• Roberta Ramonda, MD, PhD

• Rheumatology Unit, Department of Medicine

• University of Padova, Padova, Italy
Disclosures

I have the following relevant financial relationships to disclose:

Prof. Ramonda has consultancy relationships with Abbvie, MSD, Pfizer,

Janssen, Novartis, Celgene, Mylan, Fidia, Lilly
Evidence-Based Medicine (EBM)
or Key References
• Gwinnutt JM, Wieczorek M, Rodríguez-Carrio J, et al. RMD Open
2022;8:e002167. doi:10.1136/ rmdopen-2021-002167
• Daien C, Czernichow S, Letarouilly JG, et al. Joint Bone Spine;2022:105319.
doi.org/10.1016/j.jbspin.2021.105319
• Ometto F, & Ramonda R, et al, Arthritis Research & Therapy; 2021;23:219.
doi.org/10.1186/s13075-021-02600-0
• Ortolan A, & Ramonda R, et al, JBS 2022 [in press]
Agenda

The role of diet in arthritis

Dietary interventions in Rheumatic Diseases

Patients counseling

Conclusions
Diet and Rheumatic Diseases
• Diet has a complex role in the development of rheumatic diseases
• The effect of diet is not limited to inflammation and interaction with the autoimmune system

Intestinal
Microbiome

Inflammation/ Rheumatic
Autoimmunity Disease
Body Weight

Quality of Life
Diet
Function

Pain

Comorbidity
(Cardiovascular
disease,
osteoporosis)
Schoenefeld, Immunol Today 1989
Nutrients affect the Immune System

• Most human immune cells are located in the digestive tract

• Nutrients (vitamins, salt, fatty acids,..) may alter the permeability of the gut and/or exert a
direct effect on intestinal immune cells
• Nutrients can affect the microbiome which modifies gut permeability
• Activated immune cells in the gut migrate to the joints and lymphoid tissues
Tajik, Nature Communications 2020; Tourkochristou , Frontiers Immunol 2021
 Pro-inflammatory Anti-inflammatory
Nutrients Nutrients

Saturated fats Vitamins and anti-oxidants

Sugars and Fibers

High glycaemic Index foods
Moderate alcohol consumption
Sodium

Omega-6 fatty acids Omega-3, omega-9 fatty acids

(Low omega-3/omega-6 ratio) (High omega-3/omega-6 ratio)

Western Diet Mediterranean Diet

PUFA and risk of rheumatoid arthritis
• PUFA are precursors of prostaglandins and
leukotrienes
• The omega-3/omega-6 ratio contributes to the
balance between pro- and anti-inflammatory
cytokines
• Several studies have suggested a inverse
correlation between omega-3 fatty acid (or fish
oil) intake and rheumatoid arthritis incidence
• The effect is evident especially with doses>2
g/day

• A low omega-3 fatty acid consumption is also

associated with anti-citrullinated antibodies
Swedish prospective cohort study: Relative risk
of rheumatoid arthritis according daily omega-3
intake
di Giuseppe, Arthritis Res Ther 2014;
Sparks, BMC Musculoskeletal Disorders 2019;
di Giuseppe, Ann Rheum Dis 2013;
Gan, Rheumatology (Oxford) 2016.
Vitamins in Rheumatic Disorders
• Despite their beneficial effects, the effects of
vitamin supplementation on RA activity seem to
be limited
• Evidence on their efficacy on SpA or PsA activity
is lacking
• The effect of Vit E seems to be limited
on disease activity and pain
• Studies on Vit K reported that data on
clinical activity (DAS-28) are limited.
• Folic acid supplementation should
prevent methotrexate-related side
effect
• Vitamin D should be given to patients
with vitamin D deficiency to prevent
musculoskeletal complications.

Nguyen Y, & Daïen C, et al. Nutrients 2021

Sodium
• Increases development of pro-inflammatory macrophages
• Increases Th17 activity and IL-17 production
• Reduces Tregs function

• Daily sodium intake is associated with

diagnosis of rheumatoid arthritis with a
dose-dependent relationship (stronger
association in smokers)

SUN cohort (cross-sectional study in 18.555

subjects)

Salgado, Medicine 2014;

Wilck, Nature 2017;
Senhert, ACR 2017;
Dahan, Nature Rev 2017
Saturated Fats

• Saturated fatty acids increase bacterial endotoxins

lipopolysaccharides (LPS)

• Red meat consumption is

associated with rheumatoid
arthritis prevalence

Multi-country Study: rheumatoid arthritis

r2 0.877, p<0.01 prevalence in women

Grant, British Journal of Nutrition 2000.

Sugars and soft drinks
• Sugars reduce density of beneficial gut bacteria and exacerbate
autoimmunity through the activation of TGF-β and promotion of Th17 cell
differentiation
• Sugar and high glycemic index foods are associated with obesity

• Sugary soda is associated

with increased risk of
seropositive rheumatoid
arthritis and worse self-
reported outcomes (in women
>55 yrs)
Prospective cohort study: Nurses
Health Study, incident cases of RA
(581 cases, 121.700 Women)

Jones, Gut Microbes 2019 ; Dey, Nutrients 2020; Tedeschi, Arthritis Rheum 2017; Hu, Am J Clin Nutr 2014.
Alcohol
• Resveratrol (only in red wine) proved to have anti-inflammatory (reduced
activation of NF-kB, COX-2 activity) and antioxidant properties (reduced
ROS production)

• Compared with non-drinking, low or

moderate alcohol consumption was dose
dependently associated with a reduce risk
of ACPA+/- RA

Swedish population-based case-control

study: incident cases of rheumatoid arthritis
(3353 cases, 2836 matched controls)

Dahan, Nature Rev 2017; Hedstrom, RMD Open 2019.

Mediterranean diet

Oliviero F & Ramonda R, Swiss Med Wkly 2015.

Mediterranean diet has a beneficial effect in RDs because it controls CV risk, inflammation and it contributes to treatment and improves patients’ global
health
Mediterranean diet in Rheumatoid arthritis
• In population-based studies, Mediterranean diet was associated
with a lower risk of rheumatoid arthritis with some differences
based on other factors (e.g. gender, smoking, seropositivity,
country)
Swedish
epidemiological
investigation of RA
(EIRA)
• 1721 patients with
incident RA and
3667 controls,
matched on age,
gender and
residential area
Dose-response odds ratio for risk of rheumatoid arthritis by • Diet measured with
the Mediterranean diet score Mediterranean Diet
Score

Johansson, Arthritis Res Ther 2018; Nguyen, Arthritis Rheum 2020.

Mediterranean diet in Psoriatic arthritis
• An observational study showed an inverse association
between disease activity (DAPSA) and class of adherence to
the Mediterranean diet

Italian Cross-sectional observational study in 211 consecutive PsA patients

• Diet measured with PREDIMED (14-item)

Caso F, Rheumatol Int. 2020 .

Miscellaneous
Increased risk of RA and seropositive RA, possibly dose-dependent
Caffeine
Possible contribution to rheumatoid factor production

Antioxidant properties (flavonoid)

Cocoa Decreases antibody production and promotes favourable anti-inflammatory
cytokine balance in RA
Epigallocatechin-3- Antioxidant properties (flavonoid)
gallate (EGCG) Downregulation of MMPs (reduction of cartilage destruction) , reduced production
(Green tea) pf anti Il1-beta, rincreased apoptosis of synovial fibroblasys on RA

Capsaicin Increased expression of antinflammatory macrophages, modulates neurogenic

(red hot chili peppers) pain in RA

Nanopowdered red
Decrease proinflammatory cytokines in RA
ginseng

Increased Treg cell proliferation, Breg cell function, antioxidants production and
Curcumin
anti-inflammatory genes production; decreased TH1 cell proliferation in RA

Lee, Clin Rheumatol 2014; Cutolo, RMD Open 2018; Dahan, Nature Rev 2017, Dey, Nutrition 2020.
Agenda

The role of diet in arthritis

Dietary interventions in Rheumatic diseases

Patients Counseling

Conclusions
 Diet interventions in Rheumatic Diseases

• Very diverse nutritional interventions

• Mostly small or pilot studies with low quality

• Little evidence (often small effect size observed)
• Potential confounders not adequately considered (large time span, heterogeneous treatments)
• Mainly RA

Gwinnut, Ann Rheum Dis 2022. Daien, JBS 2021.

Rheumatoid
arthritis

Dietary
interventions in
Rheumatic
Diseases:
Systematic review
and meta-analyses

Gwinnutt, RMD Open 2022.

Axial Spondyloarthritis and Psoriatic Arthritis

Diet
interventions
in Rheumatic
Diseases:
Systematic
review and
meta-
analyses
Gwinnutt, RMD Open 2022.
Osteoarthritis

Diet
interventions
in Rheumatic
Diseases:
Systematic
review and
meta-
Gwinnutt,analyses
RMD Open 2022.
23
Interventions based on PUFA

• Most interventions are based on

PUFA supplementation

• Omega-3 fatty acids seem to have a

beneficial effect on all measures of
disease activity
• The effect is dose-dependent effect
(>2 g/day)

SLR and Metanalysis: RTCs of 30 randomized

controlled studies, 710 patients
Sigaux, Arthritis Res Ther, 2022
Interventions based on Mediterranean diet
Rheumatoid arthritis

Patient reported
RCTs CRP/ESR DAS28 Other outcomes
outcomes
Hansen, 1996
Improved** Improved Improved
Denmark
Sköldstam, 2003 Improved (Only
Improved Improved
Sweden CRP)
McKellar, 2007
0 Improved 0
England
Garcia-Morales,
2019 0 0 0
Mexico
Vadell, 2020
Improved (only Improvement of
Sweden Improved 0
DAS28 (ESR)) cardiovascular profile
(ADIRA trial)

Overall, reduced disease activity was observed although effect size was small
Interventions based on Mediterranean diet
Axial Spondyloarthritis
Observational study with
control group:
• 161 patients; adherence to
diet measured with
PREDIMED score
• After 6 months dietary
changes was associated with
improved ASDAS-CRP also
after adjustment for
confounders

Improved adherence to the Mediterranean diet is associated with

improvement of disease activity indices
Ometto F & Ramonda R, Arthritis Res Ther 2021.
The impact of diet on disease activity in spondyloarthritis:
a systematic literature review

Risk of
Results Study ID Population Study design
bias
Methods Lassus A 1990 PsO/PsA Quasi-experimental

Veale DJ 1994 PsA RCT

Systematic literature review (SLR) in Polyunsaturated
ethyl ester lipids Sundström B 2006 AS RCT
MEDLINE, EMBASE, Cochrane and
supplementation
SCOPUS according to the “PEO” format Madland TM 2006 PsA RCT

Leite BF 2022 PsA RCT

Population: SpA (axSpA and pSpA) Milk deprivation Appelboom T 1994 AS/RA Quasi-experimental
Exposure: any kind of diet or dietary Vitamin D Gaal J 2009 PsA Quasi-experimental
supplement Di Minno MN 2014 PsA RCT
Outcome: disease activity
Hypocaloric diet Klinberg E 2019 PsA Quasi-experimental

Type of studies: RCTs, quasi- Klinberg E 2020 PsA Quasi-experimental

interventional studies, longitudinal Brophy S 2008 SpA Internet- based RCT

Probiotics
observational studies, so that at least a Jenks K 2010 SpA RCT
pre- and post-intervention assessment Adawi M 2018 PsA Longitudinal cohort
were available Intermittent fasting
Ben Nessib D 2020 SpA Longitudinal cohort

Mediterranean diet Ometto F 2021 axSpA Longitudinal cohort

Conclusions
Type of study Instrument Legend

 Probiotics are not effective in SpA Cochrane risk of

 Weight loss is associated with MDA in PsA Risk of bias
RCT
Bias tool 2.0
High
assessment
 Mediterranean diet is associated with improved Quasi-
ASDAS in axSpA experimental
ROBINS-I tool Unclear Ortolan A & Ramonda R et al.
Longitudinal Newcastle Ottawa Low
JBS 2022; in press
cohort Scale
Elimination diets
Vegan (elimination of all animal-derived products) and Vegetarian diets
Insufficient data of a beneficial effect in inflammatory arthritides
Warning! Possible protein, iron, vitamin B12, zinc and calcium deficiency
Gwinnutt, RMD Open 2022. Daien, JBS 2021.
Dairy-free diet
No evidence of a beneficial role in inflammatory arthritides
Warning! Reduced calcium intake and increased risk of bone fractures, loss of beneficial effects
of fermented-diary (cardiovascular disease and cancer)
Kjeldsen-Kragh, Lancet 1991; Bian , BMC Public Health 2018.
Gluten-free diet
Insufficient data of a beneficial effect in inflammatory arthritides
Warning! elimination of minerals, fibers
Kjeldsen-Kragh, Lancet 1991; Bian , BMC Public Health 2018.

Fasting and ketogenic diet

Insufficient data of a beneficial effect in inflammatory arthritides: possibly a relevant effect is
mediated by calorie-restriction and weight loss
Gwinnutt, RMD Open 2022. Daien, JBS 2021; Ciaffi Frontiers Med 2021..
Agenda

The role of diet in arthritis

Dietary interventions in Rheumatic diseases

Patients Counseling

Conclusions
Recommendations

• Based on extensive literature • Inflammatory rheumatic diseases

review until 2018 • Specific recommendations on diet
• All rheumatic diseases
• General recommendations on diet
Patients counseling on diet - I
• Inform patients that nutrition may complement, not replace
pharmacological treatment
• Weight loss should be recommended in overweight patients,
associated with physical exercise
• Provide further specific dietary recommendations to patients with
other comorbidities (e.g. diabetes, cardiovascular disease,
osteoporosis, hyperuricemia, obesity)
• Promote a balanced diet and avoid elimination diets (gluten/dairy-
free diets)

Gwinnutt, Ann Rheum Dis 2022; Daien, JBS 2021.

Patients counseling on diet - II
• Omega-3 supplementation may be suggested (possibly
through consumption of fatty fish or nuts)
• Mediterranean diet may be recommended in rheumatic
patients for its benefits on comorbidities
• Spices: more frequent use (may be beneficial although data
are scarce)
• Coffee, alcohol: moderate consumption
• Salt and sugar: discourage consumption

Petersson, Autoimm Reviews 2018; Daien, JBS 2021.

Agenda

The role of diet in arthritis

Dietary interventions in Rheumatic diseases

Patients Counseling

Conclusions
 Conclusions

• Diet plays a central role in the development of inflammatory arthritis, as it pertains to

inflammation and autoimmunity

• Most available evidence is derived from rheumatoid arthritis studies, nonetheless data on
dietary interventions are lacking

• Omega-3 fatty acids have shown the best evidence of a beneficial effect

• The Mediterranean diet may be recommended in most patients owing to its positive effect
on comorbidities
 Galileo’s Chair
Rheumatology Unit, Padua University Hospital
Director Prof. A Doria
EULAR Center of Excellence in Rheumatology 2022-2027
Associate Professors Biologists PhD Students
Roberta Ramonda Anna Ghirardello Roberto Padoan
Paolo Sfriso Marta Tonello Chiara Franco
Luca Iaccarino Sara Bindoli Aula Magna, Bo’ Palace

Researchers Michela Gasparotto

Margherita Zen Chiara Baggio
Mariele Gatto Residents
Elisabetta Zanatta
Francesca Oliviero Enrico Fuzzi Mariangela Salvato
Michela Gasparotto Laura Scagnellato
Assistant Professors Debora Campaniello Filippo Visentini
Alessandro Giollo Giacomo Cozzi Marco Binda Anatomic Theatre
Rheumatologists Roberto Depascale Marta Codirenzi
(Outpatient clinic) Luana Ienna Federica Davanzo
Costantino Boktios Federico Arru Francesca Frizzera
Teresa Del Ross Claudio Cruciani Ilenia Anna Gennaio
Antonella Calligaro Anna Gamba Irina Guidea
Mariangela Favero Luca Iorio Federico Pettorossi
Mariagrazia Lorenzin Beatrice Moccaldi Zahra Rahme