Fish oils in RA: Should We Start Prescribing?

My appreciation of fish oils (FO) has been limited to its use in treating dyslipidemia. While effective in improving hypertriglyceridemia, recent evidence suggests that it does not significantly impact on actual CV outcomes. It was interesting to discover that it may have a role in treating rheumatoid arthritis (RA).

The omega-3-fatty acids – eicosapentaenoic acid (EPA) and decosahexaenoic acid (DHA) – can suppress formation of the pro-inflammatory eicosanoids PGE2 and LTB4.  This had prompted initial studies on the possible role of fish oil supplements in the treatment of RA. In fact, a meta-analysis of RCTs (Goldberg, 2007)1 reported benefits for patient-assessed pain, duration of morning stiffness, joint counts and NSAID consumption among RA patients treated with 2.7g/day of EPA+DHA after a delay of 2-3 months.

However, the meta was criticized for two things that made it difficult to interpret the impact of FO in RA: (1) included patient had established disease averaging 10.2+5.2 years in all studies; and (2) DMARDs were not used in the “recommended” manner – in fact, it was kept constant throughout the study and changes in DMARD dose was used as a withdrawal criteria. Contemporary RA management aims to achieve clinical remission – and if this is not possible, low disease activity (LDA). Guidelines recommend dose adjustments in DMARDs using a “treat-to-target” approach until remission or LDA is reached.

A recent RCT2 attempted to re-explore the role of FO in contemporary RA management. Patients included in the trial were DMARD-naïve with early RA (<12 months duration) and active disease (SJC/TJC>3 and ESR>28mm/hr or CRP>10mg/dl).  The intervention to be studied was FO given at 5.5g/day (intervention) or at 0.4g/day (control). Patients were randomized in a double blind manner to intervention and control in a 2:1 ratio.  Analyses were done following an intention to treat principle.

Patients were to be started on DMARD triple therapy (MTX 10mg/week, SSZ 500mg OD and HCQ 200mg BID) on randomization which was to be titrated using a “treat-to-target” approach. Criteria for up-titrating treatment were

  • swollen joint count>2 and at least the ESR or CRP was elevated above the upper limit for normal
  • if only one of the above criteria was met, up-titration was to be done if morning stiffness >30mins, fatigue >30mm on a 100mm VAS, pain >30mm on a 100mm VAS or tender joint count>2

The protocol for up-titration were as follows:

  • SSZ increased to 1g BID after 4 weeks then to 1.5g BID
  • MTX which may be increased up to 25mg/week
  • If still active, LEF was to be added at 10mg/day later titrated to 20mg/day if patient tolerates it

NSAIDs and oral steroids were actively discouraged but parenteral steroids may be used if warranted.  Initiation of Leflunomide was considered failure of triple DMARD therapy and used as the primary outcome measure of the study.

After 1 year, 10.5% in the FO group vs 32.1% in the control group failed triple DMARD therapy (HR 0.24; 95% CI 0.10-0.54 adjusted for smoking history, shared epitopes and presence of anti-CCP antibodies). The time to first achieving ACR remission in the the first year of treatment was lower in the FO group compared to controls (HR 2.09; 95% CI 1.02-4.30 adjusted). Although the time to achieving a Good EULAR response was decreased in the FO group, this was not statistically significant (HR 1.41; 95% CI 0.89-2.21 adjusted).

Other outcomes studied did not show a significant difference between groups – mHAQ scores, GC use and MTX dose.

Although use was actively discouraged, 34% and 38% of patients in the control and FO groups, respectively, were taking NSAIDs at baseline (p=0.72). After 12 weeks into the study, 44% and 72% of patients in the control and FO groups, respectively, ceased using NSAIDs (p=0.07).

A point of debate would be compliance to the FO regimen (which we all were expecting to be 100%).  Patients in the FO group were less compliant compared to the control group (FO was given as a liquid preparation) – resulting in average daily intake of FO of 3.7g and 0.36g in the two groups.

There was a similar proportion of patients who reported having an adverse event (AE) and serious AE during the study. However, more patients in the FO group had an SAE (3.8% vs 11.6%, p=0.13). Interestingly, 7/20 SAEs in the FO group were CV in nature (MI, ischemia, arrhythmia and TIA) vs none in control group.  However, as reported, this all occurred in the same patient throughout the study.

How would this study potentially change RA management? Fish oils may be added to treatment to reduce the chances of DMARD failure and increase the rates of ACR remission. However, this could only be achieved if a treat to target approach is followed in administering DMARDs. Fish oils can complement therapy and should not to be used as an alternative for DMARD treatment.

References:

  1. Goldberg RJ, Katz J. A meta-analysis of the analgesic effect of omega-3-polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 2007; 129: 210-23.
  2. Proudman SM, James MJ, Spargo LD, et al. Fish oils in recent onset rheumatoid arthritis: a randomized double blind controlled trial with algorithm based drug use. Ann Rheum Dis published online first 30 Sept 2013 (doi: 10.1136/annrheumdis-2013-204145).
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