A therapeutic role for potassium ( K ) to reduce pain and complications related to the cardiovascular system and bone in rheumatoid arthritis ( RA ) : A clinical research perspective

Rheumatoid arthritis is a painful inflammatory disorder. Patients seek relief mostly with analgesics and anti-inflammatory drugs which are rife with life-threatening side effects. Alterations in the body‘s potassium (K) status may be one such factor. K along with sodium is critical to cellular homeostasis and the electrophysiology of nerve impulses. This review is based on the premise that K can be used therapeutically to reduce joint pain and inflammation in RA and co-morbidity. K ion channel inhibition was shown to cause persistent nerve stimulation (a prelude to pain sensation) and altered immunity (T cells) in experimental studies. Diets rich in K (with normal/reduced salt intake) have to reduce hypertension in several large population studies. Premature atherosclerosis-related cardiovascular disorders and osteoporosis are important complications of RA. The third National Health and Nutrition Examination Survey (1994) carried out in the USA also reported hypokalemia in several RA patients. A diet deficient in K in RA patients was recently reported by an Indian study. In a controlled clinical trial (Iran), K supplementation (diet-based) led to a significant reduction in pain and arthritis in women suffering from seropositive RA. Some of the benefits of K in RA were postulated to be due to an improved cortisol status. K is not a known therapeutic agent in the treatment of RA. Vegetables and fruits are rich sources of K and provide a safe option for intervention. The existing data on the potential therapeutic role of K in RA is encouraging and merits further research.


Introduction __________________________
RA is a chronic painful inflammatory arthritis with several potentially life-threatening complications.It causes a deterioration in quality of life and crippling deformities.Treatment is difficult [1,2].The management of pain and inflammation increasingly depends on the use of analgesics, steroids, and nonsteroidal anti-inflammatory diseases (NSAID) and disease-modifying anti-rheumatic drugs (DMARD).However, these drugs come with many life-threatening side effects and toxicities [2].
There is a dire need to explore newer avenues to find safer management of RA.First, however, any other factors that contribute to pain and inflammation need to be identified.Non-pharmacological options such as diet-based approaches are promising adjunct treatments, but they have been neglected in the current guidelines [3,4].Though suspected for several decades to be beneficial, the precise role of potassium (K) in RA is largely unknown [5].
In this study, it was hypothesized that patients suffering from RA are deficient in K, and that K reduces joint pain and inflammation and complications pertaining to the cardiovascular and skeletal systems.
Multiple search strategies including Internet search engines (such as PubMed/Medline and Cochrane) and manual identification of suitable references were used.Leading investigators were contacted.Search results were discussed in pre-planned meetings with rheumatology colleagues (CRD, Pune).This article first presents a brief description of RA with special reference to its pathogenesis and the physiology of K.This will enable the reader to recognize some of the physiological actions of K that may offset the pathological mechanism in RA.This is followed by an overview of the existing data that supports the hypothesis.
Objective: This article purposed to determine and describe the potential role of K in RA.Data (and the authors' interpretation) is presented to support the

Rheumatoid arthritis (RA) ______________
RA is reported worldwide with a prevalence of 1% [6][7][8][9].However, COPCORD (Community-Oriented Program for Control of Rheumatic Diseases) population surveys, including Iran and India, have shown a lesser prevalence in the range of 0.3-0.5%;that still means millions of patients in developing countries [10][11][12].RA predominantly affects women and usually begins between the age of 40-60 years.1. Etiology and Risk Factors.The exact cause of RA is not known.Several bacteria and viruses have been implicated but never proven [13].Genetic predisposition is predominantly attributed to certain HLA D region alleles and shared epitope hypothesis [14,15].Gene environment interactions are also described.Smoking is an established risk factor [16].Dietary risk factors include the consumption of red meat and caffeine [17,18].Overweight or obese individuals may be at a higher risk [ Overall, there is an imbalance between Th1 and Th2.T cell responses are intensely driven by interleukins IL 2 and IL 17.Several other biochemical mediators like histamine, bradykinin, and prostaglandins pour into the system to promote inflammation (and pain) and facilitate several concurrent responses like that in the vascular (endothelial and blood flow) bed.T cells of the CD 4 phenotype, which express upregulated HLA DR, seem to be predominant in contrast to CD 8 cytotoxic T cells.There is an intense interaction between T cells and B cells.The T regulatory cell response is dampened.Tumor necrosis alfa (TNF-α) seems to be the prime inflammatory cytokine that stimulates and drives several immune and inflammatory responses.It acts in concert with the potent pro-inflammatory cytokines IL 17 and IL 6.Overall, there is a failure to check and control immune inflammation despite several active countercheck mechanisms (including cytokines).All this leads to intense synovial and Mediterranean diet and a diet rich in Omega oils [5].Supervised exercise, physiotherapy, and rehabilitation are mandatory for optimum function and well-being.

Potassium (K)
2.1.Physiology.K, sodium, and calcium play integral roles in the electrophysiology of pain and myriad cellular functions.K is essential for the maintenance of cellular osmolality and homeostasis.K is an important micronutrient in health and actively participates in the normal function of several organ systems-neuromuscular, cardiovascular, endocrine, respiratory, and renal.It is also important in metabolic pathways, especially glucose-related enzymes [38,39].While sodium is predominantly extracellular (blood), K is intracellular.The sodium potassium ATPase (Na-K) pump is a carrier protein for the active (energy-consuming) transport of sodium and K across cell membranes.The total body K is considered to be about 3.5 gms; maximum tissue concentration is in the skeletal muscles [40].Extracellular K is closely and dynamically regulated to maintain a plasma concentration of 4.2 mEq/l within a narrow range (usually 3.5 to 5.5 mEq/l) of safety [41,42].Plasma assay is subjected to individual laboratory methods and several potential errors.Rapid K shifts across cell membranes are an important compensatory mechanism and can mask a body K deficit or excess.Abnormal levels (low or high) of plasma extracellular K can result from (i) dilution (administration of low K fluids) or concentration (dehydration); (ii) deranged K losses in urine or other body fluids; (iii) the transfer of K between cells and body fluids.Acid-base disturbances and hormones (especially insulin) are important drivers of cellular shifts.K is regulated by the kidneys though some excretion that may take place in stools and sweat.The loss of K through urine is driven by diet intake, acid base shifts, and several hormones (aldosterone, cortisol, renin, and angiotensin).Even during the total absence of diet K intake, there is an obligatory K loss by the kidneys.While acute effects of K imbalance are well described (and researched), chronic effects are largely unknown.Moreover, it is not known whether minor shifts in plasma K within the normal range or total body K can cause any adverse physiological effects.In case of an acute K imbalance, the body attempts to rapidly compensate and restore normal plasma K mainly through cellular and renal mechanisms.However, in a chronic state, this may fail.Clinical recognition of this decompensation may be difficult in mild to moderate cases.It is likely that chronic K imbalance disorders are missed in clinical practice, because they are not primary disorders and are overshadowed by the primary disease.It is likely that chronic hypokalemia will lead to several adverse systemic effects on the basic health of an individual.2.3.1.Hypokalemia.This is defined as a serum potassium concentration of less than 3.5 mEq/L.An assay of less than 2. Several mechanisms contribute to the intensity and nature of chronic pain in RA.Small nerve endings and fibers are entrapped in inflammatory synovitis to impart a neurogenic or neuropathic component.Blocking K ion channels was demonstrated to reduce arthritis in animal models.In the pristine-induced arthritis model using Dark Agoti rats, 21 days of treatment with ShK-L5-amide significantly decreased the number of affected joints and reduced the severity of radiological and histopathological findings [72].CD4 and CD8 T lymphocytes are important in the pathogenesis of RA, and their activity has been reported to be critically dependent on constitutively-expressed K ion channels (K2pore5.1 type) [73].T cells isolated from the synovial fluid of patients with RA were characterized as mainly Kv1.3 high CCR7 [21].Experimental evidence supports the inhibitory effects of serum K on free radical formation and-oxidant damage [74].However, the relationship between dietary K and K ion channels has not been investigated.3.3.Clinical data.Nuki et al. (1970) demonstrated shifts in body K in 8 patients of RA who were prescribed oral K supplements in a 30-day interventional study; a detailed diet analysis was carried out [75,76].Patients were also treated with adreno-corticotrophic hormone or a diuretic (spironolactone) during the latter half of the study.Total body potassium (TBK) was estimated using the radio-isotope technique and found to be low at baseline.TBK remained constant throughout the study, and therefore, serum K changes were likely to be caused be a cellular shift.The authors postulated that changes in serum K were due to renal compensatory mechanisms (likely renin angiotensin aldosterone) to the K load.Rastamanesh et al. ( 2009) demonstrated a significant reduction in pain and inflammatory arthritis induced by oral K supplementation.Thirty-six female patients suffering from active seropositive RA were enrolled in a 28-day randomized double-blind, placebo-controlled intervention trial conducted in Iran.Concurrent stable treatment with corticosteroids and/or DMARD was permitted.Patients were permitted to continue their routine diet.6 gm of K salt (chloride) was administered in grape juice daily to 16 patients, while plain grape juice was consumed by 16 patients in the placebo arm.The total mean potassium daily intake was 1540 mg in the placebo group and 6495 mg in the active arm.The K supplement was well tolerated and none reported side effects [61].Both Weber (2010 and Rastmanesh (2009) postulated that K mediates its clinically beneficial effect principally by modulating the hypothalamic-pituitary-adrenal (HPA) axis [77,78].The HPA axis is known to be impaired in RA and influences immune inflammatory processes and electrolyte homeostasis [71,77,78].A disconnect has also been described between HPA and the sympathetic adrenal system [71].3.4.Effect on Cardiovascular System.Several population-based studies have validated the benefits of a K-rich diet and K supplementation in the prevention and treatment of hypertension [79][80][81][82].Though the exact mechanism is not known, several experimental studies have demonstrated the inhibitory effects of serum K on vascular smooth muscle proliferation, reducing macrophage adherence to the vascular wall, arterial thrombosis, free oxygen radicals, and reactive oxygen species [83][84][85].K ions are also released by the endothelial cells in response to neuro-humoral mediators (sympatheticadrenal and cortisol related mechanisms) and physical forces (such as shear stress) and contribute to endothelium-dependent relaxations.Though the response is believed to be slow and modest, potassium supplements lower blood pressure.Thus, K is beneficial for cardiovascular health and blood flow which is of great importance in patients suffering from RA. Cardiovascular complications are the leading cause of premature death in RA [11,86] Lin C, Boltz R, Blake J, Nguyen M, Talento A, Fischer P. et al.