28) and seropositivity for anti-cyclic citrullinated protein. RA patients with sSS had a tendency for higher numbers of tender and swollen joints and pain. None of the RA patients treated with tumor necrosis factor (TNF) inhibitors had sSS, compared to 22% of the rest of the RA population studied. The treatment of the RA patients with and without sSS was not different. CONCLUSION: Among the 307 RA patients, 28% had at least one sicca symptom. The estimated minimum of prevalence of sSS in 307 RA patients was 3.6%. Secondary Sjögren's syndrome was not found in RA patients treated with biologics such as TNF blockers.

Prevalence of IgA class antibodies to cyclic citrullinated peptide in patients with inflammatory bowel disease (IBD).

Determine the prevalence of anti-CCP isotype IgA and its relation to peripheral arthritis in patients with inflammatory bowel disease (IBD). In a population-based cohort of 654 patients with a definitive diagnosis of IBD, 521 patients were clinically examined by a rheumatologist 6 years after IBD diagnosis Blood serum samples of 416 of these patients were available and analyzed. Antibodies against cyclic citrullinated peptides anti-CCP IgA were determined in the serum samples by an immunofluoresence technique ELiA TM. Among the 416 IBD patients, 5 had a positive IgA class anti-CCP, giving a prevalence of 1.2%. Only four anti-CCP IgA-negative patients had a positive rheumatoid factor IgM, compared to two out of five anti-CCP IgA-positive IBD patients (10.2% versus 40.0%; p = 0.002). There were four patients with rheumatoid arthritis, two in each patient population (0.5% versus 40.0%; p = 0.0007). Four of the five anti-CCP IgA-positive IBD patients had arthritis, two with rheumatoid arthritis, and two with other arthritis. In this first study on the prevalence of IgA anti-CCP antibodies in IBD patients, we demonstrate a low prevalence, but these antibodies are associated with arthritis and positive IgM rheumatoid factor in IBD patients.

Prevalence of IgA class antibodies to cyclic citrullinated peptide (anti-CCP) in patients with primary Sjögren's syndrome, and its association to clinical manifestations.

This study aims to determine the prevalence and clinical significance of anti-CCP isotype IgA in a population of patients with primary Sjögren's syndrome (pSS). Sixty-two patients diagnosed according to the USA-European classification criteria for pSS were examined two to four times during a 60.4-month follow-up, and clinical and laboratory data were registered prospectively. Antibodies against cyclic citrullinated peptides (anti-CCP) isotype IgG and IgA were determined in serum samples by an immunofluorescence ELiA™ system. Healthy individuals and patients with rheumatoid arthritis (RA) with matching sex and age served as controls. The serum level of anti-CCP IgA was higher in pSS patients than healthy individuals (2.37 versus 1.37 EU/ml; p < 0.0001), and lower than matching patients with RA (2.37 versus 6.51 EU/ml; p < 0.0001). Using a cutoff for anti-CCP IgA at 4.12 EU/ml, 8.1 % pSS patients had a positive test compared to 26.7% of patients with RA. Positive test for anti-CCP IgG was demonstrated in 4.8% pSS patients. There were no significant differences between demographic and serological variables in pSS patients with positive versus negative anti-CCP IgA. There was significantly more pSS patients with cutaneous vasculitis in the anti-CCP IgA-positive population, however (40.0% versus 3.5%; p = 0.030), and there was a nonsignificant trend of lower unstimulated whole saliva collection (USWC) in the anti-CCP IgA-positive patients. There were no correlations between arthritis and anti-CCP IgG and IgA. This is the first study on the prevalence of anti-CCP isotype IgA in patients with pSS, demonstrating that anti-CCP isotype IgA is moderately increased in patients with pSS but lower than the prevalence in patients with RA. The presence of IgA and IgG anti-CCP isotypes were not associated with arthritis or other clinical manifestations in pSS patients. We demonstrated an association of anti-CCP IgA to cutaneous vasculitis.

Pregnancy outcome in patients with primary Sjögren's syndrome. a case-control study.

OBJECTIVE: To study the outcome of pregnancy in patients with primary Sjögren's syndrome (pSS). METHODS: A questionnaire covering demographic data and the outcome of pregnancies was answered by 58 patients with pSS and 157 controls. For 36 patients and 93 controls, we analyzed detailed data about pregnancy, birth, and status of the newborn from the Medical Birth Registry of Norway (MFR) for birth order one, 2, and 3. Thirty-two of 36 patients registered in MFR were diagnosed with pSS after the last birth. RESULTS: Pregnancy outcomes were not different in patients compared to controls. Two patients (3.4%) reported giving birth to a child with congenital heart block. CONCLUSION: PSS had no impact on pregnancy outcome before disease onset. The most important condition associated with pSS in anti-SSA positive mothers was congenital heart block in the offspring.

Clinical and immunological factors associated with low lacrimal and salivary flow rate in patients with primary Sjögren's syndrome.

OBJECTIVE: To study which clinical and immunological factors may be associated with low salivary and lacrimal flow in patients with primary Sjögren's syndrome (SS). Are the lacrimal and salivary flows influenced by age of the patient, age at diagnosis, disease duration, or findings in the biopsies of the minor salivary glands, or are immunological factors of importance for reduced flow rates? METHODS: In total 72 patients (mean age 57 yrs and disease duration 13.5 yrs) with primary SS diagnosed according to the European classification criteria were evaluated objectively by serological testing and by measures of exocrine gland function, such as unstimulated whole saliva collection (UWSC) and by Schirmer I test. RESULTS: Salivary flow (UWSC) in 72 patients with primary SS correlated to the presence of antinuclear antibodies (ANA) (r = -0.32, p = 0.006) and to anti-SSA/SSB (r = -0.31, p = 0.010). No such correlation was seen for the lacrimal flow, and there was no mutual correlation between lacrimal and salivary flow. UWSC was significantly lower in patients with anti-SSA versus those without anti-SSA (1.63 ml vs 2.63 ml; p < 0.007), while such a significant difference was not observed in the presence versus absence of anti-SSB. The salivary and lacrimal flow was not significantly affected by age of the patient, and did not correlate to age at diagnosis, sex, disease duration, rheumatoid factor finding, or findings in minor salivary gland biopsies. CONCLUSION: Salivary flow in patients with primary SS was negatively correlated with immunological factors such as ANA and anti-SSA/SSB, in contrast to low lacrimal flow, where no such correlation was seen. There was no association of lacrimal and salivary flow with age of patient, age at diagnosis, disease duration, and findings in minor salivary gland biopsies. The results indicate that reduced salivary flow is closely associated with immunological factors, and is not associated with the age of the patient or infiltration of lymphocytes in salivary glands.

Leukocyte protein calprotectin and outcome in rheumatoid arthritis. A longitudinal study.

OBJECTIVE: To determine if calprotectin is predictive for outcome in patients with rheumatoid arthritis (RA). METHODS: Fifty six RA in-patients with variable disease duration were prospectively followed for five years. Clinical and laboratory data were collected to assess disease activity. Health Assessment Questionnaire (HAQ) and radiographic scores (of hands and wrists) as described by Larsen were used as outcome measures. Plasma calprotectin levels were determined with ELISA technique. RESULTS: Significant correlations (r) were found cross-sectionally at follow-up between calprotectin concentration and other known parameters of disease activity and severity: CRP (r = 0.67). investigator's global assessment of disease activity (r = 0.57). Waaler titre (r = 0.50). HAQ score (r = 0.48) and number of swollen joints (r = 0.48). Calprotectin at baseline was not identified as an independent predictor for HAQ or radiographic progression in the multivariate analysis. CONCLUSION: The results confirm calprotectin as a good measure of disease activity and joint inflammation in RA. However, the level of calprotectin at baseline was not predictive for radiographic damage or functional impairment five years later.

Femoral and whole-body bone mineral density in middle-aged and older Norwegian men and women: suitability of the reference values.

The aim of this study was to compare bone mineral density (BMD) in a population-based sample of middle-aged and older Norwegians, with reference values provided by the manufacturer of the densitometer (Lunar) in order to evaluate whether these reference values are suitable for Norwegians. Additional aims were to estimate the prevalence of osteoporosis. Bone mineral density of the hip and total body was measured by dual-energy X-ray absorptiometry in 2303 men and 3105 women 47-50 and 71-75 years old, respectively, in western Norway, as part of the Hordaland Health Study (HUSK). Of these, 3403 white individuals were free of medications or diseases known to influence bone metabolism (reference group). Compared with the Lunar reference population, men and older women had a slightly but significantly lower BMD of trochanter and total femur and middle aged women had significantly higher total body BMD. Except for the higher mean BMD of total body among middle-aged women and the uniformly lower BMD values of Ward's triangle, the deviations from the reference values of the manufacturer were less than 4%. Approximately 2.6% of middle-aged men vs 0.9% of middle-aged women were classified as osteoporotic on the basis of BMD of femoral neck. While the BMD values for femoral neck in this healthy Norwegian population are similar to the reference population of Lunar, the values of trochanter and total femur are lower in all groups except middle-aged women; however, the discrepancies are not of sufficient magnitude to warrant rejection of this commonly used database among Norwegians. Use of the young adult means from the Lunar reference database classified a higher proportion of middle-aged men than women as osteoporotic and osteopenic.