The impact of curcumin supplementation on systemic lupus erythematosus and lupus nephritis: A systematic review.

OBJECTIVE: Curcumin is the active ingredient in the curry spice turmeric. It has anti-inflammatory properties due to the inhibition of transcription factors and inflammatory mediators such as nuclear factor-κß (NF-κß), cyclooxygenase-2 (COX2), lipoxygenase (LOX), tumor necrosis factoralpha (TNF-alpha), and interleukin-1 (IL-1) and 6 (IL-6). This review examines the literature regarding the efficacy of curcumin on systemic lupus erythematosus disease activity. METHODS: A search was conducted following guidelines in the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) using the PubMed, Google Scholar, Scopus, and MEDLINE electronic databases to retrieve relevant studies assessing the impact of curcumin supplementation on SLE. RESULTS: The initial search yielded three double-blind, placebo-controlled, randomized clinical trials, three human in vitro studies, and seven mouse-model studies. In human trials, curcumin decreased 24-h and spot proteinuria, but the trials were small, ranging from 14 to 39 patients, with varied curcumin doses and different study durations ranging from 4 to 12 weeks. There was no change in C3, dsDNA, or the Systemic Lupus Erythematosus Disease Activity (SLEDAI) scores even in the longer trials. The mouse-model trials yielded more data. NF-κß activation was suppressed along with inducible nitric oxide synthase (NOS) species expression when 1 mg/kg/day of curcumin was administered for 14 weeks, leading to significant decreases in dsDNA, proteinuria, renal inflammation, and IgG subclasses. Another study suggested that curcumin reduced B cell-activating factor (BAFF) when used for up to 8 weeks at 50 mg/kg/day. A reduction in pro-inflammatory Th1 and Th17 percentages, IL-6 and anti-nuclear antibody (ANA) levels were reported. The doses used in the murine models were much higher than those used in human trials, with 12.5 mg-200 mg/kg/day used for over 16 weeks; highlighting that the optimal time for an immunological effect to be observed may require 12-16 weeks of curcumin use. CONCLUSION: Despite the wide use of curcumin in everyday life, its molecular and anti-inflammatory use has only been partially explored. Current data show a potential benefit on disease activity. Still, no uniform dose can be advised because long-duration, large-scale randomized trials using defined dosing are needed in different subsets of SLE, including lupus nephritis patients.

The effect of Omega-3 fatty acid supplementation in systemic lupus erythematosus patients: A systematic review.

OBJECTIVE: Many rheumatologists are inundated with questions about what "natural remedies" and "anti-autoimmune diets" exist for decreasing Systemic Lupus Erythematosus (SLE) disease activity. Over the last three decades, there has been an abundance of data from several different trials about omega-3 fatty acids sourced from fish oil, but the findings have been contradictory. This review seeks to present this data so that evidence-based recommendations can be given to patients, supporting the use of an adjuvant regimen with their present immunosuppression. METHODS: A literature search was conducted using the PubMed, Google Scholar, MEDLINE, and Scopus electronic databases to retrieve relevant articles for this review. Trials conducted on human subjects with SLE with full publications in English were included from 1 January 1980 to 1 April 2021. The impact of fish oil-derived omega-3 fatty acid supplementation on specific clinical features, the innate and adaptive immune response, biomarkers, and disease activity measures were assessed. The initial search yielded 7519 articles, but only 13 met our criteria and were eligible for this review. RESULTS: Data from thirteen articles were assessed. Ten trials assessed disease activity as an outcome, with eight trials demonstrating an improvement in patients in the omega-3 fatty acid group as assessed by a validated clinical tool or individual patient criteria. There was a significant improvement in Systemic Lupus Activity Measure-Revised (SLAM-R) scores at week 12 (p = .009) and week 24 (p < .001). Additionally, a reduction of urinary 8-isoprostane, a non-invasive marker of disease activity, was observed. There was no treatment benefit seen with respect to renal parameters such as serum creatinine or 24-hour urine protein; or systemic parameters such as C3, C4, or anti-double stranded DNA (anti-dsDNA) levels regardless of the dose of the omega-3 LUPUS fatty acids or duration of the trial. CONCLUSION: While there is conflicting evidence about the benefits of omega-3 fatty acid supplementation on SLE disease activity, specific measures have demonstrated benefits. Current data show that there is a potential benefit on disease activity as demonstrated by SLAM-R, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and British Isles Lupus Assessment Group (BILAG) scores and plasma membrane arachidonic acid composition and urinary 8-isoprostane levels, with minimal adverse events.

Colchicine for acute gout.

BACKGROUND: This is an updated Cochrane Review, first published in 2006 and updated in 2014. Gout is one of the most common rheumatic diseases worldwide. Despite the use of colchicine as one of the first-line therapies for the treatment of acute gout, evidence for its benefits and harms is relatively limited. OBJECTIVES: To update the available evidence of the benefits and harms of colchicine for the treatment of acute gout. SEARCH METHODS: We updated the search of CENTRAL, MEDLINE, Embase, Clinicaltrials.gov and WHO ICTRP registries to 28 August 2020. We did not impose any date or language restrictions in the search. SELECTION CRITERIA: We considered published randomised controlled trials (RCTs) and quasi-randomised controlled trials (quasi-RCTs) evaluating colchicine therapy compared with another therapy (placebo or active) in acute gout; low-dose colchicine at clinically relevant doses compared with placebo was the primary comparison. The major outcomes were pain, participant global assessment of treatment success (proportion with 50% or greater decrease in pain from baseline up to 32 to 36 hours), reduction of inflammation, function of target joint, serious adverse events, total adverse events and withdrawals due to adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane in this review update. MAIN RESULTS: We included four trials (803 randomised participants), including two new trials, in this updated review. One three-arm trial compared high-dose colchicine (52 participants), low-dose colchicine (74 participants) and placebo (59 participants); one trial compared high-dose colchicine with placebo (43 participants); one trial compared low-dose colchicine with non-steroidal anti-inflammatory drugs (NSAIDs) (399 participants); and one trial compared low-dose colchicine with Chuanhu anti-gout mixture (traditional Chinese Medicine compound) (176 participants). We did not identify any trials comparing colchicine to glucocorticoids (by any route). The mean age of participants ranged from 51.2 to 70 years, and trial duration from 48 hours to 12 weeks. Two trials were at low risk of bias, one was possibly susceptible to selection bias (random sequence generation), reporting bias and other bias, and one open-label trial was at high risk of performance and detection bias. For the primary comparison, low-quality evidence from one trial (103 participants, downgraded for imprecision and bias) suggests low-dose colchicine may improve treatment outcome compared to placebo with little or no increased risk of adverse events. The number of people who reported treatment success (50% or greater pain reduction) at 32 to 36 hours was slightly larger with low-dose colchicine (418 per 1000) compared with placebo (172 per 1000; risk ratio (RR) 2.43, 95% confidence interval (CI) 1.05 to 5.64; absolute improvement 25% more reported success (7% more to 42% more, the 95% CIs include both a clinically important and unimportant benefit); relative change of 143% more people reported treatment success (5% more to 464% more). The incidence of total adverse events was 364 per 1000 with low-dose colchicine compared with 276 per 1000 with placebo: RR 1.32, 95% CI 0.68 to 2.56; absolute difference 9% more events with low-dose colchicine (9% fewer to 43% more, the 95% CIs include both a clinically important effect and no effect); relative change of 32% more events (32% fewer to 156% more). No participants withdrew due to adverse events or reported any serious adverse events. Pain, inflammation and function were not reported. Low-quality evidence (downgraded for imprecision and bias) from two trials (124 participants) suggests that high-dose colchicine compared to placebo may improve symptoms, but with increased risk of harms. More participants reported treatment success at 32 to 36 hours with high-dose colchicine (518 per 1000) compared with placebo (240 per 1000): RR 2.16, 95% CI 1.28 to 3.65, absolute improvement 28% (8% more to 46% more); more also had reduced inflammation at this time point with high-dose colchicine (504 per 1000) compared with placebo (48 per 1000): RR 10.50, 95% CI 1.48 to 74.38; absolute improvement 45% greater (22% greater to 68% greater); but more adverse events were reported with high-dose colchicine (829 per 1000 compared with 260 per 1000): RR 3.21, 95% CI 2.01 to 5.11, absolute difference 57% (26% more to 74% more). Pain and function were not reported. Low-quality evidence from a single trial comparing high-dose to low-dose colchicine indicates there may be little or no difference in benefit in terms of treatment success at 32 to 36 hours but more adverse events associated with the higher dose. Similarly, low-quality evidence from a single trial indicates there may also be little or no benefit of low-dose colchicine over NSAIDs in terms of treatment success and pain reduction at seven days, with a similar number of adverse events reported at four weeks follow-up. Reduction of inflammation, function of target joint and withdrawals due to adverse events were not reported in either of these trials, and pain was not reported in the high-dose versus low-dose colchicine trial. We were unable to estimate the risk of serious adverse events for most comparisons as there were few events reported in the trials. One trial (399 participants) reported three serious adverse (one in a participant receiving low-dose colchicine and two in participants receiving NSAIDs), due to reasons unrelated to the trial (low-quality evidence downgraded for bias and imprecision). AUTHORS' CONCLUSIONS: We found low-quality evidence that low-dose colchicine may be an effective treatment for acute gout when compared to placebo and low-quality evidence that its benefits may be similar to NSAIDs. We downgraded the evidence for bias and imprecision. While both high- and low-dose colchicine improve pain when compared to placebo, low-quality evidence suggests that high-dose (but not low-dose) colchicine may increase the number of adverse events compared to placebo, while low-quality evidence indicates that the number of adverse events may be similar with low-dose colchicine and NSAIDs. Further trials comparing colchicine to placebo or other treatment will likely have an important impact on our confidence in the effect estimates and may change the conclusions of this review. There are no trials reporting the effect of colchicine in populations with comorbidities or in comparison with other commonly used treatments, such as glucocorticoids.

The Potential of Circadian Realignment in Rheumatoid Arthritis.

In this short review, we discuss evidence supporting the modulation of peripheral circadian systems as a therapeutic strategy for rheumatoid arthritis (RA). We first review the role of proinflammatory cytokines and oxidative stress, two of the primary mediators of chronic inflammation in RA, and their regulation by circadian clock machinery. We further highlight the role of environmental and metabolic signals in regulating the central and peripheral circadian clocks, with an emphasis on seasonal variations in photoperiod and rhythmic metabolic input, respectively. Finally, we hypothesize that the entrainment and realignment of peripheral clock rhythms have the ability to modulate these mediators, improving clinical outcomes in RA patients. Our discussion emphasizes the use of light therapy and time-restricted feeding for entraining peripheral clocks either via the entrainment of the central circadian clock in suprachiasmatic nuclei (SCN) or directly by uncoupling the peripheral circadian clocks from SCN. In doing so, we highlight the use of nonpharmacologic interventions as a potential strategy for improving clinical outcomes in chronic inflammatory conditions such as RA.

Difficult-to-treat gouty arthritis: a disease warranting better management.

Gouty arthritis is the most common inflammatory arthritis in adults and is characterized by very painful flares. Gouty arthritis results from an elevated body uric acid pool, which leads to deposition of monosodium urate crystals, mainly in the joints. These crystals trigger the release of proinflammatory cytokines, in particular interleukin (IL)-1ß, which stimulates inflammation. Gouty arthritis can progress to a chronic, deforming and physically disabling disease through the development of disfiguring tophi, joint destruction and persistent pain. Standard treatments are effective in most patients. Acutely, anti-inflammatory therapies provide rapid pain relief and resolution of flares. Chronically, urate-lowering therapies reduce serum urate levels and, in combination with anti-inflammatory prophylaxis, reduce the risk of flares. However, for a growing number of patients, current standard treatments are ineffective or are contraindicated, largely due to the presence of co-morbidities. Indeed, metabolic syndrome, hypertension, dyslipidaemia, cardiovascular disease, diabetes mellitus and renal impairment are all highly prevalent in individuals with gouty arthritis, and may lead to standard treatments being ineffective or inappropriate. Such patients with difficult-to-treat disease require alternative therapies. Gouty arthritis can have a major impact on health-related quality of life (HR-QOL), especially in patients with difficult-to-treat disease, as revealed by recent studies comparing HR-QOL for patients with gouty arthritis with that of the general population. All studies revealed clinically significant reductions in physical functioning for individuals with gouty arthritis compared with the general population. The difference was particularly marked for patients with difficult-to-treat disease. Gouty arthritis also constitutes an important economic burden through absence from work and medical costs. Again, the burden is greater in patients with difficult-to-treat disease. The development of difficult-to-treat disease reflects the short-comings of current standard treatments in a growing number of gouty arthritis patients. This has been recognized by the pharmaceutical industry and has promoted the development of innovative therapies. An appreciation of the key role of IL-1ß in inflammation in gouty arthritis has led to the development of a new class of anti-inflammatory agents that block IL-1ß signal transduction. The current IL-1ß blockers in trials are rilonacept and canakinumab. Canakinumab, a fully human anti-IL-1ß monoclonal antibody, has been shown to produce rapid and sustained pain relief from acute flares in patients with difficult-to-treat disease, and both rilonacept and canakinumab have been shown to reduce the risk of recurrent flares. Promising new therapies for reducing serum urate levels are also being developed. These include the recently approved therapies pegloticase (a pegylated form of the enzyme uricase that converts urate to allantoin), inhibitors of renal urate transporter proteins, and inhibitors of purine nucleotide phosphorylase, an enzyme involved in purine metabolism. Further studies are warranted to establish the value and role of these new therapies in the management of gouty arthritis. These new options should help reduce the growing human burden associated with gouty arthritis, lowering the tophaceous burden, minimizing the risk of flares, and enabling patients to achieve rapid and effective pain relief when flares do occur.

Gout--what are the treatment options?

There has been an increase in the incidence and prevalence of gout in the past several decades. A distinction needs to be made between the treatment of gout as an acute inflammatory disease and the lowering of the serum urate (SU) levels into a normal range. Treating acute gout attacks alone is not sufficient to prevent the disease from progressing. When treating gout one needs to treat acute attacks, and lower excess stores of uric acid to achieve dissolution of monosodium urate crystals through a long-term reduction of SU concentrations far beyond the threshold for saturation of urate and provide prophylaxis to prevent acute flares. The options available for the treatment of acute gout are NSAIDs, colchicine, corticosteroids, adrenocorticotropic hormone (ACTH) and intra-articular corticosteroids. The most important determinant of therapeutic success is not which anti-inflammatory agent is chosen, but rather how soon therapy is initiated and that the dose be appropriate. Prophylaxis should be considered an adjunct, rather than an alternative, to long-term urate-lowering therapy. For purposes of maintaining patient adherence to urate-lowering therapy, there is interest in improving prophylaxis of such treatment-induced attacks. The optimal agent, dose and duration for gout prophylaxis are unknown and require further investigation. The importance of long-term management of gout is the reduction and maintenance of SU in a goal range, usually defined as less than 6.0 mg/dL. Allopurinol and benzbromarone remain the cornerstone drugs for reducing SU levels lower than the saturation threshold to dissolve urate deposits effectively. Febuxostat and pegloticase help to optimize control of SU levels, especially in those patients with the most severe gout. Other agents, such as fenofibrate and losartan may be helpful as adjuvant drugs. Treatment for gout has advanced little in the last 40 years, until recently. The recent development of new therapeutic options promises to provide much needed alternatives for the many patients with gout who are intolerant of or refractory to available therapies. It is important to note that inappropriate use of medications as opposed to an apparent refractoriness to available therapies is not uncommon.

Response to application of ice may help differentiate between gouty arthritis and other inflammatory arthritides.

AIM: The aim is to determine whether response to topical ice versus heat differentiates between patients with gout versus other arthritides. METHODS: The first 150 patients seen in our clinic with joint pain from February 2004 onward were asked to fill out questionnaires regarding their response to heat and ice. Patients who responded that topical ice eased their pain and who did not have a diagnosis of crystal-induced arthritis were asked to have a joint aspiration if they had active synovitis on presentation to the clinic. RESULTS: Of 150 completed questionnaires, 26 patients never tried heat or cold as adjuvant treatment for their arthritis. The remaining 124 patients were divided into 6 groups: patients with crystal-proven gout (n = 20), rheumatoid arthritis (RA; n = 32), osteoarthritis (OA; n = 32), other forms of inflammatory arthritis (n = 18), and soft tissue conditions (n = 22). None of the patients with gout benefited from topical heating of their affected joints and all preferred topical ice (P < 0.001). Most patients with RA preferred heat (n = 24). Of 4 patients with RA who preferred topical ice, 3 had effusions and arthrocentesis was performed. Intracellular monosodium urate (MSU) crystals were seen in 2 and intracellular calcium pyrophosphate dihydrate (CPPD) crystals were seen in one patient raising questions about coexistence of 2 diseases or previous misdiagnoses. Most patients with OA preferred heat (n = 28). A significantly higher percentage of the patients with gouty arthritis found that topical ice helped relieve their joint pain as compared with patients with RA (P = 8 x 10(-11)) and other inflammatory arthritides (P = 3 x 10(-8)). DISCUSSION: Heat and cold are adjuvant treatments for arthritis. In gouty arthritis, cold applications are a useful adjunct to treatment and may help discriminate patients with gout from other forms of inflammatory arthritis.