Pesare?et?al.
Journal of Orthopaedics
Journal of Orthopaedics and Traumatology
and Traumatology
https://doi.org/10.1186/s10195-023-00729-z
Open Access
REVIEW ARTICLE
Italian Orthopaedic and?Traumatology
Society (SIOT) position statement
on?the?non-surgical management of?knee
osteoarthritis
1 1 2,3 4 5 1
Elisa Pesare , Giovanni Vicenti , Elisaveta Kon , Massimo Berruto , Roberto Caporali , Biagio Moretti and
6,7,8
Pietro S. Randelli
Abstract
Background Knee osteoarthritis (OA) is a chronic disease associated with a severe impact on quality of life. However,
unfortunately, there are no evidence-based guidelines for the non-surgical management of this disease. While recog-
nising the gap between scientific evidence and clinical practice, this position statement aims to present recommen-
dations for the non-surgical management of knee OA, considering the available evidence and the clinical knowledge
of experienced surgeons. The overall goal is to offer an evidenced-based expert opinion, aiding clinicians in the man-
agement of knee OA while considering the condition, values, needs and preferences of individual patients.
Methods The study design for this position statement involved a preliminary search of PubMed, Google Scholar,
Medline and Cochrane databases for literature spanning the period between January 2021 and April 2023, followed
by screening of relevant articles (systematic reviews and meta-analyses). A Società Italiana Ortopedia e Traumatolo-
gia (SIOT) multidisciplinary task force (composed of four orthopaedic surgeons and a rheumatologist) subsequently
formulated the recommendations.
Results Evidence-based recommendations for the non-surgical management of knee OA were developed, covering
assessment, general approach, patient information and education, lifestyle changes and physical therapy, walking
aids, balneotherapy, transcutaneous electrical nerve stimulation, pulsed electromagnetic field therapy, pharmacologi-
cal interventions and injections.
Conclusions For non-surgical management of knee OA, the recommended first step is to bring about lifestyle
changes, particularly management of body weight combined with physical exercise and/or hydrotherapy. For acute
symptoms, non-steroidal anti-inflammatory drugs (NSAIDs), topic or oral, can be used. Opioids can only be used
as third-line pharmacological treatment. Glucosamine and chondroitin are also suggested as chronic pharmacological
treatment. Regarding intra-articular infiltrative therapy, the use of hyaluronic acid is recommended in cases of chronic
knee OA [platelet-rich plasma (PRP) as second line), in the absence of active acute disease, while the use of intra-artic-
ular injections of cortisone is effective and preferred for severe acute symptoms.
Correspondence:
Giovanni Vicenti
dott.gvicenti@gmail.com
Full list of author information is available at the end of the article
? The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
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licence, visit http://creativecommons.org/licenses/by/4.0/.Pesare?et?al. Journal of Orthopaedics and Traumatology Page 2 of 9
Highlights
1. NSAIDs (topical or oral formulations) are a better choice for acute symptoms, compared with acetaminophen
in knee osteoarthritis non-surgical treatment.
2. SIOT recommend opioid use only while patients are waiting for surgical treatment, if NSAIDs are ineffective
against pain.
3. Considering intra-articular infiltrative therapy, the use of hyaluronic acid is recommended in cases of chronic
knee OA in the absence of active acute disease, while the use of intra-articular injections of cortisone is effective
and preferred for severe acute symptoms.
4. The use of growth factor injections and/or PRP in symptomatic knee OA is only favoured in highly specialised
centres
Keywords Osteoarthritis, Knee OA, SIOT position statement, Non-surgical management
Introduction review’. Inclusion and exclusion decisions were based on
Osteoarthritis (OA) is the most common form of arthri- group consensus. A second researcher (GV) indepen-
tis and a major cause of disability [1]. The most common dently verified the number of articles identified to avoid
site of OA is the knee joint, with an estimated overall potential discrepancies. Study characteristics and data
prevalence in the general adult population of 24% [2]. The were extracted onto a Microsoft Excel spreadsheet.
frequency of this condition is bound to increase further The following data were extracted for each study: first
due to population ageing. author, title, design of the study and year of publication.
Recommendations for the management of knee OA Initially, titles and abstracts of all records were reviewed.
have been published by several different scientific Only full-text articles written in English were included,
authorities including, amongst others, the Osteoarthritis and several articles were excluded after this preliminary
Research Society International (OARSI) [3], the Ameri- review process. Full-text copies of the studies were then
can College of Rheumatology (ACR) [4], the American obtained and assessed by the authors.
Academy of Orthopedic Surgeons (AAOS) [5, 6], the The Preferred Reporting Items for Systematic Reviews
European League Against Rheumatism (EULAR) [2] and and Meta-analyses (PRISMA) guidelines [7] were
the European Society for Clinical and Economic Aspects followed.
of Osteoporosis and Osteoarthritis (ESCEO) [1]. We The material was presented to the task force in an ini-
have collated recommendations from these sources and tial meeting. A total of 16,479 articles were identified
combined them with the results of an extensive literature in the following databases: PubMed, Cochrane, Med-
search, using our own expert knowledge to produce a set line and Google Scholar. Overall, 3654 duplicates were
of evidence-based recommendations for the non-surgical removed. After inspection of the titles and abstracts and
management of this condition. applying the inclusion criteria, a total of 30 studies were
reviewed further (Fig.?1).
In subsequent meetings, a schematic chart of conserva-
tive treatment recommendations for knee OA was agreed
Material and?methods
by task force members.
A working group of five Società Italiana Ortopedia e
The consensus of the working group was based on both
Traumatologia (SIOT) members was established, con-
evidence from the literature and expert opinion.
sisting of four orthopaedic surgeons and a rheumatolo-
By electronic communication, it was possible to draft
gist with extensive experience in the treatment of knee
the manuscript, sharing corrections and suggestions
OA and the analysis and interpretation of related evi-
from individual members with the rest of the team.
dence. One member of the task force (EP) collected the
Among the several available recommendations for the
literature, searching entries in PubMed, Google Scholar,
management of knee OA, those from the Osteoarthritis
Medline and Cochrane databases dated between January
Research Society International (OARSI) [3], the Ameri-
2011 and August 2021. Keywords for the search included
can College of Rheumatology (ACR) [4], the American
‘osteoarthritis’, ‘knee OA’, ‘guidelines’, clinical practice’,
Academy of Orthopedic Surgeons (AAOS) [5, 6], the
‘non-surgical management’ and ‘conservative treatment’,
European League Against Rheumatism (EULAR) [2] and
and the results were limited to ‘humans’, ‘randomised
the European Society for Clinical and Economic Aspects
controlled trial’, ‘meta-analysis’, ‘review’ and ‘systematic ≥≥≥
Pesare?et?al. Journal of Orthopaedics and Traumatology Page 3 of 9
available treatment strategies, to reduce the likelihood
of disease progression and severity. Awareness regard-
ing OA aetiology, risk factors (especially if modifiable),
expected prognosis and therapeutic strategies can help to
reduce misunderstandings and mistakes in patients (for
example, the misconception that physical exercise can be
harmful to the joints). Education of family members can
also be useful. Self-management and education are also
strongly recommended by the OARSI [9], EULAR [2],
AAOS [5, 6] and ESCEO [8].
Balneotherapy/spa therapy
Balneotherapy represents a conservative treatment that
may have beneficial effects on pain and stiffness, with a
tolerable economic profile [10]. It consists of the use of
thermal waters that are therapeutically active by virtue of
mineral composition, mud and natural gas. In numerous
papers, balneotherapy is described as a treatment with
favourable results [11, 12]. SIOT moderately recommend
the use in mild OA.
Canes, walking sticks, crutches, walkers
Depending on the severity of the disease and the needs of
each patient, these devices can aid walking, significantly
reducing the load on the lower limbs, improving stabil-
ity and assisting movement. The risk of falls also appears
to be reduced [4, 11]. Walking assist devices are strongly
recommended in patients with symptomatic knee OA.
Fig. 1 Flowchart of study selection
Exercise (land and?water based)
For individuals with knee OA, the types of exercises per-
formed on land include muscle strengthening, aerobic
of Osteoporosis and Osteoarthritis (ESCEO) [8] were
stretching and neuromuscular balance exercises, and
selected for examination.
more. [13] However, most importantly, any proposed
programme should be based on patient needs [8, 9].
Results
Water offers natural resistance, which helps strengthen
Lifestyle and?physical therapy
muscles [14, 15]; evidence shows that exercise in water
Weight management
provides improvements in pain and quality of life in peo-
This represents one of core treatments for knee OA, in
ple who are unable to perform land-based exercise due to
combination with exercise and self-management pro-
pain. SIOT consider land and/or aquatic exercise one of
grammes. SIOT strongly recommended core treatment
core treatments together with weight loss and self-man-
in early onset OA and in mild/moderate OA, as well as
agement and education.
in severe cases. Weight loss is considered to be effec-
tive in those who are overweight [body mass index
2 2
(BMI) 25? kg/m ) or obese (BMI 30? kg/m ). Specifi- Pulsed electromagnetic field therapy (PEMT).
cally, loss of 5% of body weight can be associated with Evidence that PEMT significantly improves pain and
changes in clinical and functional outcomes [4]. function in people with knee OA is low in quality due
to the short-term nature of the follow-ups described in
Self?management and?education the literature [16]. Thus, further studies with long-term
SIOT consider self-management and education one of follow-ups should be performed. Cardiovascular defi-
the core treatments together with weigh management ciencies, blood sugar levels disorders, blood coagulation
and exercises. Structured patient education programmes diseases and anti-coagulant therapies are relative con-
aim to inform patients about their condition and the traindications in PEMF treatment [5, 17]. There is a lack Pesare?et?al. Journal of Orthopaedics and Traumatology Page 4 of 9
of consensus in literature about duration, frequency, and characterised by short follow-up periods. Thus, SIOT
intensity of PEMF therapy sessions [18]. consider the available evidence insufficient to recom-
Nevertheless, PEMT has proved therapeutically effec- mend this procedure [16].
tive for bone- and cartilage-related pathologies and can
be used to reduce pain and stiffness [19].
PEMT may be used to improve pain and/or function in First?line pharmacological treatment (management
patients with mild knee OA [20]; therefore, the SIOT rec- of?acute symptoms)
ommendation is moderate. Acetaminophen (or paracetamol)
This is generally used to treat mild-to-moderate pain
[36]. It is weakly recommended as an initial pharmaco-
Bisphosphonate
logical approach in the presumption of its overall safety
Bisphosphonates are anti-resorptive agents (currently
[8, 37]. However, while the OARSI recommends against
used in the treatment of osteoporosis). They represent
its use in both the short and long term, the ESCEO and
a potential candidate for osteoarthritis therapy [21, 22].
ACR make a weak recommendation for its use in the
Results from evidences using bisphosphonates in OA
short term, and the AAOS strongly recommends its use
have been encouraging but controversial: some studies
[5, 5, 38]. SIOT moderately recommend acetaminophen
suggest neridronate is effective in OA treatment [23],
at doses no greater than 3?g/day in mild/moderate OA if
while others contend that clodronate could play a role
not contraindicated (in cases of hypersensitivity to aceta-
as a disease-modifying drug. OARSI is weakly favour-
minophen, severe hepatic impairment or severe active
able to risedronato due to the few studies in literature
liver disease) [5].
supporting its application as a reducer of the marker of
Topical non-steroidal anti-inflammatory drugs
cartilage degradation (CTX-II) which may contribute to
(NSAIDs).
slow the radiological progression of OA, particularly in
Topical use of NSAIDs is recommended as first-line
patients who are not overweight [24, 25]. On the other
treatment, particularly in patients with comorbidities,
side, AAOS and ACR do not recommend their use [5,
owing to their proven efficacy and low risk of gastrointes-
26]. Limitations of the studies included differences in
tinal (GI), cardiovascular or renal adverse events (OARSI,
the bisphosphonate analysed, the dose and the route of
ACR, ESCEO, AAOS). Topical NSAIDs can be applied as
administration [27]. Future studies are needed: SIOT rec-
gel, cream, spray or patch formulations to the skin of the
ommendation on their use is inconclusive.
affected area [4, 8]. SIOT strongly recommend their use
in patients with comorbidities with symptomatic knee
Oxygen–ozone therapy (O therapy)
3
OA.
Ozone is known for its anti-inflammation effect and
its work on cellular metabolism [28]. In knee OA, O
3
therapy is described as a safe approach with encourag-
Second?line pharmacological treatment (management
ing effects [29] with respect to pain control and func-
of?persistent symptoms)
tional recovery in the short-to-middle term [30], with an
Oral NSAIDs
almost null adverse event rate [31] especially in combi-
Oral NSAIDs are strongly recommended for use in knee
nation with other treatments [28].It is contraindicated in
OA. They are more effective than acetaminophen in most
patients with a significant deficit of G-6PD, in pregnancy,
people (OARSI, ACR, ESCEO, AAOS). The potential
in case of hyperthyroidism, thrombocytopenia and seri-
harms of NSAIDs are well known and include GI, renal
ous cardio-vascular instability [32]. SIOT recommenda-
and cardiovascular adverse effects. Elderly people, who
tion to its use in knee OA is limited.
are at higher risk of OA, are also at higher risk of expe-
riencing these side effects. Therefore, these drugs should
Transcutaneous electrical nerve stimulation (TENS)
be used with caution in elderly patients [39].
TENS uses a low-voltage electrical current delivered
SIOT recommends the use of non-selective NSAIDs,
through electrodes attached to the patient’s skin to
preferably with the addition of a proton pump inhibitor
stimulate peripheral nerve activity (neuromodula-
(PPI) or selective COX-2 inhibitors [40]. For individuals
tion) [33–35]. TENS can be generally delivered at two
with GI comorbidities, selective COX-2 inhibitors and
different dosing, high frequency (50e100?Hz) and low
non-selective NSAIDs in combination with a PPI are
frequency (2e10?Hz): the use of TENS is not recom-
conditionally recommended due to their benefits regard-
mended in people with pacemakers and women who
ing pain. Doses should be as low as possible, and NSAID
are pregnant should not apply TENS in the abdominal
treatment should be continued for as short period as
or pelvic regions [5]. The literature on this is highly
possible.
heterogeneous, and the available clinical trials are Pesare?et?al. Journal of Orthopaedics and Traumatology Page 5 of 9
Third?line pharmacological treatment (management
[38]. The ESCEO working group underline that the ben-
of?refractory symptoms)
efits of diacerein are more than its risks and confirms that
Duloxetine (anti?depressant drug)
it can be an option for knee OA treatment [42].
The analgesic efficacy of duloxetine in central pain is pre-
Diacerein should be avoided in patients with a propen-
sumably due to its influence on the descending pathways
sity for diarrhoea and could be useful in patients with
of pain inhibition, it is contraindicated in patients with
contraindications to NSAIDs [43].
liver failure or severe renal dysfunction, uncontrolled
However, SIOT do not recommend the use, due to its
angle-closure glaucoma and concurrent or recent therapy
cost and limited benefits.
with monoamine oxidase (MAO).
The OARSI [3], ACR [4] and ESCEO [37, 41] recom-
Chronic pharmacological treatments
mend this drug in patients with knee OA and widespread
Glucosamine and?chondroitin
pain and/or depression. The AAOS does not provide any
Glucosamine and chondroitin are strongly recommended
recommendations on its use [5, 5] Evidence suggests
against for knee OA, even though they are commonly
that duloxetine presents with some tolerability issues,
used in clinical practice. To date, the available studies
being associated with adverse events such as nausea,
are burdened by several discrepancies and biases. The
dry mouth, drowsiness, fatigue, constipation, decreased
OARSI and ACR, strongly recommend against the use
appetite and hyperhidrosis [4].
of glucosamine and chondroitin, AOOS [5, 5] consider
SIOT conditionally recommended duloxetine as the
this therapy helpful in improving functional outcomes in
last line of pharmacological therapy in patients who are
patients with mild/moderate knee OA, and conversely,
candidate for surgery treatment.
ESCEO [37] guidelines recommend these treatments as
first-line therapy.
Opioids (oral) The SIOT recommendation to use glucosamine and
Opioids can be appropriate for use if other therapies are chondroitin is weak, and is limited for individuals with
ineffective or if feasible surgical options are lacking. The chronic knee osteoarthritis [16]. According to data
OARSI does not recommend opioid use in patients who sheets, adults should take these supplements orally twice
have persistent symptoms over a long period of time, due a year, for almost 2?months each day at doses of 1200?mg
to the risk for development of tolerance [38]. Therefore, of glucosamine and chondroitin.
they should only be used for short periods and as a last Allergies to shellfish, asthma or patients using warfa-
resort [3, 5, 6, 26] before considering switching to surgi- rin or diabetes drugs are considered conditions that do
cal treatment. SIOT recommend the use of oral opioids not preclude the use of glucosamine, but individuals with
in short-term therapy in patients with refractory OA who these conditions should be closely monitored for any
are awaiting planned surgical treatment [11]. potential side effects including bloating, nausea, diarrhea
and constipation [43].
Opioids (transdermal)
In opioid-tolerant individuals, SIOT encourages the use Intra?articular injection treatments: first line (acute
of transdermal patch, rather than oral formulations. The symptoms)
indications are the same as for oral opioids: patients on Corticosteroids (intra?articular injection)
the waiting list for surgery, with refractory symptoms. Intra-articular glucocorticoid injections are strongly rec-
This formulation has delayed onset of effects but pro- ommended for patients with knee OA to relieve pain in
longed duration of action [26]. Application to the skin the short term (2–4?weeks). However, clinicians should
avoids first-pass hepatic metabolism, increasing bioavail- be cautious about the potential damage of repeated and
ability and limiting fluctuations in plasma concentration. long-term use (> 6? weeks) [44]. The AAOS provide a
However, the OARSI recommendations [3] discourage moderate recommendation for use, focusing on the risks
the use of opioids with transdermal patch formulation associated with repeated injections, while other societies
following poorly documented clinical benefits and the such as the OARSI, ACR and ESCEO recommend short-
high risk of addiction and adverse events [11]. term treatment. SIOT encourage the use in patients
with acute episodes of disease exacerbation once a week
for not more than 3?weeks [45], even though literature
Diacerein and?IL1?inhibition.
did not generally provide insights into a recommended
These drugs are a group of agents able to block the activ-
schedule for repeated injections. The repeated use of
ity of a proinflammatory cytokine, IL-1, which is believed
intra-articular glucocorticoids, particularly in mild-to-
to play a role in inducing the degradation of cartilage
moderate stages of knee OA severity, may have negative
matrix through the upregulation of proteolytic enzymes
effects, according to recent studies [46].Pesare?et?al. Journal of Orthopaedics and Traumatology Page 6 of 9
Absolute contraindications to the use of corticosteroid inconclusive recommendations for use [3, 5]. However,
injections are infection, sepsis and bacteremia, and joint given the increasing number of clinical studies [53]
instability. Juxta-articular osteoporosis (because of the describing better clinical outcomes when compared
risk of subchondral osteonecrosis and weakening of the with other conventional injectable treatments [50], this
joint structures), coagulopathy and long-term therapy are task force supports the use of growth factor and/or PRP
relative contraindications [47]. injections in symptomatic knee osteoarthritis [54]. SIOT
conditionally recommends PRP when other alternatives
Intra?articular injection treatments: first line (chronic have been exhausted or have failed to provide satisfactory
therapy) benefits.
Hyaluronic acid
Intra-articular hyaluronic acid (IAHA) shows a more Intra?articular injection treatments: third line (only
favourable long-term safety profile [40] than intra-artic- in?clinical trials)
ular corticosteroids. However, according to the OARSI, Mesenchymal stem cells (MSCs)
ACR and AAOS, there is little evidence regarding effec- These cell-based products can be used in suspension after
tiveness [3, 5, 26]. IAHA are ideal for patients who do expansion in culture or enzymatic digestion. At present,
not have adequate pain relief from oral medications their use is not recommended by scientific authorities [3,
(NSAID, acetaminophen), exercise and physical therapy, 4] because of the lack of standardisation in their prepara-
or patients with existing renal or gastrointestinal intoler- tion modalities [55], including sources of cells, processing
ance for NSAIDs [48]. methods, characterisation and administration technique
There is no absolute contraindication of intra-articular [56]. Nevertheless, MSCs can be used in highly special-
injection of HA other than acute inflammation in the ised centres, particularly in clinical trials, while they are
joint cavity, although the drug effect may be reduced in weakly recommended in daily clinical practice as they are
the following cases. It is prohibited for use in diseases still being studied.
such as extensive bone edema, bone fissure or stress
necrosis on magnetic resonance imaging (MRI), and Conclusions
acute diseases such as gout [5] and scleroderma [49]. For the conservative treatment of knee OA, SIOT
SIOT recommend IAHA once a week for 2–4?weeks, strongly recommends focusing on lifestyle changes as the
this treatment can be repeated after 12? months in first step, particularly weight loss in combination with
patients without knee swelling or flares: low-molecular- physical exercise and/or hydrotherapy. Patient self-man-
weight hyaluronic acid is recommended for early/mild agement and education can be very useful, particularly
knee OA, while high-molecular-weight intra-articular if family members are involved, while aids such as canes,
hyaluronic acid is preferable in patient with severe OA walking sticks, crutches and walkers are also extremely
who either are poor surgical candidates or must post- important to assist in walking. Balneotherapy represents
pone total knee replacement [27, 28] a conservative treatment that may have beneficial effects
on pain and stiffness and can be recommended.
Intra?articular injection treatments: second line (chronic Glucosamine and chondroitin are strongly recom-
therapy) mended in clinical practice for chronic treatment, while
Growth factor/platelet?rich plasma (PRP) injection NSAIDs (topical or oral formulations) are a better choice
PRP consists of a small volume of plasma with an for acute symptoms, compared with acetaminophen.
increased concentration of autologous platelets and is Specifically, SIOT recommends the use of oral non-selec-
prepared by blood centrifugation [50]. PRP injections tive NSAIDs (preferably with the addition of a PPI) or
are contraindicated in patients with haematologic blood oral COX-2 selective inhibitor NSAIDs.
dyscrasias with platelet dysfunction; septicemia or fever; SIOT recommend opioid use only while patients are
cutaneous infections in the area to be injected; anaemia waiting for surgical treatment, if NSAIDs are ineffective
(haemoglobin less than 10 deciliters; malignancy, par- against pain.
ticularly with hematologic or bony involvement; and Considering intra-articular infiltrative therapy, the use
allergy to bovine products if bovine thrombus is to be of hyaluronic acid is recommended in cases of chronic
used [5, 51]. knee OA in the absence of active acute disease, while the
Injection with PRP has the potential to improve pain use of intra-articular injections of cortisone is effective
and function for up to 1?year after treatment in patients and preferred for severe acute symptoms and represent
with mild-to-moderate knee OA [52]. However, there the best treatment choice if their use is allowed.
is no consensus about PRP formulation in the litera- The use of growth factor injections and/or PRP
ture, and most of the available society guidelines give in symptomatic knee OA is only favoured in highly
Pesare?et?al. Journal of Orthopaedics and Traumatology Page 7 of 9
Fig. 2 Flowchart of SIOT recommendations
Author details
specialised centres, and only after intra-articular hya-
1
Orthopaedic & Trauma Unit, Department of Basic Medical Sciences, Neurosci-
luronic acid therapy has failed. The use of MSCs should
ence and Sense Organs, School of Medicine, University of Bari Aldo Moro, AOU
2
also be restricted to highly specialised centres, particu-
Consorziale “Policlinico”, Piazza Giulio Cesare 11, 70100 Bari, Italy. Biomechan-
ics and Technology Innovation Laboratory, II Orthopaedic and Traumatologic
larly for clinical trials, while their use is not generally
3
Clinic, Rizzoli Orthopaedic Institute, Bologna, Italy. Nano-Biotechnology
recommended in daily clinical practice as research into
4
Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy. ASST Centro Special-
5
these cells is ongoing (Fig.?2).
istico Ortopedico Traumatologico Gaetano Pini, CTO, Milan, Italy. Depar tment
of Clinical Sciences and Community Health, University of Milan, and IRCCS S
6
Acknowledgements
Matteo Foundation, Pavia, Italy. Laboratory of Applied Biomechanics, Depart-
None.
ment of Biomedical Sciences for Health, Università Degli Studi Di Milano, Via
7
Mangiagalli 31, 20133 Milan, Italy. U.O.C. 1° Clinica Ortopedica, ASST Centro
Author contributions
Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Piazza Cardinal
8
PR conceptualization revision, supervision; EP statistical analysis, writing,
Ferrari 1, 20122 Milan, Italy. Research Center for Adult and Pediatric Rheu-
revision; MB and RC writing; GV revision; EK revision. All authors read and
matic Diseases (RECAP-RD), Department of Biomedical Sciences for Health,
approved the final manuscript.
Università Degli Studi Di Milano, Via Mangiagalli 31, 20133 Milan, Italy.
Funding
Received: 23 March 2023 Accepted: 15 August 2023
None.
Availability of data and materials
The data underlying this article are available in the article and in its online.
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