Different modalities to manage rheumatoid arthritis: an A to Z story

Figures & data

Table 1. Inclusion criteria for search strategy.

Parameter	Criterion
Participants	Human patients with RA
Intervention	Nutritional interventions, dietary supplements, therapeutics, fasting interventions and genetic factors
Comparator	Other dietary or therapeutic intervention, placebo supplement or no control group
Outcome	Laboratory and/or clinical and/or radiological and/or symptoms of RA and/or remission RA indices
Setting	All settings

Figure 1. Flowchart of the article selection process.

Figure 2. A diagram presenting the various treatment modalities for rheumatoid arthritis.

The therapy options for RA are classified into two categories: non-pharmacological treatment and pharmacological treatment. Physical therapy, patient counseling on lifestyle variables, and surgical procedures to remove or replace the affected joint and bone regions are examples of non-pharmacological therapies. Pharmacological therapy includes NSAIDs, which are often used solely for symptomatic therapy or until a RA diagnosis is established since these therapies relieve pain and stiffness but have little effect on disease progression.

Table 2. Mechanisms of different categories of pharmacological therapeutics for the management of rheumatoid arthritis.

Category	Mechanism	Therapeutic agent	Ref.
NSAIDs	Inhibition of cyclooxygenase (COX)	Aspirin, ibuprofen
Glucocorticoids	Inhibit cytokines and chemokines	Prednisone, methylprednisolone
DMARDs	Reduction of neutrophil adhesion Inhibition of leukotriene B4 synthesis Reduction of levels of IL-6 and IL-8 Inhibition of TNF Suppression of IL-1 and TNF-α Preventing oxidative, nitrative, and nitrosative damage Inhibition of intracellular toll-like receptor TLR9	Methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide	[17,18]
Other antirheumatic drugs	Inhibition of prostaglandin synthesis Inhibition of IL(s) Inhibits the expression of NOS	Gold sodium thiomalate, Cyclosporine, Tetracyclines	[19]
Biological agents	Anti-TNF-α IL-1 inhibitors Co-stimulation blockers B-cell-targeted therapies	Infliximab, Etanercept and Adalimumab Anakinra Abatacept Rituximab

DMARD: Disease-modifying antirheumatic drug; NOS: Nitric oxide synthase; NSAID: Non-steroidal anti-inflammatory drug; TNF: Tumor necrosis factor.

Table 3. Summarized data of different referenced studies showing different treatment modalities with treatment failure of rheumatoid arthritis.

Category	Clinical outcome	Contribution factors to failure	Ref.
DMARDs	Treatment failure of Sulfasalazine (88.9%) MTX (75%) HCQ (72.2%)	Adverse effects reported (commonly bone marrow suppression and hepatotoxicity) for Sulfasalazine and MTX Addition or replacement of DMARDs for those on HCQ	[20]
Biological agents	58% overall failure for biological therapy (77% primary failure, and 23% secondary failure)	Patients with negative rheumatoid factor Patients using low-dose steroids Patients with a longer disease duration	[21]

DMARD: Disease-modifying antirheumatic drug, HCQ: Hydroxychloroquine; MTX: Methotrexate.

Table 4. Summarized data from studies of treatment success of rheumatoid arthritis.

Category/drug	Clinical outcome	Success mechanism	Ref.
Abatacept	Inhibition of the upstream immune synapse, including the APC-T-cell-B-cell axis, by abatacept can minimize compensatory pathway activity by inhibiting various downstream cytokines Lower incidence of serious infections in patients with RA, compared with other biologics	Targeting CD80/CD86	[22]
Baricitinib	Exhibited superior efficacy compared with MTX monotherapy	JAK/STAT inhibition	[23]

APC: Antigen presenting cell; CD: Cluster of differentiation; JAK: Janus kinases; RA: Rheumatoid arthritis; STAT: Signal transducer and activator of transcription.

Figure 3. Triggering factors for rheumatoid arthritis.

The mechanism and procedure for triggering action by the different factors can be explained as follows: (A) The interplay of genes and environmental variables at the various trigger sites, such as lung, mouth, and gut, might induce RA. (B) This triggering action is defined by the beginning of self-protein citrullination and the development of autoantibodies against citrullinated peptides.

Data taken from [10].

Table 5. Summarized data for referenced studies investigating the effect of different nutrients, food sources and drugs on RA risk and clinical outcomes.

Evaluation method	Duration	Population	Nutrients/foods/drugs	Outcomes (effect on RA risk)	Ref.
Self-administrated weekly retrospective FFQ	1 year (2012–2013)	968 RA patients 1037 healthy controls	Potatoes Fruits (no citrus fruits) Citrus fruits Mushrooms Dairy products Red meats Vegetables	Harmful effect No effects Protective effect Protective effect Protective effect No effects No effects	[24]
Prospective semi-quantitative FFQ at baseline and every 2 years in follow-up	22 years (1980–2002)	82,064 women in NHS (546 RA)	Proteins Iron Red meats Fish	No effects	[25]
Randomized, single-blind controlled trial. Evaluation done after 1 month of dietary regimen	3.5 months	27 RA patients on vegan diet, 26 RA Control patients	Gluten-free vegan diet followed by lactovegetarian diet	Significant decrease in leukocyte and platelet count IgM rheumatoid factors, IgG, C3 and C4 complement Calprotectin	[26]
Pilot study	2 weeks	21 RA patients on elemental diet, 9 RA patients on prednisolone 15 mg/day (Control)	An elemental diet contains amino acids (no whole proteins), mono/di-saccharides, medium/long-chain triglycerides supplemented with vitamins and trace elements	Significant improvement in Morning stiffness Ritchie articular index Clinical parameters were improved by 20% in 72% patients in elemental diet group as compared with 78% in steroid group	[27]
Randomized double-blind clinical trial	8 weeks	22 RA patients on probiotics, 24 RA patients (placebo)	10^(8) CFU of L. casei 01 supplement	Decreased CRP levels and counts of swollen and tender joints	[28]
Randomized, double-blind, placebo-controlled trial	8 weeks	30 RA patients on probiotics, 30 RA patients (placebo)	Lactobacillus acidophilus (2 × 10^(9) colony-forming units [CFU]/g), Lactobacillus casei (2 × 10^(9) CFU/g) and Bifidobacterium bifidum (2 × 10^(9) CFU/g)	Improved DAS28 Decrease in serum insulin levels and CRP levels	[29]
Food Challenge Trial	12 days	20 RA patients +ve SPT 20 RA patients -ve SPT	Allergenic food: dairy products, eggs, meat, fish, refined sugar, wheat, wheat flour, corn, rice, nuts.	72% patients in PPG group and 18% in PNG group suffered from disease aggravation on food challenge Increased levels of TNF-alpha, IL-1beta, ESR and CRP	[30]
Randomized, double-blind, placebo-controlled, parallel-design, clinical pilot	2 months	22 RA patients on probiotics, 22 RA patients (placebo)	Bacillus coagulans GBI-30, 6086	Reduction in total CRP Increase the ability to walk 2 miles, reach and participate in daily activities Pain improvement	[31]
Randomized, single-blinded, controlled crossover trial	10 weeks	50 RA patients (randomly assigned to an intervention diet or a control diet) 44 RA patients Competed both diet periods	Intervention diet: Fish (mainly salmon) three to four times per week, vegetarian dishes with legumes one to two times per week Potatoes, whole-grain cereals, vegetables, yoghurt for sauces, spices, and other flavorings were also included Snacks were composed of fruits Breakfasts contained low-fat dairy, pomegranate, whole-grain cereals, and nuts, blueberries and juice + probiotics Control diet Contained meat or chicken and refined grains daily, protein bar or quark for snacks Breakfasts based on either white bread with a butter-based spread and cheese, or a mix of quark and yoghurt with corn flakes and orange juice	Non-significant decrease in ESR in intervention group	[32]
Randomized, controlled trial	3 months	23 RA patients on Cranberry juice, 18 RA patients (Control)	Usual diet plus 500 ml/d of reduced calorie cranberry juice	Decreased disease activity Decreased DAS28 values Decreased anti-CCP values	[33]
Randomized Cross-Over trial	11 weeks	20 RA patients on blue mussels, 19 RA patients (Control)	Intervention meal: Five weekly meals with 75 g of blue mussels in addition to normal diet Control meal: Five weekly meals with meat/chicken in addition to normal diet	Reduced CRP, and disease symptoms Improved perceived health	[34]
Randomized double-blind placebo-controlled clinical trial	12 weeks	35 RA patients on ginger powder, 35 RA patients (placebo)	1500 mg ginger powder in two capsules daily	Reduction in disease activity score Increasing FoxP3 genes expression Decreasing RORγt and T-bet genes expression	[35]
Randomized double-blind clinical trial	8 weeks	20 RA patients on cinnamon powder 20 RA patients (Placebo)	2000 mg cinnamon powder in four capsules daily	Significant decrease of serum levels of CRP and TNF-α Significant decrease in diastolic blood pressure Reduced swollen and tender joints score	[36]
Randomized controlled, double-blind trial	3 months	33 RA patients on saffron, 33 RA patients (Placebo)	100 mg/d saffron in one tablet	Decreased the number of tender and swollen joints Decreased pain intensity Decreased ESR, CRP, TNF-α, IFN-γ and malondialdehyde Increased total antioxidant capacity	[37]
Randomized controlled, unblinded trial	12 weeks	29 RA patients on a Mediterranean diet, 27 RA patients (control)	Mediterranean diet Some meals in the initial 3 weeks. Margarine, olive oil, canola oil, frozen vegetables, tea.	Reduction in inflammatory activity Increase in physical function Improved vitality Reduced pain and swollen joint count Decreased CRP	[38]
Randomized controlled, double-blind trial	8 weeks	35 RA patients on alpha lipoic acid, 35 RA patients (Control)	Two capsules of 1200 mg alpha lipoic acid	Serum inflammatory biomarkers and MMP-3 were not significantly affected No significant decrease in serum levels of CRP, TNF-α, IL-6	[39]
Randomized crossover, placebo-controlled, double-blind trial	10 weeks	38 RA patients on intervention, 38 RA patients (Control)	Intervention nutrients 8 g micro algae, enriched in 60 g sausage, 8 g tomato spread, 30 g milk powder Amount of n3/d: 2.36 g Control 8 g sunflower oil, enriched in 60 g sausage, 8 g tomato spread, 30 g milk powder	Reduction in clinical and biochemical signs of inflammation	[40]
Randomized controlled, double-blind trial	3 months	21 RA patients on vitamin D3, 18 RA patients (Control)	300 000 IU (7500 μg) of vitamin D3 administered once	Ameliorates the general health of patients	[41]
Randomized controlled, double-blind trial	12 months	11 RA patients on vitamin D2, 11 RA patients (Control)	Intervention Month 1: 3*50 000 IU vitamin D2/week Month 2–11: 2*50 000 IU vitamin D2/month, 1500 mg calcium daily Placebo 1500 mg calcium daily	No improvements in disease activity, or cytokines levels	[42]
Randomized controlled, double-blind trial	28 days	18 RA patients on intervention, 18 RA patients (Control)	Intervention 6000 mg of potassium in the form of enriched white grape juice Placebo grape juice	Decreased pain intensity	[43]
Randomized controlled, double-blind trial	2 months	27 RA patients on intervention, 27 RA patients (Control)	100 mg/day CoQ10 capsules	Reduction in ESR Reduction tender in joint count Reduction in pain score, and serum MMP-3 level	[44]
Randomized controlled, unblinded trial	3 months	50 RA patients on intervention, 50 RA patients (Control)	One capsule containing 1 g resveratrol daily	Decreased level of CRP, ESR, MMP-3, TNF-α, and IL-6 Lowered disease activity Decreased swelling and tenderness	[45]
Randomized controlled, double-blind trial	12 weeks	49 RA patients on intervention, 48 RA patients (Control)	10 g cod liver oil in capsules containing: 1500 mg EPA, 700 mg DHA, 800 μg vit A, 5 μg vit D, 20 IE vit E	No significant effect on RA disease activity	[46]
Randomized controlled, double-blind trial	8 weeks	32 RA patients on intervention, 32 RA patients (Control)	10 μg/day of vitamin K1 as a chewable tablet	No significant effects on blood inflammatory biomarkers No significant effect on RA disease severity	[47]
Randomized controlled, double-blind trial	8 weeks	25 RA patients on intervention, 25 RA patients (Control)	One capsule containing 500 mg quercetin	Reduced early morning stiffness Reduced morning pain, and after-activity pain	[48]
Randomized controlled, double-blind trial	8 weeks	27 RA patients on intervention, 27 RA patients (Control)	Synbiotic capsules containing L. acidophilus, L. casei, B. bifidum (each 2 × 10^9 CFU) and 800 mg insulin	Reduced CRP Reduced disease activity Reduced pain	[49]
Randomized controlled, double-blind trial	3 months	15 RA patients on intervention, 14 RA patients (Control)	Two daily capsules of L. rhamnosus GR-1 and L. reuteri RC-14 (each 2 billion CFU), plus dextrose, potato starch, microcrystalline cellulose and magnesium stearate	No Clinical improvement Occurrence of functional improvement	[50]
Randomized, double-blind, placebo-controlled, parallel-design trial	8 weeks	31 RA patients on intervention, 31 RA patients (Control)	500 mg garlic tablets (equivalent to 2500 mg of fresh garlic, and containing 2.5 mg allicin) twice daily	Significant increment in serum TAC Significant reduction in MDA levels Improvement HAQ	[51]
A Randomized, Double-Blind, Placebo-Controlled, Two-Dose, Three-Arm, and Parallel-Group Study	12 weeks	12 RA patients on intervention 1, 12 RA patients on intervention 2, 12 RA patients (Control)	Intervention 1: curcumin 250 mg twice a day Intervention 2: curcumin 500 mg twice a day	Significant improvement in VAS, CRP, DAS28, ESR, and RF values in both interventions compared with placebo.	[52]
Randomized controlled trial	54 weeks	86 RA patients on intervention, 88 RA patients (Control)	Intervention: methotrexate + infliximab 3 mg/kg I.V every 4 or 8 weeks Control: methotrexate + placebo	Sustained reduction in the symptoms and signs of rheumatoid arthritis Quality of life significantly better	[53]
Randomized controlled trial	54 weeks	359 RA patients on intervention 1, 363 RA patients on intervention 2, 282 RA patients (Control)	Intervention 1: methotrexate + infliximab 3 mg/kg I.V Intervention 2: methotrexate + infliximab 6 mg/kg I.V Control: methotrexate + placebo	Significant improvement in physical function on intervention 1 and 2 Less radiographic progression on intervention 1 and 2	[54]
Randomized controlled trial	24 weeks	67 RA patients on intervention, 62 RA patients (Control)	Intervention: adalimumab 40 mg s.c. every 2 weeks + Methotrexate Control: methotrexate + placebo	Significant, rapid, and sustained improvement in disease activity	[55]
Randomized controlled trial	52 weeks	207 RA patients on intervention, 200 RA patients (Control)	Intervention: Adalimumab 40 mg s.c. every 2 weeks + Methotrexate Control: Methotrexate + placebo	Significant less radiographic progression Significant improvement of physical function	[56]
Multicenter, randomized, double-blind, placebo-controlled trial	24 weeks	59 RA patients on intervention, 74 RA patients (Control)	Intervention: anakinra 1 mg/kg/day s.c. + methotrexate Control: methotrexate + placebo	Significant improvements in the HAQ disability index	[57]
Randomized, double-blind, placebo-controlled study	6 months	115 RA patients on intervention, 119 RA patients (Control)	Intervention: abatacept 10 mg/kg i.v. + methotrexate Control: methotrexate + placebo	Significant improvement in disease signs and symptoms and health-related quality of life	[58]
Multicenter, randomized, double-blind, controlled study	48 weeks	40 RA patients on intervention, 40 RA patients (Control)	Intervention: rituximab 1 g i.v. + methotrexate on days 1 and 15 Control: methotrexate + placebo	Improvement in disease symptoms	[59]
Randomized, double-blind, placebo-controlled trial	6 months	78 RA patients on intervention, 80 RA patients (Control)	Intervention: Etanercept 25 mg s.c. twice weekly Control: olacebo	Significant reduction of disease activity	[60]
Multicenter, double-blind, placebo-controlled trial	3 months	55 RA patients on intervention, 53 RA patients (Control)	Intervention: tocilizumab 8 mg/kg every 4 weeks Control: placebo	Reduced disease activity	[61]
Double-blind, placebo-controlled	6 months	20 RA patients on intervention, 20 RA patients (Control)	Intervention: HCQ 200 mg and MTX (7.5 mg) once a week Control: HCQ (200 mg daily) and placebo	Reduced radiological progression in intervention group	[62]
Double-blind randomized trial	15 weeks	RA patients	Intervention: fish oil derived (n-3) fatty acid supplementation (three to six capsules/day) Control: olive/corn oil capsule supplement	Improvement HAQ, MS	[63]
Randomized, controlled, single blinded, study	6 months	33 RA patients on intervention, 33 RA patients (Control)	Intervention: Metformin 850 mg twice daily Control: placebo twice daily	Significant improved inflammation, disease severity, and quality of life Significant decrease in CRP levels	[64]

Anti-CCP: Anticyclic citrullinated peptide; CoQ10: Coenzyme Q10; CRP: C-reactive protein; DAS28: Disease Activity Score 28; EPIC-Norfolk: European Prospective Investigation of Cancer in Norfolk; ESR: Erythrocyte sedimentation rate; FFQ: Food frequency questionnaire; HAQ: Health Assessment Questionnaire; IL-6: Interleukin-6; IP: Inflammatory polyarthritis; MDA: Malondialdehyde; MMP-3: Matrix metalloproteinase-3; MMP-3: Serum matrix metalloproteinases; MS: Morning stiffness.; NHS: Nurses' Health Study; PNG: Prick-negative group; PPG: Prick-positive group; RA: Rheumatoid arthritis; SPT: Skin prick test; TAC: Total Antioxidant Capacity; VAS: Visual analog scale.

Figure 4. Different pathways for the therapeutic agents used in relieving the symptoms of rheumatoid arthritis.

The pathways are different and can be summarized as follows: (A) Control of the immune cells and inflammatory mediators leads to suppression of the inflammatory response and reduction of the activity of the disease (RA). (B) Different molecules contribute to blocking T- and B-cell-mediated responses, like glucocorticoids, DMARDs and biological agents. (C) Biological agents contribute to inflammatory mediator inhibition. (D) NSAIDs inhibit neutrophil aggregation.

Figure 5. The indirect correlation between different dietary products and the progression of rheumatoid arthritis.

(A) The effect depends on how food affects inflammatory responses, normal microbiota, and weight control. (B) Usually, diet rich in fiber, vitamins, omega 3 and low-glycemic index foods contribute to protection from RA incidence. (C) Diets with high salt, high calories and a high glycemic index contribute to RA occurrence or incidence.

Figure 6. Several lifestyle practices that might be beneficial, when applied by the patients, in controlling and managing rheumatoid arthritis.

(A) The contributing factors for enhancing RA management include dietary habits like healthy food, eating well (eating sufficient quantities of food to provide the required daily caloric need), and supplements. (B) Taking care of physical wellbeing includes good posture practice, regular light exercise, massage, heat, and cold therapy. (C) Emotional, psychological, and mental wellbeing include stress control, meditation, and good and sufficient sleep.

Figure 7. Effect of different molecules and minerals on rheumatoid arthritis.

(A) Nutrients affect cells and mediators of the immune-inflammatory ‘cascade’ leading to RA. (B) Once the mediators or cells are controlled, the inflammatory response will be mitigated, causing improvements in the signs and symptoms of RA.

Table 6. Types of diets for management of RA and their impact on disease symptoms.

Diet types	Diet components									Effects on RA
	Vegetables	Fruits	Oils	Fish and seafood	Dairy products	Eggs	Poultry	Red meat	Grains
Mediterranean diet	A wide range of raw and prepared vegetables, including legumes.	Varied range of fruits	In the main Cold-pressed extra virgin olive oil	Yes	Yes	Yes	Yes	Yes in small portions	Grains, nuts, seeds	Increase physical function, and enhance quality of life
										Decrease inflammation
										Increase physical function and vitality
										Decrease pain, stiffness, and inflammation
										Decrease pain and inflammation
Vegetarian diet	A wide range of raw and prepared vegetables, including legumes.	Varied range of fruits	Varied range of plant-based oils	Yes or no	Yes or no	Yes or no	No	No	Grains, nuts, seeds	Useful for the treatment of RA
										Decrease inflammation
										Decrease pain and inflammation
Vegan diet	A wide range of raw and prepared vegetables, including legumes.	Varied range of fruits	Varied range of plant-based oils	No	No	No	No	No	Grains, nuts, seeds	Decrease pain and inflammation
Elimination diet	The foods that typically initiate the onset of the ailment must be eliminated from one's dietary intake. Coffee must be excluded.	Trigger foods should be restricted	Varied range of plant-based oils	Yes or no	No	No	Yes or no	No	No Corn, oats and rye	Decrease pain and inflammation
										Decrease inflammation
										Decrease inflammation and the number of tenders

Data taken from [85].

Figure 8. Diagram showing the effect of different genetic variants on rheumatoid arthritis therapeutic outcomes.

(A) The therapeutic outcome is affected by the existence of different genetic variants. (B) Therapeutic efficacy may increase or decrease, toxicity may occur, or no change in efficacy may be seen.

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