Systemic lupus erythematosus: clinical guidelines

List of Abbreviations

AH – arterial hypertension

BP – blood pressure

anti-dsDNA – antibodies to native double-stranded deoxyribonucleic acid

anti-β2-GP-1 – antibodies to β2-glycoprotein 1

anti-CL – anticardiolipin antibodies

ALT – alanine aminotransferase

ANA – antinuclear antibodies

Anti-C1q – antibodies to the C1q complement component

Anti-La/SSB – antibodies to the La antigen

Anti-Ro/SSA – antibodies to the Ro antigen

Anti-Sm – antibodies to the Smith antigen

ANA – antinuclear antibody

ACE – angiotensin-converting enzyme

AST – aspartate aminotransferase

aPL – antiphospholipid antibodies

APS – antiphospholipid syndrome

#IVIG** – normal human intravenous immunoglobulin**

HIV – human immunodeficiency virus

LN – lupus nephritis

bDMARDs – biological disease-modifying antirheumatic drugs

GC – glucocorticoids

HCQ** – hydroxychloroquine**

DI – damage index

EIA – enzyme immunoassay

Type I IFN – type I interferon

CT – computed tomography

medicines – medicinal products

PT – physical therapy

MRI – magnetic resonance imaging

ADR – adverse drug reactions

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs

BSA – body surface area

RCT – randomized controlled trial

SLE – systemic lupus erythematosus

GFR – glomerular filtration rate

ESR – erythrocyte sedimentation rate

CRP – C-reactive protein

US – ultrasound examination

CNS – central nervous system

ECG – electrocardiography

EchoCG – echocardiography

EEG – electroencephalography

ACR – American College of Rheumatology

C3, C4, C1q – complement fractions

ELISA – Enzyme-linked Immunosorbent Assay

EULAR – European League Against Rheumatism

IgA – immunoglobulin A

IgG – immunoglobulin G

IgM — immunoglobulin M

ISN/RPS – International Society of Nephrology/Renal Pathology Society

KDIGO – Kidney Disease: Improving Global Outcomes

SELENA-SLEDAI – Safety of Estrogen in Lupus National Assessment - Systemic Lupus Erythematosus Disease Activity Index

SLEDAI – Systemic Lupus Erythematosus Disease Activity Index

SLEDAI-2K – Systemic Lupus Erythematosus Disease Activity Index 2K

SLICC – Systemic Lupus International Collaborating Clinics

SLICC/DI – Systemic Lupus International Collaborating Clinics/Damage Index

SPF – Sun Protection Factor

Terms and Definitions

Systemic lupus erythematosus (SLE) is a systemic autoimmune rheumatic disease with numerous clinical manifestations and an unpredictable course, affecting any organ or system, which quite often develops over several months or years, with persistent or, conversely, rapidly changing clinical manifestations, a relapsing-remitting course, and alternating remissions and flares.

Definite (criteria-based) SLE is a systemic autoimmune rheumatic disease meeting the classification criteria for SLE (SLICC 2012 and/or EULAR/ACR 2019).

Incomplete (probable, unverified) SLE is a condition that does not meet modern criteria for "definite" SLE, but presents with an incomplete set of features characteristic of this disease.

Clinical remission is the absence of signs of active internal organ involvement for one year while maintaining immunological abnormalities (elevated levels of antibodies to native double-stranded deoxyribonucleic acid (anti-dsDNA) and/or decreased levels of C3 and C4 complement fractions).

Complete remission of SLE is the absence of clinical and laboratory signs of activity and no need for glucocorticoid (GC) and immunosuppressant therapy. Hydroxychloroquine** (HCQ) is permitted.

Antirheumatic drugs are a group of medicinal products with various structures, pharmacological characteristics, and mechanisms of action belonging to different ATC groups, functionally combining drugs with anti-inflammatory effects used to treat rheumatic diseases (H02AB Glucocorticoids, selected drugs from the L04A Immunosuppressants group, P01BA Aminoquinolines (hydroxychloroquine**), L01AA Nitrogen mustard analogues (cyclophosphamide**), L01BA Folic acid analogues (methotrexate**), selected drugs from the L01XC Monoclonal antibodies (#rituximab**, obinutuzumab**)).

Nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs) are a group of synthetic drugs with symptomatic analgesic, antipyretic, and anti-inflammatory effects primarily associated with the inhibition of cyclooxygenase, an enzyme that regulates prostaglandin synthesis (M01A).

Glucocorticoids (GCs) are synthetic steroid hormones with inherent anti-inflammatory activity (H02AB).

Low-dose GCs – ≤7.5 mg/day of prednisolone** (or an equivalent dose of another GC).

Medium-dose GCs – >7.5–30 mg/day of prednisolone** (or an equivalent dose of another GC).

High-dose GCs – >30 mg/day of prednisolone** (or an equivalent dose of another GC).

Immunosuppressants (L04A Immunosuppressants) are a group of synthetic medicinal products of chemical origin that suppress the immune response by reversibly inhibiting the functions of immunocompetent cells and humoral immune responses.

Biological disease-modifying antirheumatic drugs (bDMARDs) are a group of medicinal products of biological origin, including monoclonal antibodies (chimeric, humanized, fully human) and recombinant proteins (usually including the Fc fragment of human IgG) produced using genetic engineering techniques, which target molecules and thereby specifically suppress the immunoinflammatory process (within the scope of these clinical guidelines, bDMARDs include drugs from various groups: #rituximab**, belimumab**, anifrolumab**, #abatacept**, #tocilizumab**, obinutuzumab**).

Adverse drug reaction (ADR) is any noxious, unintended effect of a drug that occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy and is not part of its anticipated therapeutic effects.

Antinuclear antibodies (ANA), antinuclear factor (ANF) is a heterogeneous group of autoantibodies, predominantly of the IgG isotype, directed against components of the cell nucleus. They serve as a marker of autoimmune diseases and are measured for their diagnosis, activity assessment, and treatment monitoring.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Systemic lupus erythematosus (SLE) is a systemic autoimmune rheumatic disease of unknown etiology, characterized by the overproduction of organ-nonspecific autoantibodies directed against various nuclear and cytoplasmic cell components, leading to immunoinflammatory damage to internal organs [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

SLE is considered a multifactorial polygenic disease, in which genetic factors are more strongly associated with specific clinical and immunological phenotypes than with the disease as a whole. The role of genetic predisposition, epigenetic alterations, ethnic factors, immunoregulation disorders, hormonal imbalances, and environmental factors is being discussed [1,2].

Etiological factors of SLE include ultraviolet radiation, smoking, infections (particularly Epstein-Barr virus), dietary factors, intestinal microflora imbalance (microbiome), estrogen overproduction, drug exposure, and psychological stress, although direct evidence for the involvement of any specific factor has not yet been established. The role of genetic factors is evidenced by a significant (10-fold) increase in the risk of developing SLE in blood relatives of SLE patients compared to the general population. Concordance for SLE risk in monozygotic twins ranges from 24% to 56%, while in dizygotic twins it is about 5%. Genome-wide screening has identified more than 100 loci associated with an increased risk of developing SLE, including those related to cytokine signaling, interferon (IFN) synthesis, immune complex clearance, apoptosis, and DNA methylation [1–3].

The pathogenetic mechanisms of SLE development are determined by complex impairments of innate and acquired immunity, leading to a breakdown of tolerance to self-autoantigens, which is associated with impaired synthesis of interleukin-2 (IL-2) and polarization of the immune response toward the Th17 (T-helper 17) phenotype, combined with a defect in regulatory T cells and excessive activation of autoreactive B cells developing against the background of B-cell lymphopenia. Of particular importance is B cell-activating factor (BAFF), also known as B lymphocyte stimulator (BLyS), which is a critical component of the cytokine regulation of B-cell function, proliferation, and differentiation. Signaling induced by the interaction of BAFF/BLyS with corresponding cell receptors regulates pre-immune B-cell homeostasis and leads to increased 'survival' of autoantibody-producing B cells by preventing their selection and apoptosis. These findings provided the theoretical rationale for developing monoclonal antibodies against BAFF/BLyS for the treatment of SLE [1–4].

The innate immune system plays a crucial role in the immunopathogenesis of SLE, manifesting as the activation of Toll-like receptors (TLRs), specifically TLR7 and TLR9, on plasmacytoid dendritic cells, which synthesize type I IFNs upon stimulation by nucleic acids and nucleic acid-containing immune complexes. The primary sources of nucleic acids are cells undergoing apoptosis and NETosis, predominantly keratinocytes, which release 'apoptotic' vesicles containing nuclear autoantibodies (Ro, La, Sm, ribonucleoproteins [RNPs]) under the influence of ultraviolet radiation. Excessive production and impaired clearance (deficiency of the C1q complement component, DNAse-1 enzyme) of this nuclear material are associated with inflammation development and the synthesis of antinuclear antibodies (ANAs). Many clinical manifestations of SLE are related to the deposition of nucleic acid-containing immune complexes, which on the one hand induce complement system activation in microvessels and on the other hand trigger the activation of plasmacytoid dendritic cells that synthesize type I IFNs and other proinflammatory mediators. In addition, type I IFN induces the activation of myeloid dendritic cells, which in turn promote T-cell activation and B-cell differentiation toward the overproduction of pathogenic autoantibodies. Type I IFN sustains the synthesis of B cell-activating factor (BAFF/BLyS), enhancing B-cell survival and differentiation. Activated T cells expressing CD154 (CD40 ligand) synthesize IL-21, which induces the differentiation of B lymphocytes into autoantibody-secreting plasma cells. Additional pathogenic effects are exerted by reactive oxygen radicals and proinflammatory cytokines synthesized by monocytes and macrophages, which stimulate vascular endothelial cells and lead to impaired repair and sclerosis. This entire process repeats in a vicious circle, ensuring the chronic character of the disease [1–4].

1.3 Epidemiology of the Disease or Condition

Over the past 40 years, there has been an increase in the incidence of SLE, which may be related to improved diagnostics, ranging from 0.3 to 31.5 cases per 100,000 population per year. Worldwide prevalence has approached 50–100 cases per 100,000 adults. In the Russian Federation, the prevalence of SLE ranges from 9.0 to 20.6 cases per 100,000 population depending on the region, and incidence ranges from 0.3 to 1.66 per 100,000 population. Women of young and middle age predominate, with a female-to-male ratio of 10:1; disability in SLE patients remains at 50–75%, and 10-year survival depends on the disease course, timely prescription of pathogenetic therapy, and activity monitoring, averaging 93% [5]. The burden of SLE reduces patients' overall life expectancy by an average of 24 years compared to the general population [6].

1.4 Features of Coding the Disease or Condition

Systemic lupus erythematosus (M32)

M32.0 Drug-induced systemic lupus erythematosus

M32.1 Systemic lupus erythematosus with organ or system involvement

M32.8 Other forms of systemic lupus erythematosus

M32.9 Systemic lupus erythematosus, unspecified

1.5 Classification of the disease or condition

1.5.1 Clinical classification of SLE

Primary diagnosis:

• Systemic lupus erythematosus

• Systemic lupus erythematosus, unspecified

• Drug-induced lupus erythematosus

In clinical practice, classification criteria are used to diagnose the disease: SLICC 2012 (see Appendix A3.1) and EULAR/ACR 2019 (see Appendix A3.2) [7–9]. An SLE diagnosis is established according to the SLICC 2012 criteria in the presence of 4 criteria, of which at least 1 must be clinical and 1 immunological (any of the following laboratory parameters: anti-dsDNA, ANA, anti-Sm, aPL, C3, or C4 hypocomplementemia). According to the EULAR/ACR 2019 criteria, the disease is classified as SLE if the cumulative score of additive criteria is 10 or more, provided that the mandatory entry criterion—a positive (≥1/80) ANA test—is met.

If fewer than 4 criteria are met (SLICC 2012) or the score is less than 10 in the presence of a mandatory positive (≥1/80) ANA test (EULAR/ACR 2019), the diagnosis of 'Undifferentiated (probable, incomplete) SLE' is established [10,11].

Drug-induced lupus is an autoimmune phenomenon chronologically associated with the long-term use (from a month to several years) of medications and regressing after their discontinuation. The symptom complex resembles idiopathic SLE in a number of clinical, histological, and immunological features [12].

1.5.2. Variants of the course of SLE depending on the nature of the onset of the disease according to V.A. Nasonova

• acute course is characterized by rapid (up to 1 year) development of multiorgan manifestations, including renal and CNS involvement, and pronounced immunological disorders;

• subacute course – at the onset of SLE, constitutional symptoms, skin and joint lesions, and hematological disorders occur. The disease runs a wave-like course with periodic exacerbations and the development of multiorgan symptoms within 2–3 years from the onset of the first symptoms;

• chronic course – prolonged predominance of one or several symptoms: discoid rashes, Raynaud's phenomenon, arthritis, seizure disorder, hematological disorders. Multiple organ lesions appear by the 5th–10th year of the disease [13].

1.5.3. SLE activity

To assess SLE activity, modifications of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) – SLEDAI-2K and SELENA-SLEDAI (see Appendix G1, G2) – are used [14–16].

There are 4 degrees of disease activity according to the SLEDAI-2K or SELENA-SLEDAI index:

- no activity / remission (0 points),

- low activity (1–4 points),

- moderate activity (5–10 points),

- high activity (more than 10 points).

An SLE flare is considered present when there is an increase in the SLEDAI-2K or SELENA-SLEDAI index values of >3 points between two visits, SLE improvement – when <3 points between two visits, and a change in the index by ±3 points – as persistent activity. A moderate SLE flare is defined as an increase in index values by 3–12 points, and a severe flare – by >12 points [17,18].

The SLEDAI index includes 24 parameters (16 clinical and 8 laboratory indicators of SLE). Each indicator is assigned from 1 to 8 points for each of the SLE signs included in the index. The maximum possible total score of the SLEDAI index is 105 points, with these indicators recorded over the preceding 4 weeks.

SLEDAI-2K or SELENA-SLEDAI (SELENA (Safety of Estrogens in Lupus Erythematosus National Assessment)) are modifications of the SLEDAI index that allow accounting for persistent activity associated with skin rashes, mucosal ulcers, alopecia, and proteinuria. While SLEDAI only scores newly occurring features or relapses of these signs, its modifications account for any variant of these features (newly occurred, relapse, persistent activity). SLEDAI-2K differs from SELENA-SLEDAI in the number of affected joints and instrumental confirmation of pleuritis and pericarditis. SELENA-SLEDAI includes three components: the SLEDAI score (range, 0 to 105, where 0 indicates inactive disease); the SLE-flare index, which assesses the emergence of new or worsening disease activity, with changes reflecting medication prescriptions and hospitalization not captured using SLEDAI; and the PGA (Physician's Global Assessment visual-analogue scale) score ranging from 0 to 3, where 0 indicates inactive disease and 3 indicates severe disease. There is a simpler Spanish version of the SLEDAI scale — Mex-SLEDAI (which excludes immunological parameters) and a modified version for pregnant patients with SLE — SLEPDAI, which accounts for physiological changes of pregnancy that could affect certain SLE activity parameters: seizures, cranial nerve disorders, headache, stroke, cutaneous vasculitis, arthritis, hematuria, proteinuria, pyuria, rash, alopecia, pleuritis, serum complement levels, thrombocytopenia, and leukopenia.

1.5.4. Irreversible organ damage

To assess organ damage, the SLICC/DI (Damage Index) is used (see Appendix G3) [19]. The DI in SLE is any irreversible change in an organ system, unrelated to active inflammation and SLE activity, occurring after the diagnosis of SLE regardless of cause (outcome of SLE activity, adverse effect of drug therapy, development of comorbid conditions), confirmed by clinical evaluation and persisting for at least 6 months unless otherwise specified (relation to SLE activity).

There are 4 grades of the DI:

- absence of damage — 0 points,

- low DI — 1 point,

- moderate DI — 2–4 points,

- high DI — more than 4 points.

The DI establishes the presence of potentially irreversible damage to various organs and includes a description of the state of 12 organ systems;

- the maximum score for individual organ systems ranges from 1 to 7 points depending on the number of evaluated parameters;

- the total maximum possible DI score is 47 points;

- the scoring includes all types of damage from the time of the established SLE diagnosis (caused directly by SLE or developing as a consequence of ongoing therapy), while only signs persisting for 6 months or more are taken into account;

- repeating episodes are evaluated at an interval of at least 6 months to be scored as 2 points (where applicable);

- the same lesion cannot be scored twice.

1.5.5. Complications

- hypercorticism syndrome (drug-induced Cushing's syndrome);

- cataract;

- retinal changes or optic atrophy;

- chronic kidney disease with stage indication;

- pulmonary hypertension;

- respiratory failure with degree indication;

- arterial hypertension;

- dyslipidemia;

- atherosclerotic vascular disease;

- thrombosis;

- heart failure with stage indication;

- steroid myopathy, muscle atrophy;

- systemic osteoporosis;

- osteonecrosis;

- Jaccoud's syndrome;

- bacterial, fungal, and viral infections;

- steroid-induced diabetes mellitus;

- reproductive system involvement (dysmenorrhea, early menopause).

1.6 Clinical presentation of the disease or condition

The onset of the disease may present with involvement of one or two organs; however, a fully developed clinical picture of SLE is characterized by multiorgan symptoms. The course of the disease is undulating, with alternating remissions and exacerbations. During exacerbations, previously uninvolved organs and systems may become engaged in the pathological process. Fatigue, fever, and weight loss reflect the overall activity of the pathological process and are frequently encountered at the onset of the disease.

As a rule, SLE begins subacutely with recurrent polyarthritis, fever, various skin rashes, loss of appetite, sleep disturbances, increased hair loss, malaise, fatigue, and weight loss. Fever does not have specific characteristics.

An acute onset with high temperature, sharp joint pain and swelling, persistent malar erythema (“butterfly” rash), and involvement of vital organs (kidneys, nervous system, blood vessels, heart, etc.) is less common.

A history of recent pregnancy, childbirth, sex hormone use, intense sun exposure, stress, infectious disease, or a history of SLE or another autoimmune rheumatic disease in close relatives is of great significance.

In children and adolescents, SLE frequently debuts with CNS involvement — depression, hyperexcitability, persistent headaches, epileptic syndrome, chorea. Brain involvement is marked by mood and memory disturbances, intense headaches, visual disturbances, and paresthesias; spinal cord involvement — by paralysis and pelvic organ dysfunction.

The development of pleuritis is characterized by complaints of breathing-associated chest pain. With kidney involvement at disease onset, edema appears insidiously — migrating initially and becoming pronounced in the fully developed stage of the disease — accompanied by decreased urine output, thirst, dry skin, and elevated blood pressure (BP).

2. Diagnostics, medical indications and contraindications for diagnostic methods

For criteria used to establish a diagnosis of SLE, see Appendix A3.1-3 [7–9].

2.1 Complaints and Anamnesis

• When taking complaints and anamnesis to identify criteria and non-criteria signs, it is recommended to clarify the presence of the following in all patients with suspected SLE:

  – photosensitivity (increased skin sensitivity to sunlight) [8];

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

– skin rashes and ulcers in the oral (palate, cheeks, tongue) and nasal cavities [8];

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

– alopecia (hair loss can be generalized or patchy) [8];

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

– pain and/or swelling in 2 or more joints, morning stiffness lasting 30 minutes or more [8];

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

– muscle pain [20–22];

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

– muscle weakness [23];

Level of Evidence CQuality of Evidence 2Strength of Recommendation - C (Level of Evidence - 2)

– chest pain in the supine position, relieved by sitting leaning forward, and worsening with deep breathing [24, 25];

GCR CLEL 4Grade of Recommendations — C (Level of Evidence — 4)

– epileptic seizures [26];

Level of Evidence CQuality of Evidence 3Strength of Recommendation - C (Level of Evidence - 3)

– lower extremity and facial edema, and decreased urine output [27–30];

GCR CLEL 4Grade of Recommendations — C (Level of Evidence — 4)

– fever [22];

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

– weight loss over a short period of time [22].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

2.2 Physical Examination

• All patients with suspected SLE are recommended to undergo a physical appearance assessment to detect underweight, fever, sweating, lymphadenopathy, and edema [22].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• All patients with suspected SLE are recommended to have their skin and hair evaluated in order to detect acute or chronic skin lesions [8].

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

Comments: skin lesion assessment includes the presence of acute active skin lesions as well as chronic ones. Acute skin lesions include malar rash (discoid rashes are not counted), bullous rashes, toxic epidermal necrolysis as a variant of SLE, maculopapular rash, photosensitivity, or subacute cutaneous lupus (non-indurated psoriasiform and/or annular polycyclic erythematous rashes that resolve without scarring, but with potential post-inflammatory depigmentation, hyperpigmentation, or telangiectasias). Chronic cutaneous lupus includes: classical discoid rash (localized (above the neck) and generalized (above and below the neck)), hypertrophic (verrucous) skin lesions, panniculitis, edematous erythematous plaques on the trunk, capillaritis (chilblain lupus, Hutchinson's lupus, manifesting as lesions on the fingertips, auricles, heel and calf areas, and the tip of the nose), periungual erythema, and lichen planus-like or overlap discoid lupus erythematosus;

Severe skin lesions in SLE are considered present if rashes cover more than 18% of the total body surface area (BSA). BSA is determined using the rule of nines (used in burn area assessment): palm (excluding fingers) = 1%, each leg = 18%, each arm = 9%, anterior trunk = 18%, posterior trunk and buttocks = 18%, head = 9%, male genitalia area = 1%.

Hair lesion assessment: non-scarring alopecia — diffuse hair thinning or increased hair fragility with visible broken hairs (in the absence of causes such as alopecia areata, drug-induced, iron deficiency-related, and androgenetic alopecia).

• All patients with suspected SLE are recommended to undergo a mucosal lesion assessment to identify clinical signs characteristic of the disease [8].

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

Comments: evaluation of oral mucosa lesions (palate, cheeks, tongue, vermilion border of the lips) – stomatitis, ulcers, enanthema of the hard and soft palate, cheilitis (in the absence of causes such as vasculitis, Behçet's disease, herpetic infection, inflammatory bowel disease, reactive arthritis, and consumption of acidic foods) and nasal cavity lesions. In individual cases, a more comprehensive assessment of oral and nasal cavity lesions is performed by a dentist and an otorhinolaryngologist.

• All patients with suspected SLE are recommended to undergo an assessment of the musculoskeletal system (joints, ligamentous apparatus, and skeletal muscles) to identify objective signs of its involvement [8].

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

Comments: to assess joint involvement, examination, palpation, and range of motion measurement are performed, specifying the number of tender and swollen joints. Pain and stiffness are detected significantly more often than objective signs of joint damage. Involvement of the ligamentous apparatus (tendinitis, tenosynovitis) with the development of transient joint flexion contractures is most commonly observed. In severe cases, a picture typical of rheumatoid arthritis is revealed: ulnar deviation and subluxation of the hand joints (Jaccoud's arthropathy). Decreased tendon strength can be complicated by ruptures at sites of increased load (Achilles tendon rupture, patellar tendon avulsion).

• All patients with SLE or suspected of having this disease are recommended to undergo a general medical examination to detect pathology of the lungs, cardiovascular system, digestive organs, kidneys, nervous system, visual and auditory organ involvement, endocrine, reticuloendothelial, hematopoietic, and other systems, and to promptly refer the patient to specialists in the relevant fields [31–37].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

Comments: to detect pathology of the lungs, cardiovascular system, digestive organs, kidneys, nervous system, visual and auditory organ involvement, and the endocrine system, consultations with a pulmonologist, cardiologist, gastroenterologist, neurologist, psychiatrist, ophthalmologist, otorhinolaryngologist, endocrinologist, hematologist, and oncologist are required.

2.3 Laboratory Diagnostics

The results of laboratory and immunological research methods are used for:

- diagnosing the disease;

- determining disease activity;

- analyzing the efficacy and safety of therapy.

2.3.1 Laboratory tests for establishing a diagnosis and determining disease activity

• To diagnose and determine the activity of SLE, all patients are recommended to have a blood total hemoglobin level test and a direct antiglobulin test (direct Coombs test) [8,33,38–41].

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

Comments: autoimmune hemolytic anemia with a positive antiglobulin test (direct Coombs test) is included in the classification criteria and develops during the active form of the disease.

- Hypochromic anemia can be the result of an iron deficiency state, a chronic inflammatory process, occult gastrointestinal bleeding, or the use of certain drugs.

• Patients with SLE and detected anemia are recommended to undergo a comprehensive evaluation to rule out causes of anemia other than SLE: serum iron, ferritin, reticulocytes, and schistocytes in the blood, and serum transferrin for the differential diagnosis of the type of anemia [22,42–44].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

• To diagnose and determine disease activity, all patients are recommended to undergo a complete blood count (CBC) with differential [8,22,45–48].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: the most important indicators of the complete blood count for diagnosing and determining disease activity are leukocytes, lymphocytes, and platelets.

Leukocyte levels less than 4.0×10⁹/L at least once (in the absence of other causes such as Felty's syndrome, use of certain drugs, and portal hypertension) or lymphocyte levels less than 1.0×10⁹/L at least once (in the absence of other causes such as the use of glucocorticoids and other drugs, or infection) are included in the classification criteria.

A platelet count of less than 100 × 10⁹/L at least once (in the absence of other causes such as drug use, portal hypertension, and thrombotic thrombocytopenic purpura) is associated with the degree of disease activity and is included in the classification criteria. Thrombocytopenia may develop in patients with antiphospholipid syndrome (APS), while rapidly progressive consumptive thrombocytopenia with hemolytic anemia and the development of multiorgan failure (e.g., renal, respiratory) occurs in thrombotic microangiopathy. The determination of anti-platelet antibodies is used to confirm autoimmune thrombocytopenia.

Biochemical parameters are nonspecific and reflect internal organ damage.

• To diagnose lupus nephritis (LN) and determine disease activity, all patients are recommended to undergo a urinalysis, a 24-hour urine protein test (proteinuria), and a glomerular filtration rate (GFR) assessment [45].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: proteinuria, hematuria, cylindruria, and leukocyturia are detected, the severity of which depends on the clinical and morphological variant of LN;

- LN is diagnosed in accordance with the ACR criteria [49]:

- persistent proteinuria ≥0.5 g/day,

- and/or: >5 erythrocytes, >5 leukocytes, or casts (erythrocytic, granular, or mixed) per high-power field in urinalysis in the absence of a urinary tract infection.

- Or immune complex glomerulonephritis based on renal biopsy results. It is advisable to perform light microscopy and immunofluorescence examination of the renal tissue biopsy specimen (pathological anatomical examination of renal biopsy material using immunohistochemical methods (evaluating glomerular deposits of IgA, M, G, lambda and kappa light chains, fibrinogen, C3 and C1q complement fractions), microscopy of renal tissue micropreparations (staining on paraffin sections: hematoxylin and eosin, Masson's trichrome stain, PAS reaction, Jones' silver impregnation), and electron microscopy of renal tissue micropreparations), allowing the detection of proliferative and membranous changes, and electron microscopy if necessary. Biopsy results should be evaluated according to the ISN/RPS classification (International Society of Nephrology/Renal Pathology Society, 2003, revised 2018) with determination of the morphological type of LN (class I–VI), and for classes III and IV LN, the glomerulonephritis activity index (AI) in points (0–24 points) and the chronicity index (CI) in points (0–12 points) (see Appendix A3.3) [49–53].

- Clinical manifestations of class I LN (minimal mesangial alterations) – no changes in urine, renal function is preserved.

- Clinical manifestations of class II LN (mesangial proliferative glomerulonephritis) – proteinuria <1.0 g/day, hematuria, preserved renal function; the development of nephrotic syndrome and renal failure is not typical.

- Clinical manifestations of class III LN (focal proliferative glomerulonephritis) – proteinuria >1.0 g/day; nephrotic syndrome develops in 20–30% of cases. Urinary sediment changes are moderate in nature. The course is characterized by steady progression. There is a high risk of developing chronic renal failure, with a relatively favorable prognosis in the case of adequate immunosuppressive therapy.

- Clinical manifestations of class IV LN (diffuse proliferative glomerulonephritis) – marked proteinuria, hematuria, cylindruria. High frequency of arterial hypertension (AH) and renal failure, low complement levels.

- Clinical manifestations of class V LN (membranous glomerulonephritis) – proteinuria >3.0 g/day, nephrotic syndrome with active urinary sediment. Renal failure and hypertension are relatively rare, and immunological abnormalities are moderately expressed. The prognosis is favorable for patients with moderate proteinuria, and more serious in the presence of nephrotic syndrome. Spontaneous remission is possible in some patients.

- clinical manifestations of class VI LN (nephrosclerosis) – clinical and laboratory signs of chronic renal failure of varying severity.

- The course of LN is characterized by fairly frequent flares, with each flare exacerbating the severity of renal structure damage and leading to the development or progression of glomerular sclerosis and interstitial fibrosis.

- The development and progression of renal failure are often accompanied by a decrease in the severity or complete disappearance of extrarenal manifestations of SLE and a decrease in laboratory signs of disease activity.

- The course of LN may be complicated by the addition of an infectious kidney and urinary tract infection (pyelonephritis).

• When a concomitant infection is suspected and to detect its signs in SLE, it is recommended to test the blood leukocyte count, erythrocyte sedimentation rate (ESR) (Westergren method, mm/h), serum C-reactive protein (CRP) level (quantitative method), and blood procalcitonin level [45,54,55].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: Assessing ESR and serum CRP levels has an auxiliary role in the diagnosis of SLE; their elevation is not a sign of SLE activity or a specific diagnostic test for this disease, as values may remain within the normal range in patients during a flare and increase during remission. In the absence of apparent causes for an increase in ESR and CRP, intercurrent infection should be ruled out.

• To determine the general somatic status and rule out comorbidities, all hospitalized patients are recommended to undergo a general therapeutic blood chemistry panel (testing levels of total protein, creatinine, total bilirubin, glucose, and determining aspartate aminotransferase and alanine aminotransferase activity in the blood) and a lipid profile blood test no later than the first day of hospital admission [22,45,56–61].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

2.3.2. Immunological tests for diagnosis and determination of disease activity

• For the diagnosis of systemic lupus erythematosus (SLE), all patients are recommended to have antinuclear and anti-DNA antibody testing, including antinuclear factor (ANF) titer determination preferably by indirect immunofluorescence (IIF) on a HEp-2 cell line (HEp-2 ANA), native DNA antibodies (anti-dsDNA), anti-Sm antibodies, as well as serum C3 and C4 complement fractions [62–64].

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

Comments: ANA, ANF is a heterogeneous population of autoantibodies reacting with various components of the cell nucleus, detected in 95% of SLE patients (usually in high titers, in the absence of drugs inducing lupus-like syndrome); their determination can be performed once. The absence of ANA/ANF calls the diagnosis of SLE into question.

- Anti-Sm antibodies are highly specific for SLE, although they are detected in only 10–30% of patients.

- A decrease in total hemolytic complement activity (CH50) and its individual components (C3 and C4), along with elevated anti-C1q antibodies, is observed in patients with lupus nephritis (LN), vasculitis, and hemorrhagic alveolitis, correlating with LN activity (especially C3 hypocomplementemia). The decrease in CH50 and individual complement protein levels may be due to their genetically determined deficiency. These parameters are among the immunological classification criteria for SLE and can reflect the degree of disease activity.

• To determine SLE activity, all patients are recommended to undergo testing for native DNA antibodies (anti-dsDNA) and serum C3 and C4 complement fractions [45].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

• When Sjögren's syndrome or interstitial lung disease is suspected, and in the presence of leukopenia, lymphopenia, thrombocytopenia, or photodermatitis, all SLE patients are recommended to be tested for rheumatoid factor, anti-Ro/SSA and anti-La/SSB antibodies in the blood [65–68].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

Comments: anti-La/SSB antibodies are frequently detected alongside anti-Ro/SSA, but their clinical significance remains unclear.

• For the diagnosis of SLE, testing for histone antibodies (characteristic of drug-induced lupus manifestations) is not recommended [69].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• When antiphospholipid syndrome (APS) is suspected, for its timely diagnosis and reduction of thrombotic risk, all SLE patients are recommended to undergo quantitative blood testing for antiphospholipid antibodies (aPL): anticardiolipin antibodies (aCL) (IgG, IgM), anti-beta-2-glycoprotein I antibodies (anti-$eta$2-GPI) (IgG, IgM), and lupus anticoagulant (LA) (Russell's viper venom or taipan snake venom test) [8,45,70–72].

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

Comments: immunological criteria for APS include:

- elevated aCL IgG or IgM isotypes detected in serum at medium or high concentrations in two or more tests at least 12 weeks apart (by standard enzyme-linked immunosorbent assay (ELISA));

- elevated anti-$eta$2-GPI IgG or IgM isotypes at medium or high concentrations in two or more tests at least 12 weeks apart (standard ELISA);

- positive LA in two or more tests at least 12 weeks apart.

2.3.3 Laboratory diagnostic tests to assess safety before initiating therapy and during treatment, and to evaluate treatment efficacy

• To identify contraindications, potential risk factors for adverse drug reactions (ADRs), and contraindications or complications of pharmacotherapy before prescribing antirheumatic drugs (all groups except GCs), all SLE patients are recommended to undergo the following laboratory tests [22,45,61,73–75]:

  – complete blood count (CBC);

  – urinalysis;

  – general therapeutic blood chemistry panel (testing levels of total protein, creatinine, total bilirubin, glucose, and determining aspartate aminotransferase and alanine aminotransferase activity in the blood);

  – lipid profile blood test;

  – testing for hepatitis B virus surface antigen (HBsAg) in the blood;

  – testing for antibodies to hepatitis C virus in the blood;

  – testing for human immunodeficiency virus HIV-1 IgM and IgG antibodies in the blood;

  – testing for human immunodeficiency virus HIV-2 IgM and IgG antibodies in the blood;

  – pregnancy test (urine human chorionic gonadotropin test).

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

• An intradermal tuberculin test (Mantoux test or recombinant tuberculosis allergen in standard dilution** or blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens) is recommended for all SLE patients to identify contraindications and potential ADR risk factors prior to initiating biologic DMARDs and immunosuppressants, and every 6 months during treatment [73].

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

• Serum human chorionic gonadotropin (free beta-subunit) testing is recommended for women of childbearing potential with SLE prior to prescribing antirheumatic drugs contraindicated during gestation and breastfeeding [76–78].

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

• Prior to prescribing #rituximab**, obinutuzumab** is recommended, serum immunoglobulin A, M, and G levels should be tested to assess the risk of immunodeficiency-related ADRs [79].

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

Comments: changes in laboratory parameters alone (especially immunological ones) do not constitute grounds for modifying therapy.

• For the diagnosis of SLE, detection of treatment complications, and differential diagnosis in all patients presenting with joint pain and swelling, it is recommended to perform synovial fluid cytological examination and microbiological (culture) examination of synovial fluid for aerobic and facultatively anaerobic microorganisms [80,81].

Level of Evidence CQuality of Evidence 3Strength of Recommendation - C (Level of Evidence - 3)

Comments: cytological and microbiological examination of synovial fluid is performed when concomitant infectious joint involvement is suspected.

2.4 Instrumental Diagnostics

• For the diagnosis of SLE, detection of treatment complications, and differential diagnosis in all patients presenting with joint pain and swelling, it is recommended to perform radiography of the affected joints. Magnetic resonance imaging (MRI) and ultrasound examination (ultrasonography) of the joints (in power Doppler mode) are recommended according to indications [80].

Level of Evidence CQuality of Evidence 3Strength of Recommendation - C (Level of Evidence - 3)

Comments: detection of early structural joint damage helps clarify the diagnosis in cases where classification criteria do not allow for a definitive diagnosis of SLE;

- erosions are not typically detected on X-ray examination in SLE;

- detection of therapy-related and disease-related complications, such as osteonecrosis;

- characterization of joint damage prior to orthopedic and surgical treatment and orthotization;

- the frequency of X-ray examination (radiography) of the joints is determined by clinical indications (suspected septic arthritis, preparation for surgery, etc.);

- MRI and ultrasound (power Doppler mode) of the joints should be used as a method complementary to clinical examination for detecting synovitis and tenosynovitis to confirm the diagnosis in complex clinical situations.

• For the diagnosis of SLE and assessment of disease activity, all patients are recommended to undergo a standard chest X-ray in anteroposterior and left lateral projections to detect potential lesions characteristic of SLE (pleuritis, interstitial lung disease, pericarditis), as well as concomitant pulmonary diseases (tuberculosis, idiopathic lung disease, etc.) during the initial evaluation and annually thereafter (more frequent evaluations must be clinically justified) [82–84].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

Comments: this is a mandatory part of the instrumental examination panel prior to the initiation of biologic DMARD therapy. If the patient is admitted to an inpatient facility, it is performed if not done within the last 6 months.

• Computed tomography (CT) of the chest is recommended for SLE patients with clinical signs of pulmonary involvement regardless of changes detected on standard chest X-ray in anteroposterior and left lateral projections; when pulmonary embolism is suspected, spiral CT of the lungs with CT pulmonary angiography and/or chest MRI should be performed as an auxiliary method to clarify the nature of lupus lung involvement and perform differential diagnosis with other conditions associated with pulmonary involvement (sarcoidosis, malignancies, etc.) [82–87].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

Comments: auxiliary methods are used to diagnose comorbid conditions that may influence the choice of therapy or increase the risk of treatment-related complications (tuberculosis, chronic obstructive pulmonary disease, etc.). If necessary, intravenous contrast enhancement may be used for these imaging studies (the necessity is determined by the specific clinical situation).

• All patients with SLE are recommended to undergo electrocardiography (ECG) at least once a year to rule out cardiac involvement (more frequent evaluations must be clinically justified) [88].

Level of Evidence CQuality of Evidence 3Strength of Recommendation - C (Level of Evidence - 3)

Comments: upon hospital admission, an ECG must be performed no later than the first day of hospitalization.

• For the diagnosis of SLE and assessment of disease activity, all patients are recommended to undergo echocardiography (Echocardiography) to clarify the nature of cardiac involvement – pericarditis, endocarditis, pulmonary hypertension – at the initial evaluation and annually thereafter (more frequent evaluations must be clinically justified) [89–91].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

• Patients with SLE presenting with new neuropsychiatric symptoms and signs are recommended to undergo initial diagnostic workups similar to those in patients without SLE presenting with the same manifestations. Depending on the type of neuropsychiatric manifestation, diagnostic studies include (ordered based on specific clinical situations): neuroimaging (MRI of the brain and/or spinal cord), lumbar puncture and cerebrospinal fluid (CSF) analysis including cytologic examination of CSF cells, analysis of CSF physical properties, microscopic examination of CSF, cell count in a counting chamber (determination of pleocytosis), complete (clinical) CSF analysis (primarily to rule out CNS infection), electroencephalography (EEG), neuropsychological assessment of cognitive functions by a psychiatrist, electroneuromyography including single-nerve stimulation electroneuromyography and needle electromyography (one muscle) to assess structural and functional disorders of the nervous system [92].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• Esophagogastroduodenoscopy (EGD) is recommended for all SLE patients regularly receiving GCs and/or NSAIDs in the presence of anemia to rule to out erosive and ulcerative lesions of the stomach and duodenum [93,94].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• X-ray densitometry of the lumbar spine and proximal femur is recommended for all patients with SLE every 12 months for the timely diagnosis of osteoporotic changes [95].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

2.5 Other Procedures

• To clarify the diagnosis of SLE in the presence of clinical and laboratory signs of renal involvement, it is recommended to perform an ultrasound-guided renal biopsy followed by pathological examination of the renal biopsy material using immunohistochemical methods (evaluating glomerular deposits of IgA, M, G, lambda and kappa light chains, fibrinogen, C3 and C1q complement fractions), microscopy of renal tissue micro preparations (staining on paraffin sections: hematoxylin and eosin, Masson's trichrome, PAS reaction, Jones silver impregnation), and electron microscopy of renal tissue micro preparations [96–99].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

Comments: renal biopsy, in the absence of contraindications, should be performed in all SLE patients with suspected lupus nephritis. The biopsy specimen must contain ≥10 glomeruli and ≥1 arteriole.

The results of the pathological examination of the renal biopsy material must be evaluated according to the ISN/RPS 2003 lupus nephritis classification, revised in 2018 (see Appendix A3).

• In all patients with high and moderate SLE activity, to determine the dynamics of disease activity and treatment efficacy, it is recommended to evaluate the SLEDAI-2K or SELENA-SLEDAI index at least once every 3 months (see Appendix G1, G2) [18,100,101].

CGR CLOE 5Clinical Recommendation Grade - C (Level of Evidence - 5)

• In all patients with low SLE activity or remission, to determine the dynamics of disease activity and treatment efficacy, it is recommended to evaluate the SLEDAI-2K or SELENA-SLEDAI activity index at least once every 6 months [18,100,101].

CGR CLOE 5Clinical Recommendation Grade - C (Level of Evidence - 5)

• In all patients with high and moderate SLE activity, to determine the presence of potentially irreversible organ damage, it is recommended to evaluate the Damage Index using the SLICC/DI scale at least once every 6 months (see Appendix G3) [18,100,101].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• In all patients with low SLE activity or remission, to determine the presence of potentially irreversible organ damage, it is recommended to evaluate the Damage Index using the SLICC/DI scale at least once every 12 months [18,100,101].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

All patients with SLE and suspected Sjögren's syndrome are recommended to undergo an initial ophthalmological appointment (examination, consultation) including the Schirmer's test, Norn's test, and corneal staining with medicinal products of the S01JA group of coloring agents (vital dyes) [102,103].

CGR CLOE 5Clinical Recommendation Grade - C (Level of Evidence - 5)

• All patients with SLE and suspected Sjögren's syndrome are recommended to undergo an initial dental or maxillofacial surgeon appointment (examination, consultation) for sialometry, contrast sialography of the salivary gland ducts, and/or minor salivary gland biopsy followed by pathological examination of the salivary gland tissue biopsy material using immunohistochemical methods [103–107].

CGR CLOE 5Clinical Recommendation Grade - C (Level of Evidence - 5)

• Follow-up by a multidisciplinary team involving specialist medical consultants is recommended for patients with relevant indications for the purpose of diagnosis or determining management strategies for conditions that may impact treatment selection and the prognosis of SLE [18,22,45].

CGR CLOE 5Clinical Recommendation Grade - C (Level of Evidence - 5)

Comments: patients may be referred to medical specialists according to the following indications:

- cardiology consultation (examination, assessment) – for the diagnosis of cardiovascular diseases in patients with cardiovascular symptoms, prescription or adjustment of ongoing cardioprotective therapy, and for patients with signs of heart failure prior to biological therapy;

- neurology consultation (examination, assessment) – to clarify the nature and extent of nervous system involvement and select symptomatic therapy in case of neurological symptoms;

- nephrology consultation (examination, assessment) – for the management of chronic kidney disease, renal failure, and hemodialysis;

- dermatovenereology consultation (examination, assessment) – to confirm cutaneous lupus erythematosus and rule out other skin conditions;

- ophthalmology consultation (examination, assessment) – for the diagnosis and management of ocular pathology, side effects of drug therapy (glucocorticoids, chloroquine/hydroxychloroquine, etc.), and keratoconjunctivitis sicca (diagnosis of Sjögren's syndrome);

- dental consultation (examination, assessment) – to evaluate oral mucosa lesions, diagnose xerostomia and salivary gland involvement (diagnosis of Sjögren's syndrome);

- psychiatry consultation (examination, assessment) – to prescribe symptomatic therapy and address the need for inpatient treatment in specialized facilities for psychotic disorders (especially psychosis and depression with suicidal ideation);

- endocrinology consultation (examination, assessment) – for the diagnosis of endocrine disorders, primarily diabetes mellitus, which may influence the choice of systemic lupus erythematosus (SLE) therapy;

- phthisiology consultation (examination, assessment) – when prescribing biological therapy in case of suspected latent tuberculosis infection, for the diagnosis and treatment of tuberculosis of various sites;

- hematology consultation (examination, assessment) – for the diagnosis and management of hematological diseases, including hematological malignancies;

- critical care medicine consultation (examination, assessment) – to provide emergency care in life-threatening situations;

- pulmonology consultation (examination, assessment) – for the diagnosis of interstitial lung disease, and the diagnosis and management of concurrent pulmonary involvement;

- orthopedic trauma consultation (examination, assessment) – for all SLE patients with indications for surgical treatment (significant impairment of hip, knee, and other joint functions, including contractures, osteonecrosis, osteoporotic vertebral fractures) or orthotic management;

- obstetrics and gynecology consultation (examination, assessment) – for patients planning pregnancy or pregnant patients, to make joint decisions on further management, follow-up, and delivery care, and for contraception counselling;

- oncology consultation (examination, assessment) – upon the development of malignant neoplasms and to develop patient management strategies;

- urology consultation (examination, assessment) – for the diagnosis and management of urinary system disorders;

- otorhinolaryngology consultation (examination, assessment) – to evaluate nasal mucosa lesions, and diagnose and manage focal ENT infections;

- medical psychology consultation (testing, assessment) – to improve treatment adherence and collaboration with physicians and medical staff to achieve disease remission; to achieve social and psychological adaptation; and to develop an individual psychological rehabilitation program for the patient.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Main management methods for patients with SLE:

1. SLE is a potentially severe disease with diverse clinical manifestations that usually requires a multidisciplinary therapeutic approach coordinated by a rheumatologist;

2. Therapy must be optimal and based on mutual understanding between the physician and the patient;

3. Optimal SLE therapy is based on a combination of non-pharmacological and pharmacological treatment methods.

Treatment of SLE patients must be individualized according to:

1. Clinical manifestations present at the time of examination (involvement of various organs and systems);

2. Severity of symptoms, disease activity, presence of irreversible organ damage, poor prognostic factors (onset in childhood and adolescence, male sex, acute course, high activity at onset, development of lupus nephritis within the first 3–6 months of disease onset, progressive renal failure, CNS involvement, severe thrombocytopenia, comorbid conditions (infections, atherosclerotic vascular disease), presence of more than 2 irreversible organ damages, pregnancy);

3. General clinical status and comorbid conditions.

The goal of SLE treatment is to achieve remission or low disease activity (alternative goal), prevent damage to vital organs and systems (primarily the kidneys and CNS), and reduce the risk of comorbid conditions, thereby stabilizing the patient's functional capacity and preserving quality of life and working capacity.

The modern treatment strategy for SLE is based on the "Treat to target" principle [108] and implies early prescription of immunosuppressive therapy and biological agents from the time of diagnosis, frequent (at least every 1–3 months until remission/low activity is achieved, and every 6 months thereafter) and objective (using quantitative methods) monitoring of the patient's condition by a rheumatologist, modification of the treatment regimen in case of insufficient therapeutic response until treatment goals are achieved, followed by continuous dynamic follow-up.

• Treatment of patients with SLE is recommended to be managed by a rheumatologist (exceptionally by a general practitioner or family physician, but with consultative support from a rheumatologist) throughout the patient's life [18,75].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

3.1 Conservative Treatment

Glucocorticoids

• All SLE patients are strongly recommended to receive short-acting glucocorticoids (prednisolone** or methylprednisolone**). The glucocorticoid dose depends on disease activity and the patient's weight [45,109].

GCR CLEL 4Grade of Recommendations — C (Level of Evidence — 4)

• Patients with low disease activity (SLEDAI-2K or SELENA-SLEDAI 1–4 scores) are recommended low doses of glucocorticoids (prednisolone** ≤7.5 mg/day), moderate activity (SLEDAI-2K or SELENA-SLEDAI 5–10 scores) – moderate doses (prednisolone** >7.5–30 mg/day) for 4 weeks with a gradual taper to low-dose maintenance therapy (prednisolone** 5–7.5 mg/day), and high activity (SLEDAI-2K or SELENA-SLEDAI >10 scores) – high doses of glucocorticoids (prednisolone** 0.5–1 mg/kg of body weight) combined with immunosuppressants [18,110–113].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: an absolute indication for high-dose glucocorticoids (prednisolone** 0.5–1 mg/kg/day) is rapidly progressive involvement of vital organs (renal involvement, CNS involvement, systemic vasculitis, alveolitis).

- the duration of high-dose glucocorticoid therapy ranges from 4 to 12 weeks depending on the severity of the clinical response.

- once improvement and a decrease in disease activity are achieved, the glucocorticoid dose can be gradually tapered (usually by 1.25 mg every 7–10 days) to a low maintenance dose (prednisolone** 5–7.5 mg/day), which needs to be taken for many years; upon achieving sustained disease remission (SLEDAI-2K or SELENA-SLEDAI 0 scores), discontinuation of glucocorticoids is an option.

- dose reduction of glucocorticoids should be performed under careful clinical and laboratory monitoring and may vary depending on the disease course, involvement of a particular organ or system, risk of flare, comorbid conditions, and complications.

- during long-term glucocorticoid therapy, patients need monitoring and prevention of osteoporosis, diabetes mellitus, atherosclerosis, hyperlipidemia, arterial hypertension, gastrointestinal tract lesions, and cataracts.

• Patients with high SLE activity (SLEDAI-2K or SELENA-SLEDAI >10 scores) are recommended intravenous administration of methylprednisolone** (250 mg) over 30 minutes by infusion or methylprednisolone** pulse therapy at 15–20 mg/kg of body weight (500–1000 mg) intravenously over 30 minutes for 3 consecutive days or more to achieve a rapid effect and reduce oral glucocorticoid doses [18,114].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Immunosuppressants

• All SLE patients with active lupus nephritis, CNS involvement, and/or development of vasculitis, hemorrhagic alveolitis, high disease activity and glucocorticoid resistance, development of adverse events from glucocorticoids in early stages of treatment, or the need for a rapid reduction or tapering of a maintenance glucocorticoid dose exceeding 15–20 mg/day of prednisolone**, are recommended immunosuppressive therapy [115–118].

GCR BLOC 2Grading of Recommendations Assessment, Development and Evaluation (GRADE) level of recommendation - B (level of evidence - 2)

• In patients with high SLE disease activity at initial presentation or during a flare, it is recommended to use cyclophosphamide** or #mycophenolate mofetil** for induction therapy of active LN [119–121].

GCR BLOC 1Grading of Recommendations Assessment, Development and Evaluation (GRADE) level of recommendation - B (level of evidence - 1)

Comments: cyclophosphamide** is prescribed at 500 mg every 2 weeks, up to 6 infusions, or at 1000 mg intravenously monthly for 6 months.

- #Mycophenolate mofetil** is administered orally at a dose of 2-3 g/day for 6-12 months [121].

- Induction therapy is carried out for 3-6 months in combination with methylprednisolone** pulse therapy and oral GCs prescribed at a dose of 0.25-0.5-1.0 mg/kg calculated as prednisolone**.

• Upon achieving a positive clinical and laboratory response, it is recommended to use immunosuppressive drugs (immunosuppressants) as maintenance therapy [45].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: as maintenance therapy, #mycophenolate mofetil** is used at a dose of 1–2 g/day or azathioprine** at 2–3 mg/kg of body weight per day for 12 months or more.

- The administration of cyclophosphamide**, #mycophenolate mofetil**, and azathioprine** in both induction and maintenance phases of therapy must be supervised by a rheumatologist due to the high risk of bacterial, viral, and fungal infections, toxic hepatitis, bone marrow suppression, and teratogenic effects.

• In GC-monotherapy-refractory lupus arthritis and skin lesions, in the absence of contraindications, it is recommended to use parenteral methotrexate** at a dose of at least 15 mg per week in combination with folic acid**, excluding the day of methotrexate** administration [45,122–124].

GCR BLOC 1Grading of Recommendations Assessment, Development and Evaluation (GRADE) level of recommendation - B (level of evidence - 1)

Comments: methotrexate** treatment also has a beneficial effect on SLE manifestations such as alopecia and pleuritis;

- in half of the patients with SLE, methotrexate** allows for a reduction in the GC dose;

- in patients receiving methotrexate**, a high incidence of cytopenia and oral mucosal ulceration has been noted, which are difficult to monitor due to their similarity to the disease activity itself.

• In the absence of contraindications, in patients with low-to-moderate SLE activity when treatment goals cannot be achieved with GCs and hydroxychloroquine** and/or when it is not possible to reduce the GC dose to ≤5 mg/day, it is recommended to use azathioprine** [18].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: despite the available data being more favorable for prescribing methotrexate**, the possibility of using azathioprine** when planning pregnancy must be considered.

Antimalarial drugs (hydroxychloroquine**)

• In all SLE patients without exception, regardless of disease activity and in the absence of contraindications, long-term administration of hydroxychloroquine** (HCQ**) at a dose of ≤5 mg/kg of body weight (200-400 mg/day) is recommended [125,126].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: long-term administration of HCQ** provides prevention of flares, reduction of SLE activity, and lowering the risk of cardiovascular complications, diabetes mellitus, and helps reduce the GC dose;

- #HCQ** at a dose of ≤5 mg/kg of body weight (200-400 mg/day) can be used in pregnant women with SLE and during breastfeeding [127];

Factors contributing to retinopathy include the duration of drug use (risk increases every 5 years of use), the drug dose, chronic kidney disease, and preexisting retinal or macular disease.

Nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs)

• In patients with SLE, for the treatment of musculoskeletal manifestations, fever, and moderate serositis, it is recommended to use NSAIDs at standard therapeutic doses for a short period of time and only in patients with a low probability of adverse drug reactions [45].

Level of Evidence CQuality of Evidence 3Strength of Recommendation - C (Level of Evidence - 3)

• When there is a moderate probability of gastrointestinal complications, it is recommended to use selective NSAIDs (coxibs, other nonsteroidal anti-inflammatory and antirheumatic drugs) without additional prophylaxis or nonsteroidal anti-inflammatory drugs (butylpyrazolidines, acetic acid derivatives and related substances, oxicams, propionic acid derivatives) along with pharmacologic prevention of adverse drug reactions (proton pump inhibitors (PPIs) [128].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: simultaneous prescription of 2 or more NSAIDs increases the risk of adverse drug reactions;

- NSAIDs should not be prescribed to SLE patients with a very high risk of cardiovascular complications.

• For mild to moderate pain when NSAIDs are ineffective, paracetamol** may be recommended to achieve an analgesic effect, and tramadol** for moderate to severe pain [129].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Genetically engineered biologic drugs

• In the absence of contraindications, in all patients with moderate and high SLE activity when treatment goals cannot be achieved with HCQ**, GCs, and immunosuppressants, and/or when it is not possible to reduce the GC dose to ≤5 mg/day, it is recommended to consider prescribing targeted synthetic/biologic DMARDs [18].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: a list of contraindications is given in Appendix A3.5.

• In the absence of contraindications, in all patients with moderate and high SLE activity (active skin and mucosal lesions and/or development of polyarthritis, mild-to-moderate hematological disorders (hemolytic anemia, thrombocytopenia, leukopenia), with autoantibodies, but without CNS involvement and without LN), frequent flares, ineffectiveness and/or intolerance of standard therapy, and the inability to reduce the GC dose to ≤5 mg/day, the use of monoclonal antibodies to type I IFN receptor — anifrolumab** — is recommended [130–133].

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

Comments: the duration of anifrolumab** use should be at least 12 months; doses and regimen are determined in accordance with the instructions.

• In the absence of contraindications, in all patients with moderate and high SLE activity (with active skin, mucosal, and joint lesions, mild-to-moderate hematological disorders (hemolytic anemia, thrombocytopenia, leukopenia), high levels of anti-dsDNA antibodies, hypocomplementemia, class III and IV LN, but without CNS involvement), frequent flares, and dependence on medium-to-high doses of GCs, as well as a high risk of therapy complications (organ damage) and infections, the use of monoclonal antibodies to BLyS — belimumab** — is recommended [134,135].

GCP ALOE 2Grade of Recommendation — A (Level of Evidence — 2)

Comments: according to the results of phase III RCTs, belimumab** can be used as an adjunct to standard therapy for class III and IV LN, both in the induction and maintenance phases. The duration of belimumab** use should be at least 12 months; doses and regimen are determined in accordance with the instructions.

• In the treatment of LN, nervous system involvement, and in case of failure of one or two induction therapy regimens using cyclophosphamide**/#mycophenolate mofetil**, and/or in case of failure of treatment with high doses of GCs and immunosuppressants, it is recommended to prescribe #rituximab** [136,137].

GoR BLoE 2Grade of recommendation - B (level of evidence - 2)

Comments: the #rituximab** dosing regimen: 500-1000 mg intravenously weekly (maximum cumulative dose – 2000 mg). The duration of treatment (number of courses) is determined individually depending on the clinical situation and response to treatment.

• In refractory SLE with articular and/or cutaneous manifestations, taking into account the ratio of potential benefits and risks for the patient, upon convening a medical panel (consilium) followed by the approval of drug therapy by a medical commission, the prescription of immunosuppressants #tocilizumab**, #abatacept**, #baricitinib**, #tofacitinib**, #upadacitinib** in individual cases is recommended [138–142].

#Tofacitinib**, #upadacitinib**: Grading of Recommendations Assessment, Development and Evaluation (GRADE) level of recommendation - B (level of evidence - 2)

#Baricitinib**: Grading of Recommendations Assessment, Development and Evaluation (GRADE) level of recommendation - C (level of evidence - 2)

#Tocilizumab**, #abatacept**: Grading of Recommendations Assessment, Development and Evaluation (GRADE) level of recommendation - C (level of evidence - 4)

Comments: the dosing regimens are presented in Table 1. The duration of treatment with each of the drugs is determined individually depending on the clinical situation and response to treatment.

Table 1 - Regimens of biological DMARDs for the treatment of SLE

Normal human immunoglobulin**

• In severe nervous system involvement, severe thrombocytopenia, or concomitant infection, intravenous administration of normal human #immunoglobulin** (IVIG) is recommended [146–149].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: #IVIG** administration regimens: total dose of 2 g/kg of body weight, administered over 2-5 days, treatment courses repeated monthly. The duration of treatment (number of courses) is determined individually depending on the clinical situation and response to treatment.

Extracorporeal treatment methods

• In the event of coma, stupor, progressive myelitis, severe thrombocytopenia, cryoglobulinemic or hypergammaglobulinemic vasculitis, or persistent high immunological activity, plasmapheresis is recommended [150].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: plasmapheresis is not a primary therapy for SLE and may be used additionally in combination therapy in cases of insufficient efficacy of standard treatment.

- Removal of 800 to 1000 ml of plasma is indicated, with or without replacement with donor fresh frozen plasma or human albumin solution** (depending on the serum total protein level), at intervals of 2-3 days.

- The efficacy of SLE therapy is increased when plasmapheresis is combined with intravenous infusions of methylprednisolone** from 250 to 1000 mg after each procedure and/or cyclophosphamide** from 200 to 1000 mg as a single dose [151,152].

3.1.1 Differentiated therapy for specific clinical manifestations of SLE

Therapy for specific clinical manifestations of SLE is directed at SLE as well as its individual manifestations, and is carried out with drugs that affect the disease as a whole. When multiple organs and systems are involved in SLE, therapy should target all clinical manifestations, prioritizing those associated with the highest risk of irreversible damage.

• For patients with skin involvement, low doses of GCs (prednisolone** 5-10 mg/day) and HCQ** 200-400 mg/day are recommended [18,153].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: topical preparations containing GCs and calcineurin inhibitors may be prescribed by a dermatologist; the use of preparations containing fluorine compounds should be avoided, especially on the facial area, due to the risk of skin atrophy; sunscreens (against α- and β-ultraviolet rays with a protection factor of at least SPF50) must be used.

• For patients with skin involvement resistant to combination therapy with low doses of GCs and HCQ**, the administration of methotrexate** 15 mg/week, or #mycophenolate mofetil** 2 g/day, or azathioprine** 2-3 mg/kg of body weight per day is recommended [22,154,155].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: the duration of treatment (number of courses) is determined individually depending on the clinical situation and response to treatment.

• For patients with generalized cutaneous vasculitis or bullous skin lesions, bolus administration of cyclophosphamide** (0.5-1 g/m²) in combination with methylprednisolone** (1000 mg) is recommended [22,155].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• If drug therapy is ineffective in patients with generalized cutaneous vasculitis or bullous skin lesions, synchronous intensive therapy—sequential use of plasmapheresis and pulse doses of cyclophosphamide** and GCs—is recommended [22,151,152].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

• For the prevention of hemorrhagic cystitis in patients receiving cyclophosphamide**, additional hydration leading to frequent bladder emptying and ample fluid intake over the subsequent 24 hours are recommended [156–158].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

• For patients with arthralgia/arthritis, low doses of GCs (prednisolone** no more than 10 mg/day), HCQ** 200-400 mg/day, and NSAIDs in standard doses are recommended [22,159].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• For patients with arthralgia/arthritis refractory to GCs, HCQ**, and NSAIDs, the administration of methotrexate** 15-20 mg/week is recommended; in case of intolerance and/or ineffectiveness of methotrexate**, #leflunomide** is recommended [22,159,160].

For methotrexate**: Level of recommendation - C (level of evidence - 5)

For #leflunomide**: Level of recommendation - B (level of evidence - 2)

Comments: the loading dose of #leflunomide** according to studies in SLE patients is 100 mg for 3 days, followed by 20 mg/day [160]. The duration of treatment (number of courses) with #leflunomide** is determined individually depending on the clinical situation and response to treatment, but should be at least 6 months.

• For patients with exudative polyserositis (pleurisy/pericarditis), the administration of medium and high doses of GCs (prednisolone** 0.25-0.5 mg/kg per day) and NSAIDs in standard doses is recommended; if ineffective, methylprednisolone** pulse therapy in combination with azathioprine** should be performed [22,161–164].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• For patients with pneumonitis (interstitial lung disease), methylprednisolone** pulse therapy (500-1000 mg) for 3 consecutive days in combination with cyclophosphamide** (0.75-1 g/m²) against the background of high doses of oral GCs (prednisolone** 1 mg/kg per day) is recommended [22,161].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• For patients with autoimmune hemolytic anemia, the administration of high doses of GCs (prednisolone** 1 mg/kg per day) is recommended. In case of a pronounced (less than 70 g/L) and rapidly progressive decrease in hemoglobin concentration, methylprednisolone** pulse therapy (500-1000 mg for 3 consecutive days) must be performed [165,166].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• For patients with autoimmune hemolytic anemia refractory to GC therapy, the addition of oral #mycophenolate mofetil** 2 g/day or azathioprine** 2-3 mg/kg per day is recommended [22,165,167].

For #mycophenolate mofetil**: Level of recommendation - C (level of evidence - 4)

For azathioprine**: Level of recommendation - C (level of evidence - 5)

Comments: the duration of treatment (number of courses) is determined individually depending on the clinical situation and response to treatment, but should be at least 6 months.

• For patients with autoimmune hemolytic anemia with severe, rapidly progressive hemolytic anemia refractory to GC therapy, #rituximab** intravenously at 500-1000 mg weekly (maximum cumulative dose 2000 mg) is recommended [168,169].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

Comments: the duration of treatment (number of courses) is determined individually depending on the clinical situation and response to treatment, but should be at least 6 months.

• For patients with thrombocytopenia (below 30x10⁹/L), the administration of high doses of GCs (prednisolone** 0.5-0.7 mg/kg per day) is recommended. In case of a rapid decrease in platelet count, methylprednisolone** pulse therapy (500-1000 mg for 3 consecutive days) should be used [18].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• For patients with severe thrombocytopenia (below 30x10⁹/L) with no effect within 1 week of GC therapy, methylprednisolone** pulse therapy (500-1000 mg for 3 consecutive days) in combination with cyclophosphamide** (0.75-1 g/m²), or oral #mycophenolate mofetil** 2 g/day, or azathioprine** (2-2.5 mg/kg per day), or oral #cyclosporine** (<5 mg/kg per day), or #rituximab** intravenously at 1000 mg weekly (maximum cumulative dose 2000 mg) is recommended [154,166,170–172].

For #mycophenolate mofetil**: Level of recommendation - B (level of evidence - 3)

For other drugs: Level of recommendation - C (level of evidence - 5)

Comments: the choice of immunosuppressant depends on the severity and rate of progression of thrombocytopenia, as well as the presence of other SLE manifestations. The duration of treatment (number of courses) is determined individually depending on the clinical situation and response to treatment.

• For patients with severe thrombocytopenia (below 30x10⁹/L) in case of ineffectiveness of immunosuppressive therapy, a decrease in platelet count (below 25×10⁹/L), and hemorrhagic syndrome, the use of #IVIG** (total course dose of 2 g over 5 consecutive days) or #rituximab** intravenously at 1000 mg weekly (maximum cumulative dose 2000 mg) is recommended [166,171,172].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: the duration of treatment (number of courses) is determined individually depending on the clinical situation and response to treatment.

• For patients with thrombotic thrombocytopenic purpura, plasma exchange combined with human fresh frozen plasma infusion and methylprednisolone** pulse therapy (500–1000 mg for 3 consecutive days) is recommended [22].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• For patients with neuropsychiatric symptoms and the development of severe, life-threatening CNS involvement, the emergency administration of cyclophosphamide** 0.75–1 g/m² intravenously and methylprednisolone** pulse therapy at 1000 mg intravenously for several consecutive days, followed by high-dose GCs (prednisolone** 1 mg/kg/day), is recommended [22, 173, 174].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

• For patients with neuropsychiatric symptoms presenting with coma, sopor, progressive myelitis, high anti-dsDNA levels, and/or cryoglobulinemic vasculitis, in addition to cyclophosphamide** therapy and high-dose GCs including pulse therapy, plasma exchange is recommended daily or every other day, with an exfusion of 20–30 ml/kg of plasma weight, along with #IVIG** administration of 2 g over 2–5 days after completion of plasma exchange procedures [175].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: the duration of treatment (number of courses) is determined individually depending on the clinical situation and response to treatment.

• For patients with neuropsychiatric symptoms who show no response within the first 3–4 days of intensive therapy, #rituximab** intravenously at 500–1000 mg weekly (maximum cumulative dose 2000 mg) is recommended [175, 176].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

Comments: the duration of treatment (number of courses) is determined individually depending on the clinical situation and response to treatment.

3.1.2 Treatment of lupus nephritis

• Treatment of lupus nephritis is recommended to be carried out in accordance with the morphological type of nephritis and clinical-laboratory parameters (degree of proteinuria and serum creatinine level) [45].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: treatment goal: reduction of proteinuria ≥25% with a stable estimated glomerular filtration rate (increase by ±10%) during the first three months from the start of therapy, reduction of proteinuria by ≥50% at six months, and proteinuria <0.5–0.7 g/day with a stable estimated glomerular filtration rate at 12–24 months from the start of therapy [177]. Induction (duration 3–6 months) and maintenance phases of lupus nephritis treatment are distinguished.

Induction therapy for lupus nephritis

• In classes I or II lupus nephritis, induction therapy is recommended if extrarenal manifestations of SLE and/or massive proteinuria are present [178].

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

Comments: induction therapy is not performed for classes I or II lupus nephritis.

• When proteinuria ≥0.5 g/day and hematuria are detected in classes I or II lupus nephritis, moderate to high doses of GCs (prednisolone** 0.25–0.5 mg/kg/day) for 4–6 weeks as monotherapy followed by tapering to low doses of GCs over 3 months, or moderate doses of GCs combined with azathioprine** 1–2 mg/kg/day, are recommended [45, 177, 178].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: if there is no effect within 3 months, more intensive treatment regimens are prescribed.

• In class III/IV lupus nephritis, induction therapy with cyclophosphamide** or #mycophenolate mofetil** in combination with a 3-day course of methylprednisolone** pulse therapy (500–1000 mg/day) followed by oral GCs in moderate or high doses (prednisolone** 0.3–0.5 mg/kg/day) is recommended [22, 177].

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

Comments: tapering of the GC dose is possible upon achieving a positive therapeutic response to ≤7.5 mg/day by month 3–6.

- #Mycophenolate mofetil** is prescribed orally at a dose of 2–3 g/day throughout the entire induction therapy period (6 months). Equal efficacy of #mycophenolate mofetil** and cyclophosphamide** has been proven, with lower toxicity of #mycophenolate mofetil** [177].

- Two cyclophosphamide** dosing regimens are possible: “low doses” – 500 mg intravenously once every 2 weeks (total of 6 infusions), followed by #mycophenolate mofetil** 2 g/day [177] or azathioprine** 2 mg/kg/day; or “high doses” – cyclophosphamide** 1.0 g/m² intravenously combined with intravenous methylprednisolone** infusion at 1000 mg monthly for 6 months, followed by #mycophenolate mofetil** or azathioprine**.

• In classes III/IV lupus nephritis with adverse prognostic factors (decreased glomerular filtration rate (GFR), histological changes – cellular crescents, fibrinoid necrosis, tubular atrophy, or interstitial fibrosis) induction therapy is recommended: administration of high doses of cyclophosphamide** (1.0 g/m² intravenously combined with intravenous methylprednisolone** infusion at 1000 mg monthly for 6 months) or oral #mycophenolate mofetil** 2–3 g/day combined with methylprednisolone** pulse therapy and high-dose oral GCs (prednisolone** at least 1 mg/kg/day) [179–182].

GOM BLOE 2Grade of Recommendation - B (Level of Evidence - 2)

Comments: the duration of treatment (number of courses) is determined individually depending on the clinical situation and response to treatment.

• In class V lupus nephritis with nephrotic syndrome, induction therapy with oral #mycophenolate mofetil** at 2–3 g/day (alternatives may include #cyclosporine** (orally at 3–5 mg/kg/day) or #tacrolimus** (orally at 0.05–0.1 mg/kg/day in 2 divided doses)) combined with prednisolone** 0.5 mg/kg/day is recommended [18, 183–187].

GCR BLOC 1Grading of Recommendations Assessment, Development and Evaluation (GRADE) level of recommendation - B (level of evidence - 1)

Comments: treatment duration (number of courses) is determined individually depending on the clinical situation and treatment response.

• If lupus nephritis is resistant to induction therapy – defined as no response to therapy for 6 months or the development of a relapse 3 months after starting therapy, "switching" from one cytotoxic drug to another within the above immunosuppressive regimens is recommended [45].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

• If there is no response to one or two induction therapy regimens using cyclophosphamide**/#mycophenolate mofetil**, administration of #rituximab** intravenously at 500–1000 mg weekly (maximum cumulative dose 2000 mg) is recommended [188].

GOM BLOE 3Grade of Recommendation - B (Level of Evidence - 3)

Comments: overall, #rituximab** treatment is associated with a reduction in disease activity in more than 80% of patients:

- administration of #rituximab** is highly effective in patients with SLE presenting with progressive lupus nephritis (classes III–IV) and active extrarenal disease manifestations (skin lesions, polyarthritis, stomatitis, serositis, fever, anemia);

- #rituximab** may be the drug of choice in patients with a critical course of SLE caused by severe CNS involvement (coma, seizures, psychosis, myelitis);

- preliminary data indicate high efficacy of repeated #rituximab** therapy courses in the event of relapse.

• If there is no response to one or two induction therapy regimens, as an alternative method to #rituximab**, the appointment of calcineurin inhibitors (#cyclosporine** or #tacrolimus**) as monotherapy or in combination with #mycophenolate mofetil** is recommended [187, 189, 190].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

Comments: the administration regimens for these drugs correspond to those recommended above. Treatment duration (number of courses) is determined individually depending on the clinical situation and treatment response.

Comments: in 27–66% of patients with lupus nephritis, despite achieving a complete clinical response to standard immunosuppressive therapy, flares and further progression to end-stage renal disease are observed [193–195]. The use of obinutuzumab**, whose efficacy in lupus nephritis as an adjunct to standard therapy was demonstrated in the recently completed phase III randomized clinical trial REGENCY (NCT04221477). The study demonstrated the feasibility of achieving a complete renal response in 46.4% of patients receiving obinutuzumab** combined with standard therapy (#mycophenolate mofetil** and GCs) by week 76 of treatment compared to 33.1% of patients receiving standard therapy alone (adjusted difference 13.4%, 95% CI, 2.0%–24.8%; P=0.0232), with a statistically significant increase in C3, C4, CH50 complement levels and a decrease in anti-dsDNA and other markers of disease activity and inflammation [191].

An advantage in achieving a complete renal response with obinutuzumab** was observed in patient subgroups who had more active lupus nephritis (predominantly class IV or in combination with class V, a higher baseline level of proteinuria, and/or greater serological activity of SLE) [191].

In 2019, obinutuzumab** received FDA breakthrough therapy designation, and it is currently undergoing registration for an additional indication in the Russian Federation for the treatment of active lupus nephritis in adults aged 18 years and older in combination with immunosuppressive therapy.

Maintenance therapy for LN

• When induction therapy for LN is applied and a good clinical and laboratory effect is achieved, to maintain it and improve the long-term prognosis, it is recommended to prescribe #mycophenolate mofetil** orally at a dose of 2 g/day or azathioprine** 2 mg/kg/day [45].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: treatment duration (number of courses) is determined individually depending on the clinical situation and treatment response.

• In active LN, in addition to baseline therapy with GCs and immunosuppressants (immunosuppressive drugs), it is recommended to prescribe angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers for renoprotective purposes, HMG-CoA reductase inhibitors (statins) for dyslipidemia, low doses of acetylsalicylic acid** for the prevention of thrombotic complications in patients with positive APLs, antithrombotic agents (anticoagulants) in nephrotic syndrome with severe hypoalbuminemia (especially in APL-positive patients), and calcium preparations in combination with vitamin D and/or other agents for the prevention of osteoporosis [18,177].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: the prescription of immunosuppressants (immunosuppressive drugs), both in the induction phase and during maintenance therapy, must be under constant monitoring. When prescribing these drugs, there is a high risk of bacterial, fungal, and viral infections, toxic hepatitis, and bone marrow suppression.

3.2 Surgical Treatment

• Surgical treatment (joint replacement, arthroplasty, arthrodesis, etc.) is recommended for patients with SLE in the presence of marked structural changes in the musculoskeletal system—presence of drug-resistant synovitis of specific joints, development of joint deformities, persistent pain, and functional impairment [196].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: surgical treatment of affected joints in patients with SLE is performed in specialized traumatology and orthopedics departments;

 - discontinuation of #methotrexate**, #mycophenolate mofetil**, calcineurin inhibitors (#cyclosporine**, #tacrolimus**), azathioprine**, and cyclophosphamide** must be carried out at least 2 weeks before surgery and resumed after complete wound healing and in the absence of complications;

- administration of bDMARDs should be suspended for a period depending on the pharmacokinetic characteristics of the drug, individual patient characteristics, and the nature of the surgery, and resumed in the absence of evidence of infection and with satisfactory healing of the surgical wound surface;

- GC treatment should be continued at the previous dose;

- replacement therapy is necessary on the day of the surgical intervention (intravenous infusions of methylprednisolone** 250–500 mg depending on the severity of the surgery).

3.3 Other Treatment

Comments: educational programs aimed at maintaining working capacity and functional status, helping to cope with pain and reduce disability, and improving quality of life are an additional component of comprehensive treatment for patients with SLE;

- in the early stage of SLE, the timing and format of training are determined based on the individual needs of the patient. Training should take place during different periods of the disease and be based on a cognitive-behavioral model;

- it is necessary to create individually tailored educational programs developed in accordance with the patient's needs. The patient must be provided with information about the disease, treatment principles, outcomes, and physical activity in daily life. Support from patient organizations and training in the basic principles of disease self-management are necessary from the moment of diagnosis;

- educational programs increase the level of knowledge about SLE, self-efficacy, social adaptation, the ability to self-monitor the disease, and adherence to pharmacotherapy.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: Exercise therapy is a necessary adjunct to medical treatment.

- With high SLE activity caused by damage to vital organs: kidneys, central nervous system, heart, or severe thrombocytopenia, exercise therapy is practically not performed, and in some cases is limited to breathing exercises.

- In patients with low SLE activity or remission, dynamic, strength, and aerobic exercises adapted to the patient's needs and capabilities improve muscle strength, functional status, aerobic capacity, and psychological state, and reduce the risk of comorbid diseases, primarily cardiovascular ones, without increasing SLE activity.

- When prescribing exercise therapy to patients with skin lesions, swimming in a pool should be avoided.

- Patients should be informed about existing physiotherapeutic methods, but the evidence base for their effectiveness in SLE is insufficient.

5. Prevention and Dispensary Observation

Primary prevention of SLE has not been developed.

• All patients with SLE are recommended to avoid factors that can provoke disease flares (insolation, intercurrent infections, stress, taking estrogen-containing drugs, etc.) [18,197].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• All patients with SLE are recommended to quit smoking, strive to maintain a normal body weight, and achieve target blood pressure and low-density lipoprotein cholesterol levels [18,197].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: smoking, overweight, dyslipidemia, and hypertension are risk factors for increased mortality, including that caused by cardiovascular diseases;

 - smoking and obesity are risk factors for reduced treatment efficacy of methotrexate** and HCQ**.

Comments: achieving low activity or remission reduces mortality and helps control the development of irreversible organ damage.

• In all patients with SLE, a rheumatologist appointment (examination, consultation) is recommended with assessment of disease activity and treatment efficacy using standardized activity indices SLEDAI-2K or SELENA-SLEDAI every 1–3 months and the SLICC/DI damage index every 6 months until remission (or low activity) is achieved, and then every 6–12 months (see Appendix G1, G2, G3) [18,75,198,199].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

6. Organization of Medical Care

• Treatment of patients with SLE is strongly recommended to be carried out by rheumatologists (as an exception—by general practitioners and general practice physicians (family doctors), but with consultative and organizational support from a rheumatologist) involving other specialists and based on close interaction between the physician and the patient [18,22,45].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: a multidisciplinary approach to the management of patients with SLE helps reduce the impact of comorbid pathology on the disease course, pharmacotherapy efficacy, and disease prognosis. If necessary, an orthopedic traumatologist, medical rehabilitation physician, cardiologist, nephrologist, neurologist, psychotherapist, ophthalmologist, and others may be involved.

6.1 Indications for referral to a rheumatologist

Comments: clinical suspicion of SLE is formed by the "first-contact" physician (general practitioner (family doctor), therapist, or physician of another specialty) based on clinical and/or laboratory manifestations included in the SLE classification criteria (see Appendix A3).

6.2 Indications for hospitalization in a specialized rheumatology department

• diagnosis of SLE / differential diagnosis and selection of therapy;

• SLE onset;

• presence of high and moderate degrees of SLE activity;

• initiation, selection and, if necessary, dose adjustment of GCs and immunosuppressants (#methotrexate**, #mycophenolate mofetil**, calcineurin inhibitors (#cyclosporine**, #tacrolimus**), azathioprine**, and cyclophosphamide**);

• resolving the issue of prescribing targeted biologic DMARDs (#rituximab**, belimumab**, anifrolumab**, obinutuzumab**) and initiating these treatment methods;

• involvement of vital organs – kidneys (active lupus nephritis), nervous system (acute impaired consciousness, seizure syndrome, psychosis, myelitis, mono-/polyneuropathy, optic neuritis), joints (polyarthritis), skin (involvement of more than 18% of the body surface) and severe mucous membrane lesions, lungs (hemorrhagic alveolitis, interstitial lung disease, exudative pleurisy), heart (peri-, endo-/myocarditis), hematological disorders (anemia with hemoglobin concentration ≤90 g/L, thrombocytopenia <100×10⁹/L, leukopenia ≤2.0×10⁹/L);

• development of SLE complications or severe adverse drug reactions (ADRs) in a patient receiving GCs, immunosuppressants (#methotrexate**, #mycophenolate mofetil**, calcineurin inhibitors (#cyclosporine**, #tacrolimus**), azathioprine** and cyclophosphamide**), targeted biologic DMARDs (#rituximab**, belimumab**, anifrolumab**, obinutuzumab**), if therapy adjustment is necessary due to the development of ADRs;

• planned therapy (course treatment) using targeted biologic DMARDs (#rituximab**, belimumab**, anifrolumab**, obinutuzumab**) and immunosuppressants (#methotrexate**, #mycophenolate mofetil**, calcineurin inhibitors (#cyclosporine**, #tacrolimus**), azathioprine** and cyclophosphamide**) in 24-hour and day hospital settings.

6.3 Criteria for discharging patients from the hospital

• achieving an improvement of at least 20% in clinical and laboratory disease activity parameters according to the SLEDAI-2K or SELENA-SLEDAI activity index, and physician's global assessment compared to baseline;

• completing the planned treatment in full in case of hospitalization as part of planned therapy (course treatment).

6.4 Outpatient care delivery for patients with SLE is applied under the following conditions

• In patients in remission or with low disease activity, without the risk of multi-organ failure, without progression of lupus nephritis, severe hematological disorders, interstitial lung disease and/or CNS involvement. At this stage, monitoring (visits) is performed by a rheumatologist depending on disease activity and vital organ involvement, but at least once every 6–12 months. In patients with moderate disease activity, without the risk of multi-organ failure, without progression of lupus nephritis, severe hematological disorders, interstitial lung disease and/or CNS involvement, monitoring (visits) is performed by a rheumatologist at least once every 3–6 months.

• After discharge from the hospital, if high/moderate disease activity and/or vital organ involvement persists, monitoring is performed at least once a month.

• Upon achieving low disease activity or remission, monitoring is performed every 6 months with disease activity assessment, identification of the risk of irreversible organ damage, and treatment toxicity. If necessary (inability to achieve SLE treatment goals), therapy is adjusted.

6.5 Diagnosis

Diagnosis of SLE should be attempted as early as possible, preferably within the first 1–3 months from the onset of the first symptoms. To establish the diagnosis, the 2012 SLICC classification criteria for SLE (see Appendix A3.1) and/or 2019 EULAR/ACR criteria (see Appendix A3.2) should be taken into account.

When diagnosing SLE, four main factors must be considered:

1. Identify at least one clinical manifestation included in the classification criteria in the patient;

2. Detect a positive HEp-2 ANA by indirect immunofluorescence assay (at a titer >1/160);

3. Fulfill the required number of criteria/points according to the 2012 SLICC classification criteria for SLE and/or 2019 EULAR/ACR criteria;

4. Exclude other diseases that may manifest with joint inflammation, erythematous skin lesions, and nephritis.

For the diagnosis of SLE, the presence of a single disease symptom or a single identified laboratory abnormality is not sufficient – the diagnosis is established based on the clinical manifestations of the disease, data from laboratory and instrumental diagnostic methods included in the classification criteria. The results of immunological studies with a positive HEp-2 ANA are of primary importance – determination of anti-dsDNA, anti-Sm, aPL, and C3 and C4 complement components concentrations.

6.6 Examples of clinical diagnosis formulation:

• M32.1 Chronic-onset systemic lupus erythematosus, moderate activity (SLEDAI-2K or SELENA-SLEDAI 10 scores), damage index 2 scores: with skin involvement (malar rash in the shape of a "butterfly", erythematous rashes on the skin of the shins, cleavage area, chest and back), joints (polyarthritis), hematological (leukopenia) and immunological disorders (elevated anti-dsDNA, hypocomplementemia in C3, C4, isolated positive Coombs test), ANA+.

  Complications: H26.2 Bilateral complicated cataract. M87 Osteonecrosis of the right femoral head.

• M32.1 Acute-onset systemic lupus erythematosus, high activity (SLEDAI-2K or SELENA-SLEDAI 22 scores), damage index 0 scores: with kidney involvement (focal proliferative lupus nephritis, class III, activity index 3, chronicity index 2 according to nephrobiopsy dated 02.03.2023), serous membranes (bilateral exudative pleurisy), hematological (thrombocytopenia), constitutional (fever, lymphadenopathy, weight loss) and immunological disorders (elevated anti-dsDNA, anti-Sm, hypocomplementemia in C3, C4), ANA+.

  Complications: N18.2 Chronic kidney disease stage C2 (GFR by CKD-EPI 75 mL/min.). Respiratory failure due to pleurisy, grade 1.

• M32.9 Systemic lupus erythematosus, unspecified: joint involvement (migratory arthralgia), hematological disorders (leukopenia), ANA+.

7. Additional Information

7.1 Comorbidity

The nature of concomitant (comorbid) conditions is of great importance for choosing the treatment strategy for patients with SLE in terms of both efficacy and safety of therapy.

• All patients with SLE are recommended to have blood phospholipid antibody levels determined [45].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

Comments: the presence of aPL is associated with thrombotic complications, obstetric pathology, and a high risk of irreversible organ damage.

Comments: In addition to its anti-inflammatory action, HCQ** has an antithrombotic effect, inhibiting platelet aggregation and the release of arachidonic acid from activated platelets.

- All patients with a high-risk aPL profile should be monitored for cardiovascular risk factors, such as hypertension, smoking, hypercholesterolemia, and oral contraceptive use, regardless of a history of previous thrombosis.

• Patients with SLE and aPL during periods of high risk of thrombotic complications, such as surgical interventions, prolonged immobilization, pregnancy, and the postpartum period, are recommended to receive therapy with heparin group drugs (unfractionated or low-molecular-weight) [18].

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

• All patients with SLE combined with APS for secondary prevention (thrombosis, pregnancy complication/loss) are recommended a therapeutic approach in the same volume as for primary APS [18].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

The increased risk of cardiovascular diseases (CVD) in SLE may be due to both traditional cardiovascular risk factors (CVRFs) and factors related to the disease itself (disease activity, lupus nephritis, presence of aPL, and GC use) [201–203].

• Patients with SLE are recommended to regularly undergo assessment of cardiovascular risk factors and their correction in accordance with Russian national guidelines [22,204].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: at the time of SLE diagnosis and periodically at subsequent visits for adult patients with SLE, it is necessary to assess traditional cardiovascular risk factors: age, body mass index and/or waist circumference, smoking status, family history of cardiovascular disease (in first-degree male relatives aged <55 years, female <65 years), arterial hypertension, diabetes mellitus, and dyslipidemia. These variables are used in algorithms for calculating cardiovascular risk (CVR) prediction. Taking into account the individual CVR profile, patients with SLE must undergo preventive measures to reduce it according to recommendations for the general population.

In patients with SLE, the risk of malignant neoplasms of the lung, thyroid, liver, and cervix is increased, and decreased for breast and prostate cancer. The risk of developing lymphomas is increased 3-fold, associated with the activity of numerous cytokines and viral infections [18,204,205].

• In SLE patients with any malignant neoplasms, immunosuppressant therapy (except for hydroxychloroquine**) and biological therapies are recommended to be suspended during chemotherapy and radiotherapy, and subsequently resumed with oncological consultation support [207].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

7.2 Pregnancy and contraception

Female patients with SLE should be counseled on the use of effective contraception methods (oral contraceptives, subdermal implants, intrauterine devices) based on their disease activity and thrombosis risk (especially aPL status) [208].

Drug therapy for patients with SLE during the preconception, pregnancy, and postpartum (lactation) periods (see Appendix A3.4) must be necessary and sufficient to suppress SLE activity and ensure successful conception, pregnancy, delivery, and postpartum course. The medications used should have a minimal effect on the embryo, fetus, and subsequent child development. Treatment with agents of uncertain effects on pregnancy and the fetus should be avoided [22].

• An intrauterine device may be recommended for all patients with SLE and/or APS who have no gynecological contraindications [208].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• In patients with remission or low SLE activity and negative aPL levels, it is recommended to consider prescribing combined hormonal contraceptives (G03A Systemic hormonal contraceptives) [208].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: prescribing hormonal contraceptives, especially estrogens, to patients with SLE and positive aPL levels and/or concomitant APS is associated with an increased risk of thrombosis; therefore, the risk/benefit ratio must be carefully evaluated when using this group of drugs.

• For menopausal patients with remission or low SLE activity and negative aPL, the use of hormone replacement therapy is recommended to treat severe vasomotor menopausal symptoms [208].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: the use of hormone replacement therapy in menopausal patients with positive aPL is associated with a risk of thrombosis and cardiovascular complications [208].

• Management of pregnant patients is recommended to be carried out jointly by a rheumatologist and an obstetrician-gynecologist, with the potential involvement of other specialists (nephrologists, cardiologists, neonatologists, etc.) in close contact with the patient [208].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• All patients during gestation are recommended to undergo dynamic monitoring with mandatory evaluation in each trimester (more frequently if there are signs of SLE flares and in patients at high risk for complicated SLE and/or pregnancy courses: patients with lupus nephritis, concomitant APS, or persistently high/moderate positive aPL, anti-Ro/SSA and/or anti-La/SSB (antibodies to extractable nuclear antigens Ro/SSA and La/SSB in the blood)) [208].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: hospitalization for delivery is generally planned. The mode of delivery is determined collegially by the managing physicians, taking into account the patient's severity and the obstetric situation.

 - Lactation and natural breastfeeding are permitted in the absence of active disease in the mother (and her receipt of permitted drug therapy) and contraindications based on the newborn's health status.

- In case of an SLE flare, persistent high SLE activity, including persistent active lupus nephritis with vital organ involvement, and resistance to ongoing therapy, early delivery should be considered, discussed collegially by a medical board consisting of an obstetrician-gynecologist, neonatologist, rheumatologist, nephrologist, and other specialists.

• Pregnant patients with SLE are recommended to have their disease activity and the benefit-risk ratio of treatment for the mother versus potential adverse effects on the fetus evaluated prior to initiating therapy [208].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: disease activity in pregnant women with SLE should be assessed using the SLEPDAI (Systemic Lupus Erythematosus Pregnancy Disease Activity Index) (see Appendix G4) [210]. Of the 24 SLEDAI symptoms, 13 symptoms (8 clinical and 5 laboratory) are adjusted in the SLEPDAI. The adjustment accounts for physiological changes in the pregnant body and potential pregnancy pathology.

• The use of cyclophosphamide**, #mycophenolate mofetil**, #methotrexate**, and #leflunomide** is not recommended due to the high risk of teratogenic effects [208,211].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• NSAIDs (by mechanism of action, non-selective cyclooxygenase inhibitors) are recommended to be taken in the first (with caution) and second trimesters of pregnancy. All NSAIDs should be discontinued no later than 30 weeks of gestation [212].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• The prescription of NSAIDs that act as selective cyclooxygenase-2 inhibitors during pregnancy is not recommended [212].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• To prevent SLE flares and minimize potential adverse effects, low-dose corticosteroids (prednisolone** ≤7.5 mg/day) are recommended [208,211].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: #Hydroxychloroquine** helps reduce the frequency and severity of SLE flares and is not associated with adverse effects on the pregnant woman and the fetus.

• In low disease activity, it is recommended to prescribe low-dose corticosteroids (prednisolone** ≤7.5 mg/day) and oral #hydroxychloroquine** 200–400 mg/day [211].

GSI CLoE 5Grade of Recommendation — C (Level of Evidence — 5)

• In moderate disease activity, it is recommended to prescribe moderate-dose corticosteroids (prednisolone** >7.5 mg/day to 30 mg/day) and oral #hydroxychloroquine** 200–400 mg/day [211].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• In high disease activity, it is recommended to prescribe high-dose corticosteroids (prednisolone** 0.5–1 mg/kg body weight/day), corticosteroid pulse therapy if necessary, intravenous normal #human immunoglobulin** at a total dose of 2 g/kg over 2–5 days [214], as well as oral #azathioprine** throughout pregnancy at a dose not exceeding 2 mg/kg/day [211], oral #cyclosporine** 3–5 mg/kg/day [211], and oral #tacrolimus** at an initial dose of 0.05–0.1 mg/kg/day [215–217], with mandatory monitoring of blood pressure, renal function, glycemia, and blood calcineurin inhibitor concentrations.

For normal #human immunoglobulin** and #tacrolimus**: Recommendation grade – B (level of evidence – 3)

For #azathioprine**, #cyclosporine**, prednisolone**: Recommendation grade – C (level of evidence – 5)

• In cases of high disease activity resulting in life-threatening conditions for the pregnant woman, #cyclophosphamide** at a dose of 500 mg once every 2 weeks (2–5 cycles total) in the late second and third trimesters of gestation may be recommended in individual cases [218].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

• Biological therapies are recommended to be discontinued at conception. During pregnancy, in severe SLE and the inability to prescribe other pregnancy-compatible drugs, continuing therapy with #belimumab** or #rituximab** may be recommended in individual cases [219–221].

GCP CLOE 4Grade of Recommendation — C (Level of Evidence — 4)

Comments: the dose of #belimumab** during pregnancy is 10 mg/kg intravenously or 400 mg subcutaneously monthly; the dose of #rituximab** is 1000 mg intravenously weekly (maximum total dose 2000 mg). Treatment duration (number of courses) is determined individually based on the clinical situation and treatment response.

• In pregnant women with lupus nephritis, several treatment options are recommended:

  - in the absence of lupus nephritis activity and extrarenal SLE manifestations, no additional therapy is required;

  - in low lupus nephritis activity, oral #hydroxychloroquine** 200–400 mg/day is recommended;

  - in pronounced lupus nephritis activity and/or extrarenal disease manifestations, corticosteroids are prescribed at doses controlling the disease, if necessary combined with oral #azathioprine** at a dose not exceeding 2 mg/kg/day [211].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• Additional intravenous corticosteroid administration during surgical delivery is recommended in patients receiving long-term medium/high-dose corticosteroid therapy [222].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• In pregnant women with positive anti-Ro/SSA and/or anti-La/SSB antibodies, if fetal antenatal therapy is necessary (development of neonatal lupus with first- or second-degree heart block detected by echocardiography), it is recommended to use fluorinated glucocorticoids: betamethasone or dexamethasone** (orally) at a dose of 4 mg/day [211].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: high doses of glucocorticoids are associated with a high risk of arterial hypertension, diabetes mellitus, osteopenia, infectious, and neonatal complications. Treatment should be limited to a few weeks, depending on the response, due to the risk of irreversible fetal and maternal toxicity. The issue of early delivery and implantation of a permanent cardiac pacemaker in the newborn is being considered.

• In severe thrombocytopenia refractory to glucocorticoids, intravenous administration of human normal #immunoglobulin** at a total dose of 2 g/kg over 2-4 days is recommended [214,223].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• In the postpartum period (in case of uncomplicated delivery), it is mandatory to recommend a complete (clinical) blood count and urinalysis, immunological blood test including determination of native DNA antibodies, evaluation of C3 and C4 complement fractions, anti-nuclear antibodies (ANA), 24-hour urine protein, and GFR in patients with renal involvement. Lactating patients are recommended to undergo follow-up monitoring until the completion of breastfeeding (with examinations at least 1, 3, 6, and 12 months postpartum) [224].

GoR BLoE 3Grade of recommendation - B (level of evidence - 3)

7.3 Vaccination

• All patients with SLE without contraindications who are receiving biologic disease-modifying antirheumatic drugs (bDMARDs) and immunosuppressants (immunosuppressive drugs) are recommended to receive vaccination (with inactivated vaccines) against influenza virus infection and pneumococcal infection (influenza vaccine [inactivated]**, pneumococcal polysaccharide conjugate vaccine [adsorbed]**) [18,225,226].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• Patients with SLE over 18 years of age receiving immunosuppressants (immunosuppressive drugs) are recommended to be vaccinated against varicella zoster virus infection [18,225,226].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• Patients with SLE under 45 years of age without contraindications and not previously vaccinated are recommended to receive vaccination (with inactivated vaccines) against human papillomavirus infection [18,225,226].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: when administering non-live attenuated vaccines, the scheduled administration of #methotrexate** and #rituximab** should be postponed for 2 weeks after vaccination. Administration of other immunosuppressants should not be interrupted.

• Administration of live vaccines (measles, rubella, mumps, poliomyelitis, rotavirus, yellow fever, etc.) to SLE patients receiving bDMARD therapy is not recommended [18,225,226].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• The administration of live attenuated vaccines is not recommended during the first 6 months of life in infants born to mothers with SLE who received bDMARDs in the second half of pregnancy [18,225,226].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Evgeny L. Nasonov – Academic Supervisor of the V.A. Nasonova Research Institute of Rheumatology, Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, Moscow, President of the Russian Association of Rheumatologists;

2. Alexander M. Lila – Director of the V.A. Nasonova Research Institute of Rheumatology, Head of the Department of Rheumatology at the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Moscow, Member of the Board and Presidium of the Russian Association of Rheumatologists;

3. Tatyana V. Popkova – Head of the Department of Systemic Rheumatic Diseases, Head of the Laboratory of Systemic Lupus Erythematosus at the V.A. Nasonova Research Institute of Rheumatology, Doctor of Medical Sciences, Moscow, Member of the Russian Association of Rheumatologists;

4. Sergey K. Soloviev – Scientific Consultant of the Laboratory of Systemic Lupus Erythematosus at the V.A. Nasonova Research Institute of Rheumatology, Doctor of Medical Sciences, Professor, Moscow; Member of the Russian Association of Rheumatologists;

5. Tatyana M. Reshetnyak – Head of the Laboratory of Thromboinflammation at the V.A. Nasonova Research Institute of Rheumatology, Doctor of Medical Sciences, Professor, Moscow, Member of the Russian Association of Rheumatologists;

6. Elena A. Aseeva – Leading Research Scientist at the Laboratory of Systemic Lupus Erythematosus at the V.A. Nasonova Research Institute of Rheumatology, Doctor of Medical Sciences, Moscow, Member of the Russian Association of Rheumatologists;

7. Dmitry E. Karateev – Head of the Rheumatology Department, Head of the Department of Rheumatology at the Faculty of Advanced Medical Training of the Moscow Region Research Clinical Institute (MONIKI) named after M.F. Vladimirsky, Chief freelance Rheumatologist of the Ministry of Health of the Moscow Region, Doctor of Medical Sciences, Moscow, Member of the Board of the Russian Association of Rheumatologists, Chairman of the Moscow Regional Branch of the Russian Association of Rheumatologists;

8. Tatyana A. Panafidina – Senior Research Scientist at the Laboratory of Systemic Lupus Erythematosus at the V.A. Nasonova Research Institute of Rheumatology, Candidate of Medical Sciences, Moscow, Member of the Russian Association of Rheumatologists;

9. Nadezhda M. Kosheleva – Senior Research Scientist at the Laboratory of Thromboinflammation at the V.A. Nasonova Research Institute of Rheumatology, Candidate of Medical Sciences, Moscow, Member of the Russian Association of Rheumatologists;

10. Polina I. Pchelnikova – President of the "Nadezhda" Russian Rheumatology Association, Ph.D., Moscow.

Conflict of interest: all members of the working group declare no conflict of interest regarding the preparation of these clinical guidelines for systemic lupus erythematosus (SLE).

Appendix A2. Methodology for Developing Clinical Guidelines

Clinical guidelines for the provision of medical care to patients with SLE have been drawn up in accordance with the requirements for the development of clinical guidelines by medical professional non-profit organizations, Part 2 of Article 76 of Federal Law No. 323-FZ dated November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation", and Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines". The clinical guidelines are based on evidence-based clinical experience describing the physician's actions regarding the diagnosis, differential diagnosis, treatment, rehabilitation, and prevention of SLE.

Target audience for these clinical guidelines:

1. Rheumatologist;

2. Physicians of other specialties involved in the diagnosis and management of patients with SLE.

Medical professionals should follow these guidelines when making clinical decisions. At the same time, the guidelines do not replace the personal responsibility of medical professionals in making clinical decisions, taking into account the individual characteristics of the course of SLE and patient preferences. These guidelines take into account accumulated Russian and international experience in the management of patients with SLE and are based on recommendations published by the Russian Association of Rheumatologists, the European League Against Rheumatism (EULAR) 2019, the British Society for Rheumatology, and the Canadian Rheumatology Association.

Appendix A2-1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Appendix A2-2. Level of Evidence (LoE) grading scale for preventive, therapeutic, and rehabilitative methods (preventive, therapeutic, and rehabilitative interventions)

Appendix A2-3. Grade of Recommendation (GoR) grading scale for preventive, diagnostic, therapeutic, and rehabilitative methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Order of the Russian Ministry of Health No. 900n dated November 12, 2012 (as amended on February 21, 2020), "On approval of the Procedure for the provision of medical care to the adult population in the profile 'rheumatology'".

2. Decree of the Government of the Russian Federation No. 1940 dated December 27, 2024, "On the Program of State Guarantees of Free Medical Care for Citizens for 2025 and for the Planning Period of 2026 and 2027".

Appendix A3.1. Classification criteria for SLE (SLICC 2012)

The diagnosis is established in the presence of biopsy-proven LN with positive ANA or anti-dsDNA, or in the presence of 4 criteria: at least 1 of which must be immunological (any of ANA, anti-dsDNA, anti-Sm, aPL, C3, C4, CH₅₀ hypocomplementemia) and 1 clinical (sensitivity 97%, specificity 84%).

Appendix A3.2. Classification criteria for SLE (EULAR/ACR 2019)

The disease must be classified as SLE if the sum of the scores of additional criteria is 10 or more, provided that a positive (≥1/80) primary classification criterion (ANA/anti-dsDNA) is present (sensitivity 89%, specificity 97%).

Appendix A3.3. Classification of lupus nephritis by the International Society of Nephrology/Renal Pathology Society (ISN/RPS, 2003)

Appendix A3.4. Use of medicinal products during planning, pregnancy, and lactation

¹Data are limited; ²Possible only in severe, life-threatening maternal conditions; ³With monitoring of maternal blood pressure, renal function, blood glucose, and drug concentration; ⁴Inadvertent treatment in the 1st trimester is likely safe; ⁵Likely safe.

Appendix A3.5. Indications and contraindications for biological DMARDs

Indications:

Contraindications:

- active infections, including skin infections, sepsis, tuberculosis, hepatitis B and C, HIV;

- hypersensitivity to the protein component of biological DMARDs or other components of the solution;

- immunodeficiency states (e.g., hypogammaglobulinemia, hepatic impairment (elevation of upper limit of normal for ALT, AST >5 times);

- history of malignancies (except for non-melanoma skin cancer and solid tumors) within the past 5 years. In specific clinical cases, earlier initiation of biological DMARDs following a history of malignancy is decided by a medical commission.

Appendix B. Physician Action Algorithms

Figure 1: Systemic Lupus Erythematosus (Algorithm)

Figure 2: Monitoring according to the Treat-to-Target strategy

*tapering glucocorticoids to ≤5 mg/day.

^assessment should be performed using validated SLE activity indices (SLEDAI)

Appendix C. Patient Information

Systemic lupus erythematosus (SLE) is a complex disease with etiology that is not yet fully understood. It is believed that the development of SLE is due to a combination of the following factors: genetic (i.e., hereditary), hormonal (puberty, systemic hormonal contraceptives, pregnancy, abortion, menopause), as well as environmental factors—ultraviolet radiation (sun exposure, tanning beds, etc.), psychological stress and trauma, infections (predominantly viruses), smoking, and others. Hereditary predisposition is thought to play a major role in the development of the disease, although a specific "SLE gene" has not yet been found.

The immune system of a healthy person produces antibodies, which are protein molecules that help the body fight and destroy viruses, bacteria, and other foreign substances entering it.

In SLE, immune system dysregulation occurs, resulting in the formation of autoantibodies ("auto" meaning "self") against the healthy cells and tissues of one's own body, which contribute to inflammation in various organs. Some autoantibodies bind to fragments of destroyed body cells (especially cell nuclear components) to form structures called immune complexes. In patients with SLE, the formation of these immune complexes leads to inflammation and damage to various organs and tissues.

The majority of SLE patients are young women aged 18 to 35 years; the disease rarely manifests for the first time in patients over 45. There are 9 to 11 female patients for every male patient. SLE occurs in all countries and among all nationalities worldwide. In Russia, the prevalence of SLE ranges from 9.0 to 20.6 cases per 100,000 population, depending on the region.

The disease presents in various clinical forms: it can be aggressive, rapidly damaging vital organs over a short period, or have a more insidious onset, where symptoms of general fatigue, fever, and blood test abnormalities develop over several years.

SLE can affect various organs and systems: the skin, kidneys, joints, lungs, heart, and brain. The disease may be accompanied by skin rashes, prolonged fever, joint pain or swelling, lymphadenopathy, serositis (pleurisy—inflammation of the lung lining, and pericarditis—inflammation of the heart sac), kidney involvement (nephritis), nervous system involvement, and inflammation of the inner heart layers (myocarditis and endocarditis). Currently, SLE is a treatable condition, and most people with this disease lead active, healthy lives.

It should be remembered that the disease follows a relapsing-remitting course: periods of well-being (remission) and relatively low disease activity can alternate with flares. A disease flare is characterized by inflammation in various organs and requires more intensive treatment. Remission is a state in which there are no symptoms of SLE. Complete or prolonged remission is quite common and is the result of proper treatment and patient compliance with all medical recommendations.

Clinical and laboratory features of SLE

Despite certain characteristic features of the disease, each patient's case of SLE is unique. The disease may begin with one or two symptoms, with new symptoms and various clinical manifestations appearing later.

Clinical features

Skin: a facial "butterfly" rash, or persistent red lesions that appear on the skin of the bridge of the nose, nasal alae, and cheeks, resembling the shape of a spread-out butterfly. Rashes can appear on any part of the body: the face or auricles, shoulders and hands, chest, and back. Often, these skin changes appear after sun exposure, especially in the spring and summer, which is referred to as cutaneous hypersensitivity to sunlight, or photosensitization. Hair loss or alopecia ("focal" or "diffuse") is also frequently observed.

Joints. Joint pain occurs in almost all patients. Joint involvement is migratory or "shifting" in nature, meaning pain in one or more joints can appear and disappear, involving both small joints (e.g., hand, foot) and large joints (e.g., knees, hip joint).

Kidneys. Kidney involvement in SLE (lupus nephritis) is one of the most serious manifestations of the disease and requires intensive drug therapy to prevent irreversible damage. Inflammation in the kidneys impairs their function, which leads to a disruption in the elimination of waste products, including toxins, from the body. Some patients may notice swelling in the lower extremities and/or around the eyes. Indicators of kidney involvement in SLE include changes in urinalysis, a decrease in urine output, and elevated blood pressure.

Nervous system. Some patients experience involvement of the central (brain and spinal cord) or peripheral (nerves) nervous system. Manifestations of central nervous system involvement include headaches, dizziness, memory impairment, difficulty concentrating, vision problems, paralysis or behavioral changes (psychosis), insomnia, and seizures; peripheral nervous system involvement manifests as polyneuritis or dysfunction of various nerves.

Heart. Inflammation can occur in the heart vessels (coronary arteries), the heart muscle (myocarditis with cardiac arrhythmias), heart valves (endocarditis), or the pericardium—the serous membrane surrounding the heart (pericarditis)—causing chest pain or other symptoms.

Lungs. Some patients with SLE experience inflammation of the serous membrane of the lungs with the accumulation of inflammatory fluid within it (pleurisy), causing chest pain with breathing, shortness of breath, and cough. Inflammation of the lung tissue caused by an autoimmune disease such as SLE is called pneumonitis.

Polyserositis. Other serous membranes (e.g., the peritoneum covering the liver and spleen) can become involved in the inflammatory process, causing pain in the respective anatomical locations of these organs.

Blood vessels. Vasculitis, meaning inflammation of the blood vessels, is observed in SLE. Manifestations of vasculitis include skin ulcers or capillaritis (redness of the fingertips, palms, and soles).

Laboratory findings

Blood. Patients with SLE may develop anemia (decreased blood hemoglobin and red blood cells), leukopenia (decreased white blood cell count), or thrombocytopenia (decreased platelet count), which increase the risk of fatigue, infections, and bleeding.

Immunological tests. Various immunological tests ordered by a physician are used to diagnose and monitor SLE. The detection of autoantibodies directed against cell nucleus components is the most valuable initial test in the diagnosis of SLE, as it is positive in 95–99% of SLE patients. Its absence in the vast majority of cases argues against a diagnosis of SLE. Certain antibodies can cause a false-positive Wassermann reaction (syphilis test); however, a positive test does not mean the patient has syphilis.

Other laboratory parameters: complete blood count chemistry panels, and urinalysis are also important in diagnosing the disease. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are markers of inflammation in the body that help identify infectious complications, which not only worsen the patient's condition but also create challenges in treating SLE.

Diagnosis of SLE

To establish a diagnosis of SLE, the physician takes into account the patient's complaints and symptoms, as well as data from immunological and other laboratory tests. Symptoms or signs of the disease may develop over a short period or over a long time, which is why an accurate diagnosis is not always made quickly.

It is essential to provide the physician with a complete and accurate medical history: for example, what health problems you have had and what triggered the disease manifestations. This information, along with a physical examination and the results of immunological and other laboratory tests, helps the physician make a timely diagnosis of SLE. This often takes time, and the diagnosis may not be established immediately, but only upon the appearance of new symptoms. There are a number of mandatory signs of SLE: the obligatory presence of antinuclear antibodies (ANA), fever, skin and mucous membrane manifestations, joint involvement, nervous system manifestations, inflammation of serous membranes, changes in blood cell counts (decreased white blood cells, platelets, etc.), and immunological manifestations (presence of antiphospholipid antibodies, antibodies to cell nucleus components, decreased complement protein levels). Based on the presence of these signs, the physician can differentiate SLE from other conditions, with each manifestation assigned a specific number of "points"; a diagnosis requires the presence of ANA and a score of at least 10 points. In addition to the primary signs of SLE, patients may have supplementary symptoms. These include weight loss, severe hair loss leading to patches of alopecia or complete baldness, "fever of unknown origin", muscle weakness, and decreased or lost appetite. To diagnose SLE, the physician relies on the 2012 SLICC classification criteria for SLE and/or the 2019 EULAR/ACR classification criteria for SLE, tallying the required number of points according to these criteria.

Pregnancy and SLE

When disease activity is low or during remission, pregnancy is permitted and can result in the successful birth of a healthy baby while maintaining the mother's well-being. However, in 20-25% of female patients with SLE, pregnancy may end in miscarriage or the birth of a child with various developmental disorders and malformations. It is important to plan and discuss pregnancy with your attending physician prior to conception. It must be remembered that pregnancy should be planned and can occur during a period of disease remission (absence of protein in the urine is mandatory) or low disease activity and stable status for at least 6 months following a disease flare. Unplanned pregnancy during an SLE flare can negatively affect the woman's health by worsening disease symptoms and creating difficulties with carrying the pregnancy. Some women may experience a return of certain SLE symptoms during or after pregnancy. During pregnancy, they may experience early and late toxicosis, as well as preterm birth. Constant self-care and good nutrition are necessary during pregnancy. When planning pregnancy, medication selection is crucial: the physician and the patient must weigh the potential risks to the mother and the unborn child when prescribing specific drugs. Some patients may experience an SLE flare or other complications related to carrying the pregnancy, especially in the presence of antiphospholipid antibodies. These antibodies cause placental thrombosis (occlusion of blood vessels by blood clots), which can lead to intrauterine fetal death or miscarriage. "Early" detection of these antibodies during pregnancy helps the physician determine patient management strategies that reduce the risk of miscarriage. Certain medications used to treat SLE must not be used during pregnancy because they can harm the baby or cause a miscarriage. A pregnant woman with SLE requires close cooperation between an obstetrician-gynecologist and a rheumatologist.

Medical treatment

The main goal of treatment is to slow down and, if possible, halt the progression of the disease and improve the patient's quality of life. To achieve this, it is necessary to suppress the inflammatory process and prevent flares and complications.

Pharmacotherapy is the mainstay of treatment for SLE. The choice of drugs required for treatment depends on the results of the patient's evaluation and the severity of the disease. Glucocorticoids, antimalarial drugs, cell growth inhibitors, immunosuppressive drugs, and biologic disease-modifying antirheumatic drugs are used to treat SLE.

Glucocorticoids (GCs) are the primary and most effective drugs for treating SLE. GCs are synthetic forms of hormones normally produced by the adrenal glands that rapidly suppress inflammation. GCs are administered as tablets, topical creams, or injections. Short-acting GCs are used for long-term therapy. Taking into account clinical manifestations, for maximum efficacy and safety, the physician selects the lowest possible dose of these drugs for the patient. Stopping GCs or rapidly decreasing/increasing the dose is prohibited; therefore, dose adjustments require close cooperation between the physician and the patient. It is important for the patient to keep a medication diary recording the initial dose, the start of tapering, and the tapering rate. This will help the physician evaluate treatment outcomes and determine the subsequent rate of dose reduction. Adverse effects of GCs include uneven fat distribution (moon facies, fat accumulation on the abdomen and upper back as a "buffalo hump"), increased appetite, weight gain and emotional instability, purple striae (stretch marks on the skin), excessive hair growth, hypertension, lipid metabolism disorders (elevated cholesterol) and glucose metabolism disorders (elevated blood sugar), early development of atherosclerosis, increased susceptibility to infections, osteoporosis, and ultimately, early development of cataracts.

Maintaining a normal body weight, smoking cessation, and physical activity help reduce the adverse effects of GCs on the cardiovascular system. GCs increase appetite and lead to abnormal fat distribution and accumulation. If the patient adheres to a specific diet restricting flour products, sweets, and certain fruits, and satisfies hunger with vegetables and low-fat dairy products, weight gain will be minimal—about 3–5 kg during the period of maximum GC dosing. Reducing the GC dose to low therapeutic levels (5–7.5 mg of prednisolone** per day) during remission or low disease activity is accompanied by normalization of appetite and appearance, and most patients return to their pre-illness weight.

Patients with high-activity SLE (involving the kidneys or central nervous system, or multi-organ involvement) are prescribed drugs known as immunosuppressants. These drugs suppress the "overactive" immune system by blocking the production of certain immune cells and reducing the action of others. Immunosuppressants must be taken long-term (for up to several years), while regular monitoring and individualized dose titration can significantly reduce the number of adverse effects and complications. These drugs are administered as tablets, or via subcutaneous or intravenous infusion.

Patient Monitoring and Treatment Safety Control

Medical treatment for SLE can yield very excellent results, but requires regular monitoring by a qualified rheumatologist. A special system for such monitoring has been developed. To achieve the best therapeutic outcomes, the rheumatologist periodically assesses treatment efficacy. An SLE patient should visit the physician at least once every 1–3 months at the beginning of treatment (depending on disease activity), undergo blood and urine tests, undergo additional diagnostic tests depending on organ involvement, and annually undergo echocardiography, dual-energy X-ray absorptiometry (DEXA) of the lumbar spine and femoral neck, and an ophthalmological examination. Depending on the activity of the inflammatory process and other parameters, the treatment regimen may be adjusted by the rheumatologist's decision (drug doses decreased or increased, drugs added or changed, etc.). After achieving a good therapeutic response (remission or low disease activity) while on maintenance doses, it is recommended to see the rheumatologist at least once every 6–12 months.

Another aspect of monitoring is assessing parameters that ensure treatment safety. Thus, when taking #methotrexate**, #leflunomide**, azathioprine**, cyclophosphamide**, and #mycophenolate mofetil**, liver function and blood cell counts are monitored; additionally, for #cyclosporine** and #tacrolimus**, creatinine levels and blood pressure are monitored. When biological DMARDs (bDMARDs) are prescribed, their intravenous administration is performed in a specially equipped treatment room under medical supervision. All bDMARDs and immunosuppressants can decrease resistance to infections.

There are several methods to improve the tolerability of certain drugs. To improve the tolerability of #methotrexate**, folic acid** is recommended at a dose of at least 5 mg per week, no earlier than 24 hours after taking #methotrexate**. When GCs are prescribed, calcium and vitamin D supplements are co-prescribed for the prevention of osteoporosis—weakening of bone tissue that can occur during long-term hormone therapy. When GCs and NSAIDs are co-prescribed, proton pump inhibitors may be used to reduce adverse gastric effects, but their administration requires medical supervision. Special vaccines are used for infection protection.

Unfortunately, in many cases, patients are overly apprehensive about drug therapy, believing that "chemicals cure one thing and cripple another." This is fundamentally incorrect for a number of reasons. First, despite the potential occurrence of adverse drug reactions, the probability of their development is relatively low. Second, for most medications, the monitoring system is well-developed (described in detail in reference books and package inserts) and allows for the active detection of adverse reactions before they become a health hazard. Third, the risk of complications from the disease itself is much more serious than the risk of adverse events from therapy.

Extracorporeal treatment methods

Plasmapheresis is a method used to treat the most severe patients with rapidly progressive damage to vital organs (kidneys with renal failure, central nervous system, lungs) in combination with active cyclophosphamide** and GC therapy.

Non-Pharmacological Treatment Methods

In addition to drug therapy, patients are advised to monitor their diet, perform therapeutic exercises, quit smoking, and avoid exposure to ultraviolet rays.

Sunbathing, using tanning beds, and receiving UV therapy are strictly prohibited for patients with SLE. It must be remembered that insolation (sun exposure or UV irradiation) is not only harmful but also dangerous for an SLE patient. Even short-term sun exposure (no more than 30 minutes) or ultraviolet procedures (tanning salons, photoepilation, etc.) trigger various skin rashes in 60–80% of SLE patients. Photoprotection excludes midday sun exposure, requires regular application of high-SPF sunscreens (SPF 50 and above), and wearing protective clothing. Special protective and luminescent window films reduce UV exposure and lower the risk of SLE flares in patients with photosensitivity.

The diet of SLE patients must be both complete and balanced. The main groups of substances in the diet are: proteins, fats, carbohydrates, vitamins, minerals, and water.

A nutritious diet with adequate vitamin D and calcium is essential for the prevention of osteoporosis (impaired bone tissue structure). Preference is given to animal proteins, such as milk, fermented dairy products, cheese, eggs, meat, and fish. Dairy and fish proteins are preferred because they are digested more easily than meat protein, are better absorbed, and contain an optimal amino acid profile. Spicy dishes should be avoided. Meat and fish dishes are best boiled, steamed, stewed, or baked.

Regular physical exercise helps maintain joint mobility and strengthens muscles. It is important to exercise correctly; excessive strain or improper exercise technique can harm joints.

Participation in specialized education programs (schools) for SLE patients is strongly recommended. In these schools, experts discuss treatment, exercises, prevention, psychological aspects of the disease, patient rights protection, pressing issues, and key concerns troubling most patients. Information about the disease and an understanding of how to control it play a vital role in successful treatment and the preservation of quality of life.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. SLE disease activity index (SLEDAI-2K)

Russian Title: Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K)

Original Title: Systemic lupus erythematosus disease activity index -2000

Source: [14]

Type: Index

Purpose: Assessment of overall SLE activity

Content: Points are entered into the SLEDAI score column if the given manifestation is identified at the time of examination or was present during the 10 days preceding the examination

Note: SLEDAI accounts only for newly onset or recurrent manifestations, whereas its modifications, SLEDAI-2K and SELENA-SLEDAI, account for the presence of any variant of these manifestations (newly onset, relapse, persistent activity). SLEDAI-2K differs from SELENA-SLEDAI in the absence of scleritis and episcleritis in visual disturbances, dizziness in cranial nerve disorders, the number of affected joints, and instrumental confirmation of pleuritis and pericarditis.

Key (interpretation):

• no activity / remission (0 points),

• low activity (1–4 points),

• moderate activity (5–10 points),

• high activity (more than 10 points).

Note:

A universally recognized method for evaluating the efficacy of SLE therapy is based on assessing the baseline SLEDAI index values and the dynamics of this parameter during therapy.

A SLE flare is defined as an increase in SLEDAI-2K or SELENA-SLEDAI index values >3 points between two visits, SLE improvement as <3 points between two visits, and a change of ±3 points in the index as persistent activity. Moderate SLE flare is defined as an increase in index values by 3–12 points, and severe flare as an increase by >12 points [14].

Appendix G2. SLE disease activity index (SELENA-SLEDAI)

Russian title: SLE Disease Activity Index (SELENA-SLEDAI)

Original title: Safety of Estrogen in Lupus National Assessment - Systemic Lupus Erythematosus Disease Activity Index Systemic lupus erythematosus disease activity index

Source: [15,16]

Type: Index

Purpose: Assessment of overall SLE activity

Content: Points are entered into the SLEDAI score column if the given manifestation is identified at the time of examination or was present during the 10 days preceding the examination.

Note: SLEDAI accounts only for newly-onset or recurrent manifestations, whereas its modifications SLEDAI-2K and SELENA-SLEDAI account for the presence of any variant of these manifestations (newly-onset, recurrent, persistent activity). SLEDAI-2K differs from SELENA-SLEDAI in the absence of scleritis and episcleritis among visual disturbances, dizziness among cranial nerve disorders, the number of affected joints, and instrumental confirmation of pleuritis and pericarditis.

Key (interpretation):

• no activity / remission (0 points),

• low activity (1–4 points),

• moderate activity (5–10 points),

• high activity (more than 10 points).

Note:

A universally recognized method for evaluating the efficacy of SLE therapy is based on assessing the baseline SLEDAI index values and the dynamics of this parameter during therapy.

A SLE flare is defined as an increase in SLEDAI-2K or SELENA-SLEDAI index values >3 points between two visits, SLE improvement as <3 points between two visits, and a change of ±3 points in the index as persistent activity. Moderate SLE flare is defined as an increase in index values by 3–12 points, and severe flare as an increase by >12 points [14].

Appendix G3. Damage index (SLICC/DI)

Russian title: Damage Index (SLICC/DI)

Original title: Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for Systemic Lupus Erythematosus

Source: [19]

Type: Index

Purpose: Assessment of cumulative organ damage in SLE

Content: The patient must have had the following symptoms for at least 6 months

Key (interpretation):

Four degrees of DI are distinguished:

• no damage - 0 points,

• low DI - 1 point,

• moderate DI - 2-4 points,

• high DI - more than 4 points.

Appendix G4. SLE disease activity index in pregnancy (SLEPDAI)

Russian title: Systemic Lupus Erythematosus Pregnancy Disease Activity Index (SLEPDAI)

Original title: Systemic Lupus Erythematosus Pregnancy Disease Activity Index (SLEPDAI)

Source: [210]

Type: Index

Purpose: Assessment of overall SLE activity in pregnant women

Content: Points are entered into the SLEPDAI score column if the given manifestation is identified at the time of examination or was present during the 10 days preceding the examination

Key (interpretation):

• no activity / remission (0 points),

• low activity (1–4 points),

• moderate activity (5–10 points),

• high activity (more than 10 points).