The Effect of n-3 Polyunsaturated Fatty Acids in Patients With Psoriatic Arthritis
Condition: Psoriatic Arthritis
MeSH terms: Arthritis; Arthritis, Psoriatic
Study type: Interventional

Summary: 
      Background: There is evidence for a high cardiovascular risk in rheumatic and inflammatory
      diseases . Recent evidence suggest that psoriatic arthritis is also associated with an
      increased cardiovascular risk with accelerated atherosclerosis and increased cardiovascular
      risk. However, data regarding cardiovascular comorbidity and cardiovascular risk factors in
      patients with psoriatic arthritis are limited.

      Objective: The aim of this study is to investigate the effect of daily supplementation with 3
      g n-3 polyunsaturated fatty acids on risk markers for cardiovascular disease and inflammation
      in patients with psoriatic arthritis.

      Design: Randomized double-blind, placebo-controlled, multicenter trial with n-3
      polyunsaturated fatty acids in patient with psoriatic arthritis.

      Setting: Departments of Rheumatology, Nephrology and Cardiology at Aalborg University
      Hospital and Vendsyssel Hospital in Region Northern Denmark

      Participants: 156 men and women aged > 18 years with psoriatic arthritis classified by the
      CASPAR criteria will be included. Exclusion criteria: cardiac arrhythmias, conduction
      disturbances, treatment with biological drugs or oral corticosteroids. Inclusion time: spring
      2013 to spring 2015.

      Method: The following data will be collected for each participant: Interview including
      dietary records, assessment of tender and swollen joints, enthesitis, dactylitis, patient
      global assessment of disease activity (Visual Analogue Scale ), global assessment of pain
      (Visual Analogue Scale), psoriatic skin involvement by Psoriatic Area and Severity Index
      (PASI), laboratory parameters of disease activity and risk markers of cardiovascular disease.

      For detection of early cardiovascular risk markers Heart Rate Variability (HRV) and Pulse
      Wave Velocity (PWV) will be performed.

      Main outcome measures: The primary endpoint will be HRV and secondary endpoints will be PWV,
      inflammatory activity and use of analgesics.

      The trial is approved by The local Ethics Committee, registration number N20120076
    

Detailed description: 
      Method Study design: The study was designed as a randomized, double-blind,
      placebo-controlled, multicenter trial. The patients were randomly assigned in blocks of five
      by a computer-generated block sequence. For 24 weeks patients were assigned to daily intake
      of 6 capsules containing either 3 g of n-3 PUFA (50% EPA and 50% DHA) from fish oil capsules
      or 3 g of olive oil (approximately 80% of oleic acid and 20% linoleic acid). All the
      investigators, patients and research staff were blinded to the supplementation codes.
      Patients were asked to maintain their usual diet during the whole study. The study was
      conducted in accordance with the Declaration of Helsinki and Good clinical practice (GCP).

      Subjects: Patients with PsA defined by Classification criteria for psoriatic arthritis
      (CASPAR) (25) were enrolled from the Departments of Rheumatology, Aalborg University Hospital
      and Department of Rheumatology, Vendsyssel Hospital, in Denmark. The inclusion criteria were
      PsA in adult above 18 years of age with any disease activity while exclusion criteria were
      documented cardiac arrhythmias, treatment with biological drugs or treatment with oral
      corticosteroids.

      Compliance was assessed by counting capsules during the last visit. Patients were defined as
      non-compliant if >150 capsules were returned and those were not included in the per-protocol
      analysis.

      All participants gave their written informed consent and the regional ethics committee of
      Northern Region Denmark, approved the study.

      Clinical assessment: Patients were assessed at baseline, after 12 weeks of supplement and
      after 24 weeks. At baseline, duration of disease, medical history, smoking habits and diet
      were obtained Medical history of diabetes mellitus, hypertension and dyslipidemia were
      assessed and was defined as present if the patient received dietary or medical therapy for
      the condition. A food questionnaire was used to assess patients' fish consumption at lunch
      and dinner. A score for fish intake was given according to the following: never eat fish = 1;
      eat fish once a month =2; eat fish two to three times a month = 3; eat fish once a week = 4;
      eat fish two to three times a week = 5; and eat fish at least once daily = 6.

      At each visit conventional cardiovascular risk factors such as smoking habits, blood
      pressure, body mass index (BMI) and waist to hip ratio (WHR) were assessed in all patients.
      Additionally, a clinical evaluation was performed, consisting of 68 tender joint count, 66
      swollen joint count, disease activity score (DAS) and psoriatic skin area involvement (PASI).

      Blood samples: Blood samples were taken non-fasting in the morning for assessment of fatty
      acid composition of granulocytes and routine laboratory evaluation. Granulocytes were
      isolated from whole blood, and lipids were extracted and fatty acids esterified as previously
      reported (26). The fatty acid composition in granulocytes were determined by gas
      chromatography with a Chrompack CP-9002 gas chromatograph (Varian, Middelberg, The
      Netherlands) and expressed as weight percent (wt. %) of total fatty acids.

      HRV: Five min HRV recordings were obtained with SphygmoCor Technology (SphygmoCor, Software
      version 8.2; AtCor Medical, Sydney, NSW, Australia).

      HRV was recorded in each patient according to current recommendations (27). The measurements
      were obtained in the morning hours after resting for 15 min in a room with a constant
      temperature of 20°C. Patients were instructed not to smoke and avoid alcohol and
      caffeine-containing beverages within 12 h prior to investigation. A trained technician
      blinded to the type of supplement performed these analyses. The patients were placed in a
      supine position (resting) for 10 min, breathing spontaneously without talking. HRV were
      analysed in the time-domain and the following variables were used:

        -  RR: mean of all normal RR intervals during the 5 min recording

        -  SDNN: standard deviation of all normal RR intervals in the 5 min recording

        -  SDNNindex: mean of the standard deviation of all the normal RR intervals.

        -  pNN50: percentage of successive RR-interval differences > 50 ms

        -  RMSSD: square root of the mean of the sum of the squares of differences between adjacent
           intervals

      PWV: PWV and pulse wave analysis were performed non-invasively with the Sphygmocor system
      (AtCor Medical, Sydney, NSW, Australia), as described previously (28) and according to
      international recommendations (29). All measurements were made in duplicate by a single
      trained operator and the mean of the two values was used in the analysis.

      Carotid-radial and carotid-femoral PVW was measured using arterial tonometry. All
      measurements were performed on the right side extremities. The surface distance was measured
      with a tape measure as a straight line from the suprasternal notch to the carotid location
      (proximal pulse) and subtracted the distance from the suprasternal notch to the radial or
      femoral location (distal pulse) (30,31). The pressure wave transit time was determined as the
      time between the R-wave of the ECG and the proximal pulse subtracted from the time between
      the R-wave of the ECG and the distal pulse. PWV was subsequently calculated by dividing the
      surface distance by the pressure wave transit time.

      The central BP was estimated using the SphygmoCor® device. After 10 min of rest in the supine
      position, brachial BP was measured three times at 2-min intervals on the left arm with the
      automatic Microlife® device, and the last measurement was taken as representative of brachial
      artery BP. Hereafter, radial artery pressure waveforms of the right arm were sampled. Using
      the validated generalized transfer function, central BP was estimated using brachial systolic
      and diastolic BP (32,33). Aortic augmentation index (AIx) was standardized to a heart rate of
      75 beat per minute to minimize the effect of the heart rate. Only measurements with T1 (the
      time to the initial upstroke of the pressure wave) >80 and <150 ms and augmentation index
      (AI, the difference between the first and second peak of the arterial waveform as percentage
      of the pulse pressure) <50% and operator index (an arbitrary number between 1 and 100
      describing the quality of the derived pulse wave) >80 were accepted according to
      recommendations (AtCor Medical® website).

      Statistical Analysis All statistical analyses were performed using STATA version13 (StataCorp
      LP, TX, US) We hypothesized that intervention with n-3 PUFA would increase the HRV parameter
      RR by 0.5 of a standard deviation (SD).

      To achieve this at p<0.05 and 1-β = 0.80 we needed a sample size with 63 subjects in each
      group.

      The difference in the continuous outcomes between baseline and 24 weeks after randomization
      was compared between the two treatment groups in a one-sided analysis of variance (ANOVA).
      Equality of variances between the treatment groups was assessed using Bartlett's test. Due to
      the potential for confounding after the random treatment assignment an analysis of covariance
      (ANCOVA) was performed. Prior to this analysis a check for collinearity between the
      covariates was performed and the model was modified accordingly. In this model equality of
      variances was assessed using Levene's test.

      The total number of parameters in the models was restricted to one tenth of the number of
      study participants or number of each category when specifying the models.

      All analyses were performed both as intention to treat (none of the patients are excluded and
      the patients are analyzed according to the randomization scheme) and per-protocol (patients
      who complete the entire clinical trial according to the protocol) analyses. The analyses were
      controlled for age, sex, smoking status, presence and absence of diabetes mellitus,
      hypertension and hypercholesterolemia, the use of nonsteroidal anti-inflammatory drugs
      (NSAID) and disease activity scores.

      Differences were considered significant with a p-value of <0.05 (two-tailed).
    

Intervention name(s): n-3PUFA; olive oil
Intervention type(s): Dietary Supplement; Dietary Supplement
Other intervention name(s): n-3 polyunsaturated fattyacids from fishoil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention