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Current Rheumatology Reviews, XXXX, XX, 1-27 1
REVIEW ARTICLE

Saudi National Clinical Practice Guidelines for Management of Adult

Systemic Lupus Erythematosus
Ahmed H. Al-Jedai1,2, Hajer Y. Almudaiheem , Ibrahim A. Al-Homood , Ibrahim Almaghlouth ,
1 3,4 5,6

7 1,8 9
Sami M. Bahlas , Abdulaziz Mohammed Alolaiwi , Mohammad Fatani , Maysa Tariq
Eshmawi10,11, Bedor A. AlOmari12, Khalidah Ahmed Alenzi13, Rayan G. Albarakati14 and Nayef Al
Ghanim15,*
1
Deputyship of Therapeutic Affairs, Ministry of Health, Riyadh, Saudi Arabia; 2Colleges of Medicine and Pharmacy,
Al Faisal University, Riyadh, Saudi Arabia; 3Medical Specialties Department, King Fahad Medical City, Riyadh, Sau-
di Arabia; 4Medicine Department, College of Medicine, Al Faisal University, Riyadh, Saudi Arabia; 5Department of
Medicine, College of Medicine, King Saud University. Riyadh11461, Saudi Arabia; 6College of Medicine Research
Center, King Saud University, Riyadh11461, Saudi Arabia; 7Department of Internal Medicine, Faculty of Medicine,
King Abdulaziz University, Jeddah21589, Saudi Arabia; 8Department of Rheumatology, King Saud Medical City,
Riyadh, Saudi Arabia; 9Hera General Hospital, Ministry of Health, Makkah, Saudi Arabia; 10King Abdullah Medical
Complex, Jeddah, Saudi Arabia; 11College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi
Arabia; 12Department of Pharmaceutical Services, Prince Sultan Military Medical City Riyadh, Saudi Arabia; 13Tabuk
Health Cluster, Tabuk, Saudi Arabia; 14Department of Obstetrics and Gynecology, Majmaah University, Al-Majmaah
11952, Saudi Arabia; 15Department of Rheumatology, King Saud Medical City, Riyadh, Saudi Arabia
© 2024 The Author(s). Published by Bentham Science Publisher. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

Abstract: Objective: To provide evidence-based clinical practice recommendations for managing

Systemic Lupus Erythematosus (SLE) in Saudi Arabia.

Methods: This EULAR-adapted national guideline in which a multidisciplinary task force utilized
the modified Delphi method to develop 31 clinical key questions. A systematic literature review
was conducted to update the evidence since the EULAR publication. After reaching a consensus
agreement, two rounds of voting and group discussion were conducted to generate consolidated re-
commendations/statements.
ARTICLE HISTORY

Results: A significant number of patients in Saudi Arabia experience delays in accessing rheuma-
Received: November 27, 2023
Revised: March 04, 2024 tologists, highlighting the significance of timely referral to SLE specialists or rheumatologists to
Accepted: March 10, 2024 ensure accurate diagnosis and prompt treatment. The primary goal of Glucocorticoid (GC) therapy
DOI:
in SLE patients is to establish disease control with a minimum dose and duration. Steroid-sparing
10.2174/0115733971275638240429063041 agent utilization facilitates steroid-sparing goals. Hydroxychloroquine is recommended for all
SLE patients, though physicians must carefully monitor toxicity and prioritize regular medication
adherence assessment. SLE management during pregnancy starts from preconception time by as-
sessing disease activity, major organ involvement, hypercoagulability status, and concomitant dis-
eases that may negatively impact maternal and fetal outcomes. Multidisciplinary care with close
monitoring may optimize both maternal and fetal outcomes. For patients with antiphospholipid
antibodies, low-dose aspirin prophylaxis is recommended. Also, Long-term anticoagulant medica-
tions are fundamental to prevent secondary antiphospholipid syndrome due to high thrombosis re-
currence.

Conclusion: This Saudi National Clinical Practice guidelines for SLE management provide evi-
dence-based recommendations and guidance for healthcare providers in Saudi Arabia who are ma-
naging patients with SLE. These guidelines will help to standardize healthcare service, improve
provider education, and perhaps lead to better treatment outcomes for SLE patients.

Keywords: Systemic lupus erythematosus, SLE, disease activity, guidelines, Saudi Arabia.

*Address correspondence to this author at the Department of Rheumatology, King Saud Medical City, Riyadh, Saudi Arabia; E-mail: N.alghanim@
ksmc.med.sa

1573-3971/XX XXXX Bentham Science Publishers

2 Current Rheumatology Reviews, XXXX, Vol. XX, No. XX Al-Jedai et al.

1. INTRODUCTION and the methodologist have worked alongside the medical

writers to conduct a Systematic Literature Review (SLR) to
Systemic Lupus Erythematosus (SLE) is an autoimmune
identify relevant studies addressing the clinical key ques-
disease affecting various body organs and systems [1]. It is
tions, following the EULAR Standardized Operating Proce-
characterized by autoantibodies that are produced against
dures (SOPs) and the Appraisal of Guidelines Research and
self-antigens, causing deposition of the immune complexes
Evaluation instrument (AGREE II) [8]. PubMed was used to
followed by inflammation and organ tissue damage [1]. SLE
conduct the systematic literature search using the relevant
has a variable course and wide presentations, with periods of
search terms, and the studies were screened and selected
flares and remission [2, 3]. Due to its chronic nature and po-
based on our predefined inclusion and exclusion criteria.
tentially life-threatening complications, it poses a significant
Since this guideline is adapted based on EULAR 2019 rec-
burden on patients, families, and healthcare systems world-
ommendations, we include all English-language publica-
wide.
tions from Jan-1995 till Nov-2022, with exceptions made for
The management of SLE requires a systematic approach sections discussed in EULAR 2019 recommendations [7] in
and a tailored treatment plan based on the individual patien- which the search was limited to publications after Jan-2019.
t's disease activity, organ involvement, complications, and More information on the search strategy can be found in Ap-
associated comorbidities. The current understanding of SLE pendix 1. The final evidence categorization, grading of rec-
pathogenesis and the availability of novel therapeutic op- ommendations, and level of agreement considered the quali-
tions have led to significant advancements in the manage- ty of evidence that supported our recommendations/state-
ment of SLE. ments. The Task Force developed a consensus of 70 state-
In Saudi Arabia, the prevalence of SLE is estimated to ments, grouped into five broad categories, and each member
be around 19 cases per 100,000 individuals, with a higher in- rated their agreement with each statement. The recommenda-
cidence in women and young adults [4]. The burden of SLE tions were formulated based on the evidence and expert
on patients and healthcare systems is significant, with a high consensus, considering the balance between benefits and
risk of morbidity and mortality and decreased Quality of harms, patient preferences, and resource implications. After
Life (QoL) [5]. Furthermore, the rapid development of new two rounds of voting and discussion, the final statements
therapeutics and the rising cost of such therapies underscore were consolidated after getting the agreement of more than
the necessity for standardized and evidence-based recom- 75% of the members' votes. We ensured that our recommen-
mendations in managing SLE. dations were based on the best available evidence and expert
consensus and that they were relevant and applicable to clini-
This paper aims to provide the Saudi national clinical cal practice in Saudi Arabia (Supplementary Appendix 1).
practice recommendations for SLE management, highlight-
ing the key recommendations and their rationale. It also dis- 3. RESULTS
cusses the implications of these recommendations for clini-
cal practice, research, and healthcare policymaking in Saudi The search strategy retrieved 13400 records; 7300 re-
Arabia and the Middle East. These evidence-based clinical cords underwent title/abstract screening. One hundred eigh-
practice recommendations are expected to improve the quali- ty-three records were sought for retrieval, and finally, 112
ty of care and treatment outcomes for SLE patients in Saudi studies were eligible to be included (Fig. 2).
Arabia and serve as a crucial resource for clinicians and re-
3.1. Overarching Principles
searchers in the Middle East and worldwide.
Despite the significant advances in treatment regimens
2. METHODS that have led to a better prognosis, there are numerous chal-
The Saudi group of experts (task force) has adopted the lenges and unmet needs in diagnosing and treating SLE. The
European League Against Rheumatism (EULAR) methodol- diagnosis of SLE is complex and requires a comprehensive
ogy to develop national clinical practice guidelines and rec- evaluation of both clinical and serological findings. While
ommendations in response to the current needs [6, 7]. Our classification criteria can help guide the diagnosis process,
methodology involves a rigorous and transparent process to they should not be used in isolation to diagnose or exclude
ensure high intrinsic quality and credibility in our evi- SLE. SLE disease activity and damage accrual monitoring
dence-based recommendations (Fig. 1). After approval from are crucial in SLE management. The disease activity and da-
the Saudi Ministry of Health, the convenor (IH) and the mage score indices can be used to build these activities. Mul-
methodologist (IM) have invited our multidisciplinary task tidisciplinary care in lupus centers is preferable for patients
force consisting of nine experts in SLE management, includ- with advanced disease.
ing rheumatologists, dermatologists, and pharmacists, to
3.2. Introduction of Common Drugs in SLE
work on developing these national clinical practice recom-
mendations. We used the Modified Delphi method and devel- 3.2.1. Glucocorticoids/Steroids
oped 31 clinical key questions covering the most important
clinical aspects of SLE management, with input from all The potent anti-inflammatory properties of glucocorti-
members of the Task Force. Due to the complexity and rich coids (GCs) justify their use for managing SLE [9, 10]. GCs
literature on the topic, we deferred guidelines for lupus are used in SLE for controlling disease activity, decreasing
nephritis to a separate subsequent publication. The convenor inflammation, and preventing disease flares in SLE patients;
Saudi National Clinical Practice Guidelines for Management Current Rheumatology Reviews, XXXX, Vol. XX, No. XX 3

however, several potential adverse events are related to GC initial dose of steroids depends on the severity of the disease
usage, including osteoporosis, diabetes, hypertension, and the involved organs. To optimize treatment and control
weight gain, and an increased risk of infection [11-14]. disease flares, intravenous steroid pulses at varying dosages
Thus, the primary goal of GC therapy in SLE patients is to can be utilized. This approach capitalizes on the immediate
establish disease control with a minimum dose and duration non-genomic effects of GC, allowing for a lower initial dose
as well as utilize steroid-sparing agents to reduce the need and faster tapering [16]. In cases of acute organ-threatening
for GCs [15]. disease, such as neuropsychiatric involvement, a high dose
The risks associated with continuous doses of GC ex- of intravenous steroids (typically 250-1000 mg/day for three
ceeding 7.5 mg/day are significantly increased, and some days) is commonly administered, provided that infections
studies suggest that even lower doses may be harmful. The have been ruled out [17].

Fig. (1). Methodology flowchart. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
4 Current Rheumatology Reviews, XXXX, Vol. XX, No. XX Al-Jedai et al.

Fig. (2). PRISMA flow chart for systematic literature review. (A higher resolution / colour version of this figure is available in the electronic
copy of the article).

The goal was to reduce the daily doses to ≤7.5 mg/day 3.2.2. Hydroxychloroquine
of prednisone equivalent or to stop them altogether [18, 19] All SLE patients ought to receive Hydroxychloroquine
to avoid long-term GC therapy-related complications, includ- (HCQ). The advantages of HCQ in SLE are broad, and pa-
ing irreversible organ damage [15, 20-22]. The ultimate goal tients report improvements in constitutional symptoms, Mus-
of GC discontinuation is related to the observations of side culoskeletal (MSK) manifestations, and mucocutaneous
effects, even on low doses [23]. For example, a low-dose signs [29, 30]. Evidence from a few trials highlights that
GC, 5.0-7.5 mg prednisolone, was found to increase the in- HCQ decreases the frequency of flares [30-33] and reduces
fection risk, as shown in a time-dependent Cox regression thrombotic events, organ damage, and death [30, 34-36]. De-
analysis of 509 SLE patients from the Japanese SLE registry spite HCQ’s various advantageous effects in SLE, medica-
data suggesting that prednisolone dosage in SLE patients tion noncompliance is prevalent [30, 37, 38]. While detect-
should be as low as possible to prevent infection [23]. ing blood drug levels is a useful compliance assessment tool
A more realistic goal is Lupus Low Disease Activity and a guide to effective therapeutic level targets, its applica-
State (LLDAS), which has been offered and verified as a sus- bility in clinical practice is limited due to its unavailability
tainable target to be sought in SLE care [24, 25]. Less organ in the commercial market [37, 39]. Antimalarial medications
damage accumulation and higher quality of life have been are often well tolerated, and severe adverse effects are un-
linked to prolonged remission and LLDAS. An SLE patient common. However, with a frequency of more than 10% for
with long-term minimal disease activity and no recent flare- retinal abnormalities after 20 years of continuous usage, con-
ups for 4-6 months, even with prior severe organ involve- cerns about vision-threatening toxic retinopathy due to long-
ment, is a suitable candidate to begin GC withdrawal term HCQ treatment prompted the introduction of more sen-
[26-28]. sitive screening methods [40, 41]. Baseline and regular
Saudi National Clinical Practice Guidelines for Management Current Rheumatology Reviews, XXXX, Vol. XX, No. XX 5

screening is performed to detect any retinal toxicity before it cy, and decreased CS usage in individuals with severe organ
causes visual impairment, and the primary screening tools involvement [49, 50]. Its inferiority to Cyclophosphamide
are automated visual fields and Spectral Domain Optical Co- (CYC) led to a decline in its usage for induction in lupus
herence Tomography (SD-OCT) [42]. A fundus examination nephritis throughout the subsequent decades [51, 52]. AZA
of the macula should be part of the initial examination to is commonly used to treat extrarenal lupus and is considered
rule out any underlying condition that might confound a corticosteroid-sparing medication [53]. For individuals
screening test results. Individualized risk assessment allows with inadequate disease control after a trial of HCQ, it is rec-
for flexible follow-up screening schedules throughout the ommended to consider MTX or AZA as they are widely
first five years of therapy. The American Academy of Oph- used and generally safe options [47].
thalmology (AAO) recommends waiting five years after first Mycophenolate Mofetil (MMF) has been shown to be ef-
exposure for follow-up tests in individuals with normal base- fective in renal and extra-renal manifestations [54-56]. Enter-
line exams and no significant risk factors for toxic retinopa- ic-Coated Mycophenolate Sodium (EC-MPS) has been used
thy [42]. A daily HCQ dosage of more than 5 mg/kg actual in cases intolerant to MMF in many immunosuppressant reg-
body weight, antimalarial usage for >5 years, renal disease, imens to improve quality of life [57]. It is not universally rec-
concurrent tamoxifen use, and/or macular disease are all ma- ommended in women of reproductive age due to its higher
jor risk factors for toxic retinopathy [42]. cost and teratogenic risk; it must be stopped at least six
The daily HCQ dosage was recommended not to exceed weeks prior to conception [58, 59]. A Cochrane systematic
5 mg/kg of actual body weight (up to a maximum of 400 mg review echoed this finding but with poor certainty evidence
daily). While the dosing with 5 mg/kg/real BW might be as- [60]. Given the concerns about the reproductive toxicity of
sociated with less eye toxicity, more recent evidence MMF and the acknowledgment that CYC has more serious
suggests a higher level might be warranted to achieve better reproductive risks, an alternative drug that is commonly con-
disease activity. Several studies found a reduced flare rate as- sidered for patients with organ injury in SLE is AZA. AZA
sociated with higher HCQ doses [43]. These findings pro- is often chosen in cases where MMF might not be universal-
vide preliminary evidence that reducing the daily HCQ ly recommended, especially in women of reproductive age
dosage to 5.0 mg/kg/day of actual body weight may impact [61]. While AZA also has considerations and should be used
the frequency of flares in a population of people with SLE. cautiously, it is sometimes preferred due to its established
Vázquez-Otero et al. documented that adjusting the daily safety profile during pregnancy compared to MMF [61]. Ad-
dosage of HCQ to ≤5.0 mg/kg/day of real body weight did ditionally, it does not carry the same level of reproductive
not affect the short- and mid-term outcomes [44]. There is toxicity as Cyclophosphamide [62, 63].
an increased risk of SLE flares following tapering or stop- Although CYC therapy effectively treats severe organ in-
ping HCQs [31]; therefore, physicians should be cautious. volvement, it has been associated with teratogenicity [64,
Hyperpigmentation can occur in patients undergoing long- 65], hemorrhagic cystitis [66], male and female gonadal
term treatment with chloroquine or HCQ [45]. Patients with toxicity [67-74], bladder and other cancers [75-77], leukope-
diseases linked with easy bruising (for example, using antico- nia [78], hyponatremia, as well as infections. During preg-
agulants or antiplatelet medications) appear to be more sus- nancy, CYC should be avoided except for disease complica-
ceptible to developing pigmented lesions, and these lesions tions that pose grave health threats to the mother. In organ-
are typically preceded by local ecchymotic alterations [45, or life-threatening occasions, administering CYC to preg-
46]. HCQ use is compatible with pregnancy and breastfeed- nant women is an option after a detailed discussion of such
ing. Shared decision-making should be considered between treatment's potential risks and benefits with the patient or
physicians and patients who flare on doses within 5 their substitute decision-maker [64, 65, 79]. Moreover, CYC
mg/kg/real body weight regarding the use of higher doses therapy has been associated with lower testosterone and
(up to 400 mg/day, regardless of the BW) and the frequency sperm abnormalities [66, 67]. Thus, CYC should be utilized
of ophthalmological screening for toxicity. cautiously in fertile women and men. Some evidence sup-
ports that in premenopausal individuals with SLE, utilizing
3.2.3. Immunosuppressive/Cytotoxic agents
Gonadotropin-Releasing Hormone agonists (GnRHa) 10-14
Evidence supports using Immunosuppressive (IS) and cy- days before the administration of CYC therapy may reduce
totoxic agents to manage severe lupus activity affecting ma- the risk of ovarian reserve loss [68-70]. A recent meta-analy-
jor organs. Consecutive administration of IS medications fa- sis documented that women of reproductive age with autoim-
cilitates rapid tapering of GC and prevents disease flare-ups mune rheumatic disease may benefit from GnRHa when
[47]. The agent used is determined according to the preva- combined with intravenous CYC [71].
lent disease symptoms, the patient’s age and reproductive po-
Calcineurin Inhibitors (CNIs) are a class of immunosup-
tential, safety considerations, and costs.
pressive agents that decrease T-cell activation by targeting
Methotrexate (MTX) demonstrated efficacy in treating the calcium/calmodulin-dependent phosphatase calcineurin
joint and skin conditions, reducing disease activity, minimiz- [80]. Agents such as cyclosporine A and tacrolimus are wide-
ing corticosteroid usage, and improving anti-dsDNA and ly utilized in organ transplantation. These agents decrease
complement levels [48]. The use of Azathioprine (AZA) has calcineurin activity by binding to cyclophilin and FKBP12,
been associated with lower mortality, reduced flare frequen- respectively [81]. This binding inhibits the nuclear transloca-
6 Current Rheumatology Reviews, XXXX, Vol. XX, No. XX Al-Jedai et al.

tion of critical transcription factors such as NF-AT, inhibit- patients with and without lupus nephritis who have not re-
ing IL-2 gene transcription [82]. Several prospective and ret- sponded to standard therapy [102-106]. Short-term improve-
rospective studies have highlighted the efficacy of CNIs in ments were seen among patients with active SLE refractory
addressing both renal and extrarenal manifestations of SLE to GCs and/or immunosuppressive agents regarding disease
[83-86]. Recent Randomized Controlled Trials (RCTs] fur- activity, immunologic parameters, arthritis, and thrombocy-
ther validate the noninferiority of CNIs compared to traditio- topenia, as well as a GC-sparing effect [107]. On the other
nal IS agents in the induction and maintenance therapy of lu- hand, the EXPLORER and LUNAR trials revealed no signif-
pus nephritis [87-89]. Moreover, a combination of low-dose icant advantage of RTX compared with controls [108, 109].
tacrolimus and MMF showed superiority over CYC pulses Each study failed to assess the effectiveness of RTX because
in inducing remission of lupus nephritis in Chinese patients both control groups were given high dosages of GCs in addi-
[90]. tion to immune suppression. RTX is only used off-label for
Previous studies support the use of CNIs in SLE treat- individuals with severe renal or extrarenal disease refractory
ment, with a study by Mok et al. indicating significant im- to other IS agents or in patients with contraindications to th-
provement in renal function and reduced disease activity in ese drugs due to the negative results of RCTs [7].
lupus nephritis patients treated with tacrolimus [ 91 ]. Addi- Combined therapy with RTX and BLM halted the repop-
tionally, another study by Liu et al. highlighted the efficacy ulation of all B cells (including DN B cells) and simultane-
of cyclosporine in achieving remission in lupus nephritis cas- ously reduced SLE-relevant autoantibodies. Further research
es [ 90 ]. These findings highlight the valuable role of CNIs on RTX and BLM is warranted in light of the positive im-
as a therapeutic option for SLE, particularly in lupus nephri- munological and clinical effects shown in a cohort of pa-
tis. tients with severe therapy-refractory SLE [110].
3.2.4. Biological Agents 3.3. SLE Flares
Belimumab (BEL), a monoclonal antibody, blocks solu- SLE patients may have unexpected disease flares and re-
ble human B lymphocyte stimulator from binding to B cell missions throughout their clinical course. While there is no
receptors, reducing B lymphocyte survival [72, 73], and it
universal agreement on what defines a “flare,” many physi-
was the first biological therapy approved in Europe and the
cians agree that it is an increase in the disease activity that is
United States to be used for SLE. Current evidence supports
significant enough to warrant a therapy change [111-113].
BEL’s consistent efficacy against MSK and skin manifesta-
As disease flares are prevalent and contribute considerably
tion and satisfactory safety profile in SLE patients [74-78,
92, 93]. Add-on therapy with BEL might be considered for to the accrual of organ damage and less favorable outcomes
patients who do not adequately respond to, or are intolerant [114-117], avoiding such flares is a crucial goal of SLE ther-
of, standard-of-care, as characterized by persistent disease apy [115-117]. Younger age at disease onset, non-com-
activity that does not permit tapering of GC and/or recurrent pliance with the antimalarials, chronic generalized disease
relapses [7]. activity, and serological activity have all been documented
constantly as risk factors for an increased disease flare rate
Anifrolumab, a monoclonal antibody to the type I inter- [25, 118-121]. Flares can be avoided in this population by as-
feron (IFN) receptor, was approved for treating moderate to sessing adherence to pharmacological therapy, careful moni-
severe SLE patients receiving standard therapy (excluding toring, and optimizing disease care. Many studies showed
severe active lupus nephritis or neuropsychiatric SLE) [94]. that belimumab and anifrolumab reduced the flare rate of
The approval was based on the findings from three ran- SLE [122-124].
domized trials demonstrating that there was a reduction in
overall disease activity and GC dose with adding anifrol- 3.4. Gaps and Challenges Regarding the Pharmacologic
umab to standard therapy in the patient group compared Treatment of SLE in KSA
with placebo [95-97]. In a recent study, 36.4% of patients
treated with anifrolumab were GC-free (0 mg/day) at year 4, Depression and non-adherence to treatment are common
and 74.4% were receiving a dosage of 0 to 5 mg/day, which among Saudi patients with SLE [125]. The complexity and
may have contributed to the decreased serious adverse duration of treatment plans might put patients at risk for fail-
events rate [98]. ing to adhere to their medications. Medication non-adher-
ence among SLE patients is associated with disease flares,
Anifrolumab shows a good safety profile [97]. Anifrol- poor quality of life, and higher expenditures to the health-
umab’s role in therapy is still being determined, but it ap- care system [126, 127]. Several factors can influence pa-
pears to be especially beneficial for patients with skin and tients' compliance with medication, including access to
joint involvement [98] as well as hematological manifesta- healthcare systems and services [125, 128]. Saudi Arabia’s
tion [98]. Anifrolumab has emerged as a potential treatment healthcare system offers free services to all Saudi nationals,
option for refractory cutaneous lupus [96, 99, 100].
with the government covering the costs [129]. This feature
The role of RTX, a B cell-depleting chimeric monoclon- eliminates the influence of patients’ income on compliance.
al antibody, in treating SLE patients remains uncertain Despite this, up to 62.1% of the patients acknowledged medi-
[101]. RTX has been shown to be effective in treating SLE cation non-adherence [125]; this is crucial for developing a
Saudi National Clinical Practice Guidelines for Management Current Rheumatology Reviews, XXXX, Vol. XX, No. XX 7

strategy to increase drug adherence. rheumatologists, highlighting the importance of early refer-
ral to SLE specialists or rheumatologists for accurate diagno-
The time of diagnosis and treatment of SLE are crucial
sis and prompt treatment [134].
and impact survival and quality of life, as delays in therapy
have been associated with a worse prognosis [130-133]. In The agreed recommendations/statements on the pharma-
Saudi Arabia, many patients experienced delays in accessing cologic treatment of SLE are presented in Table 1.

Table 1. Expert recommendations and statements on pharmacologic treatment of SLE.

Percentage of
Statement/Recommendation
Agreement
Glucocorticoids/Steroids
Whenever a high dose of steroids is needed, we recommend pulses of IV methylprednisolone (typically 250-1000 mg daily, for 1-3 days) in
100%
order to achieve an immediate therapeutic effect while minimizing steroid exposure through the use of a reduced initial dose of oral GC.
GC dosage for chronic maintenance regimens should be decreased to less than 5 mg daily (prednisone equivalent) and, when feasible, dis-
100%
continued.
Withdrawing GC medications is possible after achieving remission or a lupus low disease activity state (LLDAS). This can help reduce the
77%
risk of side effects associated with long-term GC use. However, careful monitoring is crucial as flares can still occur after stopping GC.
Despite the benefits supporting GC withdrawal, close observation after withdrawal is required and advisable due to the risk of a flare-up 89%
Rapid initiation of immunomodulatory drugs can hasten the GC tapering/discontinuation 89%
Hydroxychloroquine
Previously, the maximum dose of HCQ was 5 mg/kg/real BW, while recent evidence supports higher dosing (up to 400 mg/day, regardless
100%
of the BW).
The current evidence regarding the impact of HCQ dose tapering on the short-term and midterm outcomes in SLE is controversial. There-
88%
fore, the decision to maintain or reduce HCQ should be personalized according to different subgroups of patients.
In patients who are using an HCQ dose higher than 5 mg/kg/real BW or have renal impairment, ophthalmological screening (by visual
77%
fields examination and/or spectral domain-optical coherence tomography) should be performed on an annual basis.
Immunosuppressive/Cytotoxic Agents
The choice of immunosuppressive/cytotoxic agents depends on the predominant disease symptom(s), age, possibility of pregnancy, and safe-
100%
ty considerations.
MTX and AZA should be taken into consideration for patients who have poor symptom control following a trial with GC and HCQ or when
100%
HCQ alone is not sufficient due to the experience acquired with their utilization and their overall safe profile.
In organ-threatening diseases (especially renal, cardiopulmonary, or neuropsychiatric) CYC may be used and only as a rescue therapy for re-
100%
fractory non-major organ symptoms; due to its gonadotoxic effects, it should be used with caution in patients of reproductive age.
Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium can be used instead of CYC and or azathioprine (AZA) in patients
89%
with active systemic lupus erythematosus.
Biological Agents
For patients who do not respond adequately to standard-of-care treatments (combinations of HCQ, GC, and immunosuppressive agents) or
who develop intolerance to them (as defined by residual disease activity that prevents tapering of glucocorticoids and/or frequent relapses), 100%
additional treatment with belimumab and anifrolumab should be contemplated.
Belimumab or anifrolumab are considered therapeutic options for patients with SLE with mucocutaneous and/or musculoskeletal manifesta-
100%
tions with a manageable safety profile.
The only indications for off-label prescription of RTX are in patients who have severe renal or extrarenal (mainly hematological and neu-
100%
ropsychiatric) disease resistant to other IS agents and/or belimumab and anifrolumab or when these drugs are contraindicated.
SLE Flares
Preventing the flares represents an extra milestone of SLE treatment. Although there is no agreed-upon definition, the majority of experts
100%
agree that a flare is a measurable escalation in the activity of a disease, usually leading to treatment change.
Assessment of adherence to drug treatment, close monitoring, and optimization of disease control in these patients may reduce the risk of a
100%
flare
GC withdrawal should be made with caution, especially in patients with serologically active yet clinically quiescent to avoid flare. 100%
Gaps and Challenges
Medication adherence is not optimal in SLE patients, including Saudi populations. A routine review of treatment compliance during each
100%
visit may ensure medication adherence.
8 Current Rheumatology Reviews, XXXX, Vol. XX, No. XX Al-Jedai et al.

3.5. Specific Manifestations of SLE ychloroquine is another standard treatment for cutaneous LE
because of its efficacy and better side effect profile com-
3.5.1. Skin Involvement pared to chloroquine [144, 145]. In individuals with aggres-
The subtype of the disease influences the approach to sive, rapidly progressing disease, a combination of systemic
and local treatment is the most effective approach. Particular-
treating skin-specific manifestations of LE. General treat-
ly during the initial weeks of treatment, topical GC serves as
ment measures include stopping smoking and sun protection
a bridge therapy until the slower-acting systemic medicines
measures by applying 50 or greater sun protection factor sun-
take effect. Intralesional GC may treat individuals with per-
screen in adequate amounts (2mg/cm2) at least 20 to 30 min-
sistent DLE lesions that have not responded to systemic or
utes before known exposure and optimizing vitamin D lev-
topical CNIs [146].
els [135].
MTX has demonstrated effectiveness in managing pa-
Initial therapy for cutaneous lupus erythematosus (CLE) tients with refractory localized DLE with an acceptable safe-
is based on the extent and level of skin involvement. The ini- ty profile [147]. However, certain well-known adverse ef-
tial approach involves topical CSs and CNIs, alongside anti- fects (gastrointestinal responses, increase of liver enzymes,
malarial medications [136]. Local treatment is generally ade- and pancytopenia) necessitate monitoring blood tests. AZA
quate for patients with Discoid lupus erythematosus (DLE) and CYC should not be used for CLE without systemic in-
or subacute cutaneous lupus erythematosus (SCLE), which volvement since there is insufficient evidence in the litera-
affects a small portion of the body. ture and no control studies to back up their routine usage
Because topical CNIs are higher in cost than other topi- [142, 143, 148]. However, AZA, particularly in resistant
cal GCs, topical GCs are frequently used as a first-line thera- leukocytoclastic vasculitis, has demonstrated good outcomes
py [136]. Additionally, compared to topical tacrolimus, in non-specific cutaneous LE symptoms [146]. Recent
some research indicates ultra-high-potency topical GCs are studies on the use of thalidomide and lenalidomide in indivi-
more effective for DLE. The effectiveness of topical GC has duals with CLE have shown encouraging benefits; however,
been shown in several early studies [137-139]. Nevertheless, side effects, such as peripheral neuropathy and thromboem-
physicians and patients must be aware of the potential ad- bolic events associated with thalidomide, and cytopenia asso-
verse effects of long-term use of these medications, includ- ciated with lenalidomide, may restrict their usage [149]. It
ing skin shrinkage, telangiectasia, striae, solar purpura, and should only be considered a “rescue” therapy as a result of
hypertrichosis. Topical CNIs are preferably used on the face its explicit contraindication during pregnancy and the side ef-
and other regions of delicate skin or on skin damaged by pro- fects [150, 151] (Supplementary Tables 1-3).
longed use of topical GC [140, 141]. Biological treatment options include belimumab and ani-
Systemic GC therapy is an option for those with aggres- frolumab, which have demonstrated efficacy in treating mu-
sive, rapidly progressive diseases. Systemic antimalarial cocutaneous manifestations of SLE without any notable in-
medication is preferable when local treatment is infeasible crease in significant side effects [74, 95, 99, 152-155].
due to widespread disease or when limited disease does not The agreed recommendations/statements on the manage-
respond sufficiently to local treatment [142, 143]. Hydrox- ment of skin involvement in SLE are presented in Table 2.

Table 2. Expert recommendations and statements on the management of skin involvement in SLE.

Percentage of
Statement/Recommendation
Agreement
Skin Involvement
For patients with Cutaneous Lupus Erythematosus (CLE), general measures to be considered include smoking cessation and sun protection
measures by applying 50 or greater Sun Protection Factor (SPF) sunscreen in adequate amounts (2mg/cm2) at least 20 to 30 minutes be- 100%
fore known exposure in addition to optimization of vitamin D levels.
Topical agents (GC and/or CNIs) and antimalarials, with or without systemic GC, depending on the severity of skin involvement, are the
100%
recommended first-line treatment for SLE.
Prolonged use of topical corticosteroids is known to cause atrophy, telangiectasia, and steroid-induced rosacea-like dermatitis. Therefore,
100%
topical CNIs can be used as effective steroid-sparing agents in areas at high risk of steroid complications (e.g., facial skin).
HCQ is preferred as antimalarial over chloroquine due to its numerous beneficial effects and feasibly lower risk for retinal toxicity. 100%
MTX or other agents, such as retinoids, dapsone, MMF, or EC-MPS, can be used when first-line treatment fails to show a response in
100%
SLE.
Belimumab and anifrolumab can be considered in resistant mucocutaneous manifestations of SLE after the failure of immunosuppressive
100%
therapy.
Saudi National Clinical Practice Guidelines for Management Current Rheumatology Reviews, XXXX, Vol. XX, No. XX 9

3.5.2. Musculoskeletal Manifestations of SLE 3.6. Treatment of Specific Conditions

MSK involvement is a common feature in patients with 3.6.1. Pregnancy
SLE. Previous studies have shown that more than 50% of
Saudi SLE patients experience MSK manifestations during Active SLE at conception is associated with a higher risk
their disease journey, which include polyarthritis, arthralgia, of maternal and obstetric adverse outcomes [150, 173].
Distinguishing pregnancy-related physiologic changes from
and myalgia [156-159]. In addition, these symptoms can sig- disease-related symptoms during flare-ups in SLE pregnan-
nificantly impact patients' quality of life and overall disease cies is challenging. Thus, optimizing maternal and fetal out-
prognosis [160]. comes necessitates a multidisciplinary team, including inten-
HCQ and MTX are commonly used to manage MSK sive medical, obstetric, and neonatal monitoring [151]. Poor
manifestations in patients with SLE. However, in cases obstetric outcomes and flares should be tracked with the
where there is no adequate response to these medications, al- help of assessments of disease activity, such as renal func-
tion measures and serological markers [70]. Active disease,
ternative treatment options can be considered. Biological
antihypertensive medication, earlier lupus nephritis, pree-
agents such as belimumab inhibit the B-lymphocyte stimula- clampsia, eclampsia, antiphospholipid antibodies (aPL) pres-
tor. Belimumab has shown promising results in improving ence, primigravidas, and thrombocytopenia have all been re-
MSK outcomes and improving the overall disease activity of ported as indicators of unfavorable outcomes among preg-
SLE when other therapies have been ineffective [161-164]. nant women with SLE [174-176].
Furthermore, studies on anifrolumab have demonstrated sig-
Pregnancy should be sought after six months of disease
nificant improvement in MSK manifestations compared to remission on pregnancy-compatible medications [177-179].
placebo. Anifrolumab also exhibits a steroid-sparing effect, Even in the absence of active disease, medication adjust-
which can benefit patients with SLE who require long-term ments may be required to ensure the well-being of both the
CS use [97]. mother and the fetus. A preconception evaluation is recom-
mended for women with SLE to assess potential risks to
3.5.3. Hematological Manifestations of SLE both the fetus and mother during pregnancy.
Frequent hematological abnormalities are identified in HCQ should be continued for all SLE women during
patients with SLE, with anemia and leukopenia being the pregnancy to lower the probability of SLE flares. Patients
most common manifestations among Saudi SLE patients who continue HCQ during pregnancy have shown benefits,
[157, 159, 165]. Anemia in SLE can result from hemolytic including a lower incidence of preeclampsia, as demonstrat-
anemia or anemia of chronic disease and other causes (e.g., ed in previous studies [180-187].
bleeding), which can contribute to fatigue and diminished Blood pressure monitoring, disease activity control using
quality of life [157, 165, 166]. Other hematologic manifesta- safe medications, especially HCQ, and limiting GC expo-
tions of SLE include thrombocytopenia and lymphopenia [4, sure are recommended in SLE pregnant patients [70, 188].
165-167]. Thrombocytopenia may increase bleeding risk, Patients with SLE have a 16-30% higher likelihood of de-
while lymphopenia may impair the immune system and in- veloping preeclampsia. It has been established that initiating
crease susceptibility to infections [168, 169]. aspirin treatment between 12 and 16 weeks of pregnancy re-
The treatment of such abnormalities necessitates a collab- duces the absolute risk of preeclampsia in women at in-
orative, multidisciplinary approach. Excluding drug-induced creased risk, including SLE [189, 190]. It has been shown
that combination treatment with LDA and low molecular
cytopenias is imperative in the assessment of cytopenic con- weight heparin is more effective than monotherapy in reduc-
ditions. Mild cytopenias usually necessitate no specific treat- ing the likelihood of poor pregnancy outcomes among wom-
ment. However, for moderate to severe cytopenias, GCs en with SLE-associated APS or primary APS.
serve as the primary therapeutic approach, with AZA, or in-
frequently cyclosporine-A, employed as steroid-sparing Using NSAIDs beyond 20 weeks of pregnancy raises the
risk of oligohydramnios; hence, the United States FDA ad-
agents. In cases of severe and refractory cytopenias, a range
vises only using the lowest dose that is effective for the
of interventions may be considered, including IV pulse dose shortest time between 20 and 30 weeks. Avoiding Nonsteroi-
steroids, MMF, rituximab, CYC, plasmapheresis, recombi- dal Anti-Inflammatory Drugs (NSAIDs) after 30 weeks of
nant Granulocyte colony-stimulating factor (G-CSF), or pregnancy is recommended to reduce the risk of premature
splenectomy [170, 171]. Additionally, Anifirulimab was closure of the ductus arteriosus and other shortcomings
used as an emerging agent to treat hematological manifesta- [191]. Treatments such as high-dose GC (which involves IV
tion [172]. In managing hematological manifestations within pulse therapy), IV immunoglobulin, and plasmapheresis
the context of SLE, a personalized approach based on the (which can be employed in refractory nephrotic syndrome)
unique manifestations and individual patient characteristics may be explored for moderate to severe flares [192-195].
is essential. Regular monitoring and collaboration among Neonatal Lupus (NL) is responsible for 80-95% of con-
various specialists are pivotal components of optimizing pa- genital complete heart block cases when structural abnormal-
tient care in these complex cases [171]. ities are not detected during prenatal or neonatal diagnosis
10 Current Rheumatology Reviews, XXXX, Vol. XX, No. XX Al-Jedai et al.

[196, 197]. Thus, all pregnant lupus women should undergo the availability of other treatment options. Women of child-
preconception or early pregnancy testing for anti-Ro/SSA bearing age taking mycophenolate should use effective con-
and anti-La/SSB antibodies [198]. traception, and pregnancy should be avoided while on this
medication. Conversely, Belimumab has limited data con-
GCs are commonly used during pregnancy to manage
cerning its safety in SLE during pregnancy and should not
SLE flares. However, current evidence suggests that high--
be used; however, its preliminary data is reassuring [209].
dose glucocorticoid (>20 mg/day) is associated with an in-
creased risk of adverse pregnancy outcomes (APO), such as 3.6.2. Antiphospholipid Antibodies (aPL) and Antiphospho-
preterm birth and low birth weight [199-201]. Therefore, lipid Syndrome (APS)
GCs should be administered a dose that is as low as possible
throughout pregnancy to avoid the risk of APO. Antiphospholipid syndrome (APS) is an autoimmune
condition that leads to the occurrence of thrombosis and/or
Certain medications used to treat SLE, such as CYC, pregnancy morbidity in individuals with persistent positive
MMF, leflunomide, and MTX, are known for their terato- test results for aPL [210]. Observational studies showed an
genicity and should be withdrawn before a planned pregnan- elevated risk of arterial and venous thromboembolic events,
cy and avoided during pregnancy [202-204]. During the se- non-thrombotic events (i.e. thrombocytopenia), and death in
cond or third trimester, CYC should be reserved for severe SLE patients [211-214]. A high-risk profile involves the
or refractory SLE manifestations. presence of triple or double antibody positivity, while a low-
HCQ, AZA, cyclosporine A, and tacrolimus are safe to risk aPL profile involves isolated aCL single antibody, anti--
be used during pregnancy [61, 70, 205]. AZA is compatible beta2GPI antibodies at low to medium titers, or transiently
with controlling renal and extrarenal disease throughout positive aPL [215, 216].
pregnancy due to the lack of 6-MMP generation in the fetus According to recommendations from the EULAR [217],
[206, 207]. A retrospective study reported no significant dif- due to the high likelihood of recurrent thrombosis, se-
ferences in fetal outcomes between the SLE women exposed condary thrombosis prevention using long-term anticoagula-
to AZA and those not exposed, with no major congenital ab- tion is the fundamental therapy for individuals with APS.
normalities reported [61]. Nonetheless, several specialists maintain that the regular
The safety of mycophenolate during pregnancy is a mat- dose of warfarin is just as beneficial in this setting. All of th-
ter of concern, as it may increase the risk of birth defects, es- ese strategies for secondary prevention of arterial thrombo-
pecially when used during the first trimester [202, 208]. For sis are included in the EULAR guidelines [217], with the
SLE patients who require mycophenolate for disease con- provision that the patient’s likelihood of bleeding and recur-
trol, the decision to continue the medication during pregnan- rent thrombosis must be considered. The agreed recommen-
cy should be made on a case-by-case basis, considering the dations/statements on the treatment of specific conditions of
patient’s disease activity, the potential teratogenicity, and SLE are presented in Table 3.

Table 3. Expert recommendations and statements on the treatment of specific conditions and monitoring of SLE.

Percentage of
Statement/Recommendation
Agreement
Pregnancy
Current evidence shows maternal and fetal complications were significantly higher in SLE-associated pregnancies. Therefore, SLE should
89%
be considered a high risk for pregnancy.
Given the possible complications and morbidity, pregnant women with SLE are regarded as high risk for adverse outcomes of pregnancy
and should be under the care of a multidisciplinary team, which ideally consists of a rheumatologist, an obstetrician with lupus expertise, an 100%
internist, and, if necessary a nephrologist.
The status of SLE is intimately correlated with maternal and neonatal outcomes. Thus, accurate prediction of at-risk females before concep-
100%
tion is crucial to avoid the negative impact of SLE on pregnancy outcomes.
Prior to attempting pregnancy, remission or low lupus disease activity state (LLDAS) is the desired condition before pregnancy. Good preg-
100%
nancy outcomes could be achieved in case of remission and adequately controlled disease activity before pregnancy.
Counseling prior to conception is recommended for women with SLE and/or APS to implement preventive strategies and develop a personal-
100%
ized plan for monitoring before and during pregnancy.
Patients should be in LLDAS or remission for 4-6 months prior to attempting conception on pregnancy-compatible medications. Pregnancy
should be postponed for individuals with moderate to severe disease activity until the condition is effectively managed with stable, pregnan- 100%
cy-compatible medications.
HCQ is recommended prior to conception and during pregnancy for patients with SLE. 100%
HCQ can improve pregnancy outcomes in SLE patients by reducing the risk of preeclampsia. All patients should use HCQ as long as it is
78%
not contraindicated.
Saudi National Clinical Practice Guidelines for Management Current Rheumatology Reviews, XXXX, Vol. XX, No. XX 11

Percentage of
Statement/Recommendation
Agreement
Blood pressure monitoring, using safe medications to control disease activity, especially HCQ, and limiting glucocorticoid exposure are es-
100%
sential measures.
In pregnant women with SLE, assessment of disease activity, including renal function parameters and serological markers (serum C3/C4, an-
100%
ti-dsDNA titers), is recommended to monitor adverse obstetrical outcomes and disease flares.
LDA should be administrated to women with SLE at risk of preeclampsia (particularly those with lupus nephritis or positive aPL). In women
with SLE-associated APS or primary APS, combination therapy with LDA and heparin is suggested to decrease the risk of pregnancy ad- 89%
verse outcomes.
Current evidence shows that Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) can be used during the first and second trimesters. 100%
Additional therapeutic approaches, such as glucocorticoids, intravenous pulse therapy, intravenous immunoglobulin, and plasmapheresis,
89%
can be used to manage moderate to severe flares.
Current evidence shows an increased risk of pregnancy adverse outcomes with glucocorticoid use (> 20 mg/day of prednisolone), especially
100%
preterm birth and low birth weight. Prednisolone/prednisone can be used throughout pregnancy at the lowest effective dose.
Mycophenolic acid, CYC, leflunomide, and methotrexate should be avoided during pregnancy due to known or possible teratogenicity. 100%
Current evidence shows that CYC is associated with a higher incidence of congenital malformations. Withdrawal of CYC is required prior to
100%
a planned pregnancy.
CYC should not be used during the first trimester of pregnancy due to the risk of fetal loss. It should be reserved exclusively for the treat-
100%
ment of severe, life-threatening, or refractory SLE manifestations throughout the second or third trimester.
Current evidence indicates an increased rate of congenital malformation with methotrexate. In a planned pregnancy, withdrawal of
89%
methotrexate should be three months prior to pregnancy.
HCQ, oral glucocorticoids, azathioprine, ciclosporin A, and tacrolimus can be used to prevent or manage SLE flares during pregnancy. 100%
Patients who showed a response to initial treatment with MPA should continue to take it, but once the pregnancy is planned, a pregnancy--
100%
planned transition to AZA is recommended at least six weeks prior to conception.
Mycophenolate should be discontinued six weeks prior to conception. The teratogenic potential of enteric-coated mycophenolate sodium pre-
89%
vents it from being recommended universally for women of reproductive age who have non-renal manifestations.
Preliminary data about the safety of Belimumab during pregnancy is reassuring; nevertheless, more data are needed. Using such agents in
89%
pregnant SLE patients should be approached with caution and close monitoring.
Thalidomide exhibits efficacy in a range of subtypes of cutaneous disorders. On account of its explicit contraindication during pregnancy,
the risk for irreversible polyneuropathy, and the frequent relapses associated with discontinuing the drug, its use should be limited to patients 100%
who have tried and failed numerous prior therapeutic agents as a “rescue” measure.
Antiphospholipid Antibodies (aPL) and Antiphospholipid Syndrome (APS)
All patients with SLE should be screened at diagnosis for aPL due to the high risk of thrombotic events, adverse fetal outcomes, non-throm-
88%
botic events, and mortality.
After balancing the bleeding hazard, patients with SLE who have a profile of elevated risk for aPL (persistently positive medium/high titers
or multiple positivity) may be offered primary prophylaxis with ASA, particularly in the presence of other atherosclerotic/thrombophilic fac- 100%
tors.
The therapeutic strategy for secondary prevention (thrombosis, pregnancy complications/loss) should be identical to that used for primary an-
77%
tiphospholipid syndrome.
Monitoring and Optimal Treatment Targets
aPL, Anti-Ro, and anti-La antibodies should be checked prior to pregnancy. 78%
Comorbidities, including atherosclerotic disease, avascular necrosis, osteoporosis, malignancy, and infection, are more prevalent among pa-
tients with lupus. It is important to review the management of modifiable risk factors, including diabetes, hypertension, dyslipidemia, high 100%
BMI, and smoking.
Immunosuppressive therapy and hydroxychloroquine both have the potential to induce toxicities. Drugs should be closely monitored by rou-
100%
tine laboratory tests, and clinical evaluations should be done following the guidelines for drug monitoring.
If the remission is unachievable, SLE Treatment should aim to decrease disease activity in all organ systems. 100%
Data concerning the optimal timing and duration of therapy discontinuation in renal and extrarenal disease are scarce. It is possible to at-
tempt a gradual withdrawal of immunosuppressive agents following a complete clinical response for a minimum of three to five years of ther- 100%
apy. Hydroxychloroquine should be continued long-term.
12 Current Rheumatology Reviews, XXXX, Vol. XX, No. XX Al-Jedai et al.

3.7. Comorbidities and Adjunct Therapy for SLE laboratory tests, and imaging studies, depending on the spe-
cific comorbidity being screened for. HCPS should consider
3.7.1. Common Comorbidities in SLE the individual patient's risk factors and tailor the screening
Patients with SLE are at increased risk of developing co- approach accordingly [218]. Early detection and manage-
morbidities such as Cardiovascular Disease (CVD), Hyper- ment of comorbidities in SLE patients can help optimize
tension (HTN), Diabetes Mellitus (DM), mood/cognitive dis- their overall health outcomes and improve their QOL.
orders (particularly depression), thromboembolic events, os-
teoporosis, or osteopenia. CVD and HTN were among the 3.7.2. Cardiovascular Diseases
most reported comorbidities in SLE patients in the literature Patients with SLE are at high risk of developing CVD
[14, 218-220]. The risk of CVD increases in SLE patients [236-238], and non-pharmacological interventions such as
due to inflammation, dyslipidemia, and other risk factors smoking cessation, maintaining a healthy weight, maintain-
[221-223]. In previous studies, the prevalence of CVD ing healthy dietary habits, and avoiding sedentary lifestyles
among SLE patients ranged from 1.5% to 20% [157, 219, should be considered for all SLE patients [239]. Regarding
219, 224-227]. In a case-control study on 571 German SLE the pharmacological treatment options, HCQ use in SLE on
patients, HTN was reported in 48% of the included patients CVD risk is reported to be beneficial. HCQ is also recom-
[224]. Also, Walbi et al. reported a 20% prevalence of HTN mended in all cases, unless contraindicated, due to its poten-
among Saudi SLE patients [227]. tial atheroprotective role [240, 241].
DM has a high prevalence in SLE patients compared to CVD risk prediction tools may underestimate actual Car-
non-SLE cohorts and is associated with increased morbidity diovascular Risk (CVR) in patients with SLE. SLE patients
and mortality [228]. The prevalence of DM in SLE patients may be at higher risk of CVD than what is captured by tradi-
might be higher than in the general population, with a preva- tional risk assessment tools such as cardiovascular risk score
lence among Saudi SLE patients ranging from 9% to 15% 2 (QRISK2) [242]. The adjusted global antiphospholipid syn-
[227, 229]. The exact mechanism underlying this possible as- drome score (aGAPSS) better predicted CVD events in SLE
sociation between DM and SLE is not fully understood. patients than QRISK3 [243]. Additionally, factors such as
Still, it is thought to be related to the chronic inflammation male gender, resting heart rate, history of lupus nephritis, ini-
and immune dysregulation seen in SLE, which can lead to in- tial SLE disease activity index 2000 (SLEDAI-2K) score,
sulin resistance and impaired glucose metabolism [228]. Ad- and metabolic syndrome were associated with increased
ditionally, some treatments for SLE, such as corticosteroids, CVD risk [243, 244]. Meanwhile, younger age at onset and
can also contribute to the development of DM [230, 231]. the use of certain medications such as hydroxychloroquine
Mood and cognitive disorders, particularly depression, and MMF were protective factors [244]. These findings high-
are prevalent among SLE patients and may be related to the light the need for tailored CVD risk assessment in SLE pa-
disease itself or the use of corticosteroids [232]. The use of tients to ensure appropriate management and prevention
corticosteroids, often prescribed to manage SLE symptoms, strategies.
may contribute to the development of these disorders. Corti- Studies investigating glucocorticoid treatment in SLE
costeroids can impact mood and cognition through modula- showed that a higher current dose was correlated with a high-
tion of neurotransmitter concentrations within the brain, af- er risk of atherothrombotic events, ischemic heart disease (I-
fecting the hypothalamic-pituitary-adrenal axis and causing HD), and/or stroke [21, 245]. Furthermore, hormonal thera-
changes in brain structure and function [233]. py has been reported to induce SLE flares and cardiovascu-
Thromboembolic events, such as Pulmonary Embolism lar or venous thromboembolic events [246]. Additionally,
(PE), Deep Vein Thrombosis (DVT), and stroke are also higher cumulative doses, higher daily doses, and ever-use
more common in SLE patients due to hypercoagulability -se- prednisone exceeding 30 mg/day were associated with an in-
condary to chronic inflammation and sometimes overlap creased risk of incident cardiovascular events in a more con-
with APS- and other risk factors [234]. Previous studies re- sistent manner [247, 248]. Therefore, as endorsed in EU-
ported a ~7% prevalence of DVT/PE in SLE patients [156, LAR 2022 recommendations [249], treatment with the low-
166]. Finally, SLE patients are at increased risk of develop- est possible corticosteroid dose is recommended to minimize
ing osteoporosis and osteopenia due to chronic inflamma- any potential cardiovascular risk.
tion, corticosteroid use, and other factors (such as female There is a paucity of studies examining the management
gender, menopause, and IS drugs) [235-237]. Albrecht et al. of HTN in patients with SLE, although HTN is a common
and Gergianaki et al. reported >20% prevalence of osteo- comorbidity and a major risk factor for CVD. This is partly
porosis as well as osteoarthritis among SLE patients [218, because SLE patients are often excluded from clinical trials
224]. on HTN management, leading to a lack of evidence-based
Healthcare Providers (HCPs) need to be mindful of the guidelines for treating HTN in this population. Additionally,
comorbidities associated with SLE and conduct regular SLE patients may have unique pathophysiological mech-
screenings to identify these conditions early and implement anisms contributing to their HTN, such as renal involvement
suitable management strategies. The screening process may and inflammation [250], which require tailored management
include a range of assessments, such as clinical evaluations, strategies.
Saudi National Clinical Practice Guidelines for Management Current Rheumatology Reviews, XXXX, Vol. XX, No. XX 13

According to the National Heart Center/Saudi Heart As- females), as it can improve BMD and reduce the risk of frac-
sociation's recent guidelines [251], the initial treatment op- tures [264-267]. However, HRT use in SLE patients may al-
tions for HTN encompass a range of antihypertensive medi- so increase the risk of certain adverse effects, such as cardio-
cations. These options include Angiotensin-Converting En- vascular events, breast cancer, stroke, and venous throm-
zyme Inhibitors (ACEIs), Angiotensin Receptor Blockers boembolism [268]. Therefore, the decision to use HRT for
(ARBs), diuretics (such as thiazide and thiazide-like agents), osteoporosis in SLE patients should be carefully judged indi-
and long-acting dihydropyridine Calcium Channel Blockers vidually, considering the patient's risk factors, medical histo-
(CCBs). Beta-blockers may be considered an initial treat- ry, and personal preferences.
ment option in specific conditions, such as younger patients
with hypertension accompanied by sympathetic overdrive, 3.7.4. Vaccination
or in cases where compelling indications exist (such as heart Patients with high disease activity of systemic lupus ery-
failure, ischemic disease, obesity/bariatric surgery). thematosus (SLE) benefit significantly from vaccination as
On the other hand, Beta-blockers and diuretics are better they are more susceptible to infections, immune dysregula-
to be avoided in primary management of HTN in lupus due tion, and frequent administration of IS therapy [269].
to the high risk of metabolic syndrome [252, 253]. Regular Vaccines can prevent infections and reduce morbidity and
monitoring and treatment adjustments are recommended. As mortality in SLE patients [270]. However, since SLE pa-
recommended in the European Society of Cardiology/Euro- tients have a higher risk of adverse events following vaccina-
pean Society of Hypertension (ESC/ESH) 2007 guidelines, tion, HCPs should carefully evaluate the risks and benefits
laboratory tests and imaging studies are necessary and of each vaccine and individualize vaccination strategies
should be performed annually to monitor for any changes in based on the medical history of the patient, disease activity,
CVD risk factors [254]. Current studies suggest a cut point and current medication regimen.
of SBP ≥130 mm Hg and/or DBP ≥80 mm Hg for diagnosis SLE patients commonly contract viral infections during
of HTN [251, 255]. Patients with specific conditions (such their disease journey, including Herpes Zoster (HZ), Cytome-
as APS) should also follow the same recommendations used galovirus (CMV), Human Papillomavirus (HPV), Hepatitis
in the general population for HTN management. B and C, parvovirus B19, and influenza [269, 271]. As per
SLE patients with a high estimated risk of CVD and/or a our clinical practice, the most important vaccines for Saudi
high-risk aPL could also use Aspirin after carefully evaluat- SLE patients include the influenza vaccine, pneumococcal
ing the risk of bleeding [217]. vaccine, hepatitis B vaccine, and non-live HZ vaccine (SH-
INGRIX). Influenza is an infection that affects the respirato-
3.7.3. Osteoporosis ry system and can cause severe illness and complications in
SLE patients, and the influenza vaccine is recommended for
Osteoporosis is a prevalent complication among SLE pa- all SLE patients annually. In addition, aligned with the CDC
tients, often due to the inflammatory process of the disease it- recommendations for HZ vaccination, the Task Force mem-
self, chronic use of glucocorticoids, or presence of epidemio- bers recommend using the non-live, recombinant SHIN-
logical risk factors for bone loss (such as old age, abnormal GRIX vaccine over the live attenuated Zostavax vaccine in
vitamin D level, postmenopausal status, or ovarian dysfunc- SLE patients, even if they received IS or biologics [272].
tion) [256-258]. These factors can adversely impact bone
mass density (BMD) and increase SLE patients' risk of bone Our recommendations align with the recent American
fractures. To improve bone health in SLE patients, HCPs College of Rheumatology (ACR) guidelines on vaccination
should evaluate and manage risk factors that impact BMD, [273]. The pneumococcal vaccine is also recommended for
particularly the use of glucocorticoids. Certain lifestyle mod- SLE patients, as they are at increased risk of pneumococcal
ifications, such as weight reduction, weight-bearing exercis- infections, which can lead to pneumonia, meningitis, and
es, and smoking cessation, can also help improve bone sepsis [274]. Also, the hepatitis B vaccine is suggested for
health in these patients [259, 260]. Vitamin D and calcium SLE patients due to the increased risk of hepatitis B infec-
supplementation have been found to significantly improve tion, which can cause liver damage and other complications
BMD, particularly in vitamin D-deficient patients [261]. A [275]. Additionally, due to lifelong IS drug use, patients
study by Caetano et al. found that around 50% of the postme- with SLE are at higher risk of HPV infection and its possible
narcheal females with juvenile SLE had altered nutritional complications [276-278]. Therefore, HPV vaccines should
status. Low BMD was observed in 42.8% of patients, corre- be considered for SLE patients, particularly those with a his-
lated with inadequate vitamin D supplementation [262]. tory of cervical dysplasia or human papillomavirus infec-
Another study found that oral vitamin D and calcium supple- tion. The agreed recommendations/statements on the com-
mentation in SLE patients improved BMD and reduced the mon comorbidities and adjunct therapy for SLE are present-
frequency of osteopenia and osteoporosis without effect on ed in Table 4.
SLE disease activity or related immune markers [263]. Hor- We have compiled Table 5 to illustrate the differences
mone replacement therapy (HRT) can be effective for osteo- and deviations between our recommendations and EULAR
porosis in patients with SLE (especially in postmenopausal guidelines.
14 Current Rheumatology Reviews, XXXX, Vol. XX, No. XX Al-Jedai et al.

Table 4. Expert recommendations and statements on comorbidities and adjunct therapy.

Percentage of
Recommendation/Statement
Agreement
The Most Common Comorbidities in SLE
The high prevalence of multimorbidity among patients with SLE in the community advocates for multidisciplinary care to optimize clini-
89%
cal outcomes.
Comorbidities Screening
Screening for various comorbidities at SLE diagnosis is recommended to reduce organ damage, complications, and mortality risk. 100%
Patients with SLE should adhere to the screening recommendations for the general population, particularly for cervical cancer and cardio-
100%
vascular diseases.
Cardiovascular Diseases
Clinicians need to be aware of the increased cardiovascular risk among patients with SLE. Therefore, non-pharmacological interventions
for CVD, such as smoking cessation, avoiding sedentary lifestyles, and maintaining an optimal BMI, should be considered for all SLE pa- 100%
tients.
Unless contraindicated on account of its hypothesized atheroprotective effect, HCQ could be used in all lupus cases. 89%
Hormone replacement therapy (HRT) is better avoided in SLE patients due to the associated increased risk of CVD and venous throm-
89%
boembolism.
ACEIs or ARBs (in case of intolerance) are preferred as first-line treatment for HTN in patients with SLE due to their renoprotective ef-
100%
fects (i.e., improve serum creatinine levels and reduce proteinuria).
If the blood pressure cannot be controlled by monotherapy alone or when concurrent pulmonary arterial hypertension is present, a calcium
78%
channel blocker (CCB) or thiazide diuretic should be added.
All SLE patients who have begun antihypertensive medication are recommended to return at least every two months for monitoring and
78%
treatment adjustment until they achieve their BP goal.
Osteoporosis
Factors adversely impacting BMD, particularly chronic use of glucocorticoids, should be evaluated and managed. 100%
To improve bone health in SLE patients, certain lifestyle changes such as weight loss, weight-bearing exercises, and smoking cessation
100%
should be implemented.
Vitamin D and calcium supplementation significantly improved the BMD in vitamin D-deficient SLE patients. 100%
Due to the high prevalence of osteoporosis and osteopenia among Saudi SLE patients, screening for BMD is advocated, especially in high-
100%
-risk patients (such as the elderly and patients on chronic GC therapy).
Vaccination
Adult patients with SLE should be urged to receive vaccinations according to Saudi national guidelines. In addition, influenza, pneumo-
coccal vaccination, and SHINGRIX (Zoster Vaccine Recombinant, Adjuvanted) should be considered in all SLE patients, irrespective of 100%
their treatments.

Table 5. Changes/Deviations between our guidelines and EULAR recommendations.

Statement/Recommendation
Glucocorticoids/Steroids
EULAR guidelines may recommend standard oral glucocorticoid regimens for high-dose needs, while our recommendation emphasizes pulses of IV methyl-
prednisolone.
While EULAR guidelines suggest a tapering approach for glucocorticoid maintenance, we recommend decreasing chronic regimens to less than 5 mg daily.
Hydroxychloroquine
EULAR guidelines might propose a maximum dose of HCQ based on body weight, whereas we support higher doses (up to 400 mg/day) regardless of weight.
While EULAR may suggest a standardized approach to HCQ maintenance, our recommendation is for personalized decisions on maintenance or reduction
based on patient subgroups.
Saudi National Clinical Practice Guidelines for Management Current Rheumatology Reviews, XXXX, Vol. XX, No. XX 15

Statement/Recommendation
Immunosuppressive/Cytotoxic agents
EULAR guidelines may prioritize certain immunosuppressive agents in specific scenarios, but our recommendation considers MTX and AZA earlier in the
treatment sequence.
EULAR guidelines may have a more prominent role for CYC in certain cases, but our recommendation limits its use and favors MMF or enteric-coated my-
cophenolate sodium.
Biological agents
EULAR guidelines might have specific criteria for considering belimumab or anifrolumab, but our recommendation includes these as therapeutic options for
patients not responding adequately or developing intolerance.
The off-label use of RTX in specific cases may deviate from EULAR guidelines, which might have different recommendations for severe renal or extrarenal
disease.
Skin involvement
EULAR guidelines may provide recommendations on first-line treatments for cutaneous lupus erythematosus (CLE), but our recommendation emphasizes cer-
tain measures like smoking cessation and sun protection.
Our recommendation includes specific alternatives such as belimumab and anifrolumab for resistant mucocutaneous manifestations, which might differ from
EULAR guidelines.
SLE Flares
While EULAR guidelines may have a definition for flares, our recommendation provides a measurable escalation in disease activity.
Our emphasis on assessing adherence and close monitoring may go beyond the general recommendations in EULAR guidelines.
Gaps and challenges
The EULAR guidelines may not explicitly address medication adherence issues in Saudi populations, whereas our recommendation highlights this as a signifi-
cant gap.
Pregnancy
EULAR may recommend standardized oral glucocorticoid regimens during pregnancy, while our recommendation emphasizes the use of HCQ as a preventive
measure.
EULAR may recommend standardized oral glucocorticoid regimens during pregnancy, while our recommendation emphasizes the use of HCQ as a preventive
measure.
The use of NSAIDs during the first and second trimesters is supported in our recommendation, while EULAR guidelines may have different considerations.
EULAR guidelines may provide more specific recommendations for the use of glucocorticoids during pregnancy, whereas our recommendation suggests pred-
nisolone/prednisone at the lowest effective dose.
Our recommendation emphasizes a cautious approach to CYC, particularly avoiding its use during the first trimester, which may differ from EULAR guide-
lines.
The recommendation to transition from MPA to AZA six weeks before conception may deviate from EULAR guidelines.
The consideration of Belimumab during pregnancy is approached with caution and close monitoring in our recommendation, which might differ from EU-
LAR guidelines.
Antiphospholipid Antibodies (aPL) and APS
Our recommendation includes screening all SLE patients for aPL at diagnosis, while EULAR guidelines may have different criteria.
The primary prophylaxis with ASA in patients with elevated aPL risk factors may differ from EULAR guidelines.
Our recommendation suggests an identical therapeutic strategy for secondary prevention in patients with SLE and APS, which may not align exactly with EU-
LAR guidelines.
Monitoring and Optimal Treatment Targets
Our recommendation includes checking aPL, Anti-Ro, and anti-La antibodies prior to pregnancy, which may be more specific than EULAR guidelines.
The emphasis on reviewing and managing modifiable risk factors is in line with general guidelines but may be more explicitly stated in our recommendation.
Routine laboratory tests and clinical evaluations for monitoring immunosuppressive therapy and hydroxychloroquine align with general principles but may be
emphasized more explicitly in our recommendation.
16 Current Rheumatology Reviews, XXXX, Vol. XX, No. XX Al-Jedai et al.

Statement/Recommendation
The suggestion to attempt a gradual withdrawal of immunosuppressive agents after a complete clinical response for three to five years may not be specifically
outlined in EULAR guidelines.
The Most Common Comorbidities in SLE
Both our recommendation and EULAR guidelines advocate for multidisciplinary care to optimize clinical outcomes, showing alignment in this aspect.
Comorbidities Screening
The recommendation to screen for various comorbidities at SLE diagnosis aligns with general principles in EULAR guidelines.
The emphasis on adhering to general population screening recommendations, particularly for cervical cancer and cardiovascular diseases, is in line with EU-
LAR guidelines.
Cardiovascular Diseases
Non-pharmacological interventions for cardiovascular diseases are emphasized in both recommendations and general EULAR guidelines.
The hypothesized atheroprotective effect of HCQ is acknowledged in both recommendations.
The avoidance of hormone replacement therapy (HRT) in SLE patients due to increased CVD and venous thromboembolism risk aligns with general princi-
ples.
The preference for ACEIs or ARBs as first-line treatment for hypertension, considering their renoprotective effects, is in line with general EULAR guidelines.
The recommendation to add a calcium channel blocker (CCB) or thiazide diuretic if blood pressure control is inadequate aligns with general hypertension man-
agement principles.
The suggested monitoring and treatment adjustment every two months for SLE patients on antihypertensive medication is more specific but aligns with the
general goal of achieving blood pressure control in EULAR guidelines.
Osteoporosis
The evaluation and management of factors adversely impacting bone mineral density (BMD), particularly chronic use of glucocorticoids, are in line with gen-
eral EULAR guidelines.
Lifestyle changes such as weight loss, weight-bearing exercises, and smoking cessation to improve bone health align with general principles.
Vitamin D and calcium supplementation for improving BMD in vitamin D-deficient SLE patients is a general recommendation.
The advocacy for screening for BMD, especially in high-risk patients, aligns with general EULAR guidelines.
Vaccination
The urging of adult SLE patients to receive vaccinations according to Saudi national guidelines aligns with general principles.
The consideration of influenza, pneumococcal vaccination, and SHINGRIX for all SLE patients, irrespective of treatments, aligns with general vaccination re-
commendations.

CONCLUSION Many comorbidities, including cardiovascular diseases,

Systemic Lupus Erythematosus (SLE) has a high preva- mood/cognitive disorders, and osteoporosis, affect SLE pa-
tients and could endanger their safety. Therefore, monitoring
lence in Saudi Arabia, causing a burden on both patients and
plans, adjunct therapy, and vaccines should be implemented
healthcare systems. The disease and many confounding fac-
for them.
tors play a role in determining the most suitable treatment
plan for each patient. RECOMMENDATIONS FOR FUTURE RESEARCH
GCs are the cornerstone treatment that helps control dis- Future research is required to develop precision
ease and prevent flares. However, they cause many unwant- medicine approaches in SLE based on genetic, environmen-
ed adverse events, including hypertension and diabetes. Hy- tal, and clinical factors to enhance diagnosis and treatment.
droxychloroquine is also used as SLE treatment, leading to It is also necessary to explore the development of new medi-
significant improvements in symptoms as well as a decrease cations, addressing unmet needs such as long-term remis-
in the flare frequencies. Cytotoxic and immunosuppressive sion maintenance and steroid-sparing agents. Furthermore,
agents could manage the severe organ damage caused by lu- long-term clinical trials are required to assess the safety and
pus. Monoclonal antibodies also play a significant role in efficacy of current and emerging therapies for SLE, focusing
managing SLE. on high-risk populations such as children, patients with co-
A good treatment plan should be carefully customized morbidities, and pregnant women. We should aim to identi-
for each patient to decrease the number of flares during the fy better diagnostic tools and biomarkers for accurate SLE
clinical course of the disease and to encourage the patients diagnosis and monitoring of disease activity over time.
to adhere to medications. Studies into SLE within the Saudi population are necessary
Saudi National Clinical Practice Guidelines for Management Current Rheumatology Reviews, XXXX, Vol. XX, No. XX 17

to comprehend disease prevalence, risk factors, clinical mani- HPV = Human Papilloma Virus
festations, and treatment outcomes specific to this demo-
graphic. HR = Hazard Ratio
HRT = Hormone Replacement Therapy
AUTHORS’ CONTRIBUTIONS
HTN = Hypertension
Each author listed has significantly contributed to the
work, providing substantial, direct, and intellectual input, HZ = Herpes Zoster
and has given their approval for its publication. IFN = Interferon
LIST OF ABBREVIATIONS IHD = Ischemic Heart Disease
AAO = American Academy of Ophthalmology IS = Immunosuppressive
ACEIs = Angiotensin-converting Enzyme Inhibitors LA = Lupus Anticoagulant
aCL = Anticardiolipin LLDAS = Lupus Low Disease Activity State
aGAPSS = Adjusted Global Antiphospholipid Syn- MMF = Mycophenolate Mofetil
drome Score MSK = Musculoskeletal
AGREE II = Appraisal of Guidelines Research and MTX = Methotrexate
Evaluation Instrument
NL = Neonatal Lupus
aPL = Antiphospholipid Antibodies
NSAIDs = Nonsteroidal Anti-inflammatory Drugs
APS = Antiphospholipid Syndrome
OR = Odds Ratio
ARBs = Angiotensin Receptor Blockers
PE = Pulmonary Embolism
AZA = Azathioprine
QOL = Quality of Life
BEL = Belimumab
RCTs = Randomized Controlled Trials
BICLA = British Isles Lupus Assessment Group-
RTX = Rituximab
based Composite Lupus Assessment
SCLE = Subacute Cutaneous Lupus Erythematosus
BILAG = British Isles Lupus Assessment Group
SD-OCT = Spectral-domain Optical Coherence Tomo-
BMD = Bone Mass Density
graphy
CLE = Cutaneous Lupus Erythematosus
SLE = Systemic Lupus Erythematosus
CMV = Cytomegalovirus
SLEDAI = Systemic Lupus Erythematosus Disease
CNIs = Calcineurin Inhibitors Activity Index
CVR = Cardiovascular Risk SLEDAI-2K = Systemic Lupus Erythematosus Disease
CYC = Cyclophosphamide Activity Index 2000
DLE = Discoid lupus Erythematosus SLR = Systematic Literature Review
DM = Diabetes Mellitus SOPs = Standardized Operating Procedures
DVT = Deep Vein Thrombosis SRI-4 = SLE Responder Index 4
EC-MPS = Enteric-coated Mycophenolate Sodium VTE = Venous Thromboembolism
ESC/ESH = European Society of Cardiology/European CONSENT FOR PUBLICATION
Society of Hypertension Not applicable.
EULAR = European League Against Rheumatism
AVAILABILITY OF DATA AND MATERIALS
GCs = Glucocorticoids
The original contributions presented in the study are in-
GnRHa = Gonadotropin-releasing Hormone Agon- cluded in the article. Further inquiries can be directed to the
ists corresponding author.
HCPs = Healthcare Providers
FUNDING
HCQ = Hydroxychloroquine
The Ministry of Health, Kingdom of Saudi Arabia, fund-
18 Current Rheumatology Reviews, XXXX, Vol. XX, No. XX Al-Jedai et al.

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el and accommodation expenses from the Ministry of 30987856
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