Gonarthrosis: Clinical Guidelines

List of Abbreviations

ACR – American College of Rheumatology

anti-CCP – antibodies to cyclic citrullinated peptide

KOA – knee osteoarthritis

GI – gastrointestinal tract

IL – interleukin

BMI – body mass index

PPI – proton pump inhibitors

Ph.D. in Medicine – Candidate of Medical Sciences

Knee – knee joint

HDL – high-density lipoproteins

LDL – low-density lipoproteins

LT – leukotrienes

MRI – magnetic resonance imaging

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs

OA – osteoarthritis

PG – prostaglandins

RCTs – randomized controlled trials

RF – rheumatoid factor

SSRI – selective serotonin reuptake inhibitor

SYSADOA – symptomatic slow-acting drugs for osteoarthritis

ESR – erythrocyte sedimentation rate

CRP – C-reactive protein

US – ultrasound examination

TNF – tumor necrosis factor

COX – cyclooxygenase

JR – joint replacement

AAOS – American Academy of Orthopaedic Surgeons

ACR – American College of Rheumatology

ASA – American Society of Anesthesiologists

ESSKA – European Society for Sports Traumatology, Knee Surgery and Arthroscopy

MMP – metalloproteinase

NO – nitric oxide

Terms and Definitions

Arthroscopic surgeries – surgical interventions on the knee joint performed using an arthroscope (a type of endoscope) through micro-incisions.

Hyperalgesia – an excessive response to minor pain stimulation

Contracture – limitation of the range of motion in a joint.

Corrective periarticular osteotomies – surgical interventions on the femur and/or tibia and/or fibula resulting in a change of the limb axis in one or more planes.

Lavage – washing out of a joint affected by a degenerative-dystrophic process.

Mechanical allodynia – pain produced by non-painful mechanical stimuli.

Unicompartmental knee arthroplasty – partial arthroplasty of one of the compartments of the femorotibial articulation.

Osteophytes – marginal osteocartilaginous growths along the edges of the femur and tibia, as well as the patella.

Total knee arthroplasty – replacement of the articular surfaces of the femorotibial and femoropatellar articulations, and sometimes the patella.

Knee arthroplasty – a high-tech surgery consisting of replacing the knee joint with an artificial one.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Knee osteoarthritis (KOA) (gonarthrosis, osteoarthrosis, osteoarthritis) – a heterogeneous group of diseases of various etiologies with similar biological, morphological, and clinical manifestations and outcomes, based on damage to all components of the knee joint: cartilage, subchondral bone, menisci, synovial membrane, ligaments, capsule, as well as periarticular muscles [1, 2, 3].

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

Osteoarthritis (OA). The fundamental cause of the disease development lies in the mismatch between the mechanical axial load on the lower limb and the ability of the structural elements of the knee joint to withstand this load. The biological properties of the tissues forming the knee joint may be genetically compromised or altered under the influence of exogenous and endogenous acquired adverse factors.

Population studies conducted in recent decades have made it possible to establish factors associated with the development and progression of knee osteoarthritis, among which the following are distinguished [4]:

• Age

• Obesity (with BMI > 30, the risk of early OA increases threefold)

• Alteration of the lower limb axis (in any of the three planes) or dysplasia of the femoropatellar articulation

• Decreased volume and strength of the lower limb muscles

• Any disturbance of normal joint biomechanics

• Traumatic injury to cartilage, ligaments, and menisci, intra-articular fractures of the femoral and tibial condyles, as well as the patella

• Polymorphism of individual genes (both structural and regulatory).

According to modern concepts, knee osteoarthritis is the result of the interaction of age-related, hormonal, inflammatory, immunological, genetic, and environmental factors leading to cellular stress and extracellular matrix degradation arising from macro- and micro-injuries. Thus, the pathogenesis is based on the predominance of catabolic processes over anabolic ones, in particular due to the inadequacy of the reparative response, including the activation of pro-inflammatory pathways of the immune system. Pathological processes at the molecular level occur simultaneously in the cartilage tissue, subchondral bone, menisci, and synovial membrane, leading to structural changes and loss of the biological properties of all joint tissues: cartilage degradation, bone remodeling, formation of osteophytes and chondrophytes, inflammation, and edema. Subsequently, the capsular-ligamentous structures and muscles surrounding the joint are involved in the pathological process.

Chondrocytes in knee osteoarthritis are characterized by overexpression of COX-2 (an isoenzyme of cyclooxygenase necessary for the synthesis of prostaglandins) and the inducible form of nitric oxide synthase (nitric oxide has a toxic effect on cartilage). Under the action of IL-1, chondrocytes synthesize matrix proteinases that destroy collagen and cartilage proteoglycans. The synthesis of chondrocyte anabolic mediators (insulin-like growth factor, transforming growth factor b) under conditions of osteoarthritis is impaired.

The connective tissue matrix, along with chondrocytes, forms the basis of articular cartilage. The connective tissue matrix includes type II collagen molecules and aggrecan (a proteoglycan consisting of a protein core and peripheral chains of chondroitin sulfate, keratan sulfate, and hyaluronic acid). The connective tissue matrix provides the unique shock-absorbing properties of cartilage. Matrix remodeling is controlled by chondrocytes; however, under conditions of osteoarthritis, their catabolic activity exceeds anabolic activity, which leads to negative changes in the quality of the cartilage matrix.

Inflammation in knee osteoarthritis, along with other pathogenetic mechanisms, is of great importance in the development and progression of this disease, although it is not as intense as in arthritides. Nevertheless, pro-inflammatory mediators, acute-phase proteins (in low concentration), and mononuclear infiltration are present. A slight increase in the concentration of a number of pro-inflammatory cytokines is noted in the blood serum and synovial fluid: TNF-alpha, IL-1, IL-6, IL-17, IL-22, and a decrease in anti-inflammatory cytokines, IL-10, with the development of adaptive immune cell reactions in joint tissues, albeit on a limited scale. In histological studies in OA, changes characteristic of chronic inflammation are determined in the synovial membrane: thickening, mononuclear infiltration, and varying degrees of fibrosis.

The mechanical abilities of articular cartilage are ensured by the correct structural organization of the cartilage matrix, i.e., the concentration and interaction of water and macromolecules – collagen, proteoglycans, and non-collagenous proteins, which in turn depends on the normal functioning of chondrocytes. With age or under the influence of other factors, the functional activity of chondrocytes, i.e., the ability to synthesize matrix macromolecules and respond to the stimulating effect of growth factors, decreases, leading to a disruption in the normal ratio of articular cartilage components. Degraded molecules of the matrix network, metabolic products, cytokines, and growth factors, in turn, also affect the functional activity of chondrocytes. The main pro-inflammatory cytokines and mediators include interleukin 1 (IL-1), tumor necrosis factor (TNF- ), IL-6, 17 and 18, nitric oxide (NO), prostaglandins (PG), and leukotrienes (LT). IL-1 induces the expression of metalloproteinases (MMP) and eicosanoids, which are capable of causing the degradation of matrix macromolecules and inhibiting the synthesis of collagen and proteoglycans. TNF- can be activated by a number of aggrecanases (in particular ADAM-17), the minimum concentration of which is determined in normal articular cartilage and significantly increases in OA. NO activates MMP, induces the synthesis of COX-2 and PGE2, inhibits the synthesis of collagen and proteoglycans, as well as the IL-1 receptor antagonist. A number of cytokines are produced by chondrocytes, in particular IL-1, IL-1 , converting enzyme, and type 1 IL-1 receptor. The synovial membrane can also be a source of cytokines, from which they are transported to the overlying cartilage. MMPs are involved not only in the degradation of cartilage tissue but also participate in maintaining the homeostasis of normal cartilage. mRNA of MMP-1, 3, and 13 are constitutively expressed in articular cartilage. MMP-13 plays a crucial role in the degradation of type II collagen, demonstrating a 5-10 times higher activity against type II collagen than MMP-1 and 8.

Maintenance of normal bone structure is ensured by preserving the balance between bone formation and resorption. A number of hormones, growth factors, and cytokines take part in regulating this process. The key role in regulating bone cell metabolism belongs to the molecular triad osteoprotegerin/receptor activator of nuclear factor kB/ligand of this receptor (OPG/RANK/RANKL). One of the factors regulating the functioning of this triad is the level of sex hormones. Hormonal deficiency leads to increased RANKL expression by stromal cells. RANKL, by binding to RANK expressed on osteoclast precursors, stimulates their differentiation and the functional activity of mature cells. At the same time, expression of the RANK antagonist OPG by stromal cells and osteoblasts decreases. Simultaneously, bone formation slows down - a decrease in osteoblast proliferation and their functional activity, likely associated with reduced production of IGF-1 and TGF-. It has been established that acceleration of metabolic processes in the subchondral bone in OA leads to inadequate bone mineralization and a reduction in its mechanical properties. Another consequence of this process is a change in the phenotype and impaired function of subchondral bone osteoblasts and osteoclasts, which produce various cytokines, growth factors, PGs, and LTs that initiate degradation of the articular cartilage. Increased local synthesis of IL-1,6, TNF, and IL-17 also contributes to the acceleration of osteoclastogenesis and bone resorption.

Static loads also play a significant role in the pathogenesis of gonarthrosis. Excessive loading activates mechanoreceptors in chondrocytes and osteocytes, leading to the activation of the latter, which stimulates the production of proteases and inflammatory cytokines, and consequently, the progression of degenerative processes.

Obesity plays a significant role in the pathogenesis of gonarthrosis. On the one hand, it acts as a factor of mechanical overload; on the other hand, adipose tissue, functioning as an independent secretory organ, releases numerous biologically active substances with various negative effects. Thus, adipokines (including leptin, resistin, visfatin, etc.) can enhance catabolic processes in the cartilage and increase the synthesis of pro-inflammatory mediators (IL-1, IL-6, TNF-, etc.) in joint tissues.

Due to the variety of pathogenetic chains leading to the manifestation of gonarthrosis symptoms, drugs capable of reliably halting disease progression in all clinical situations have not yet been found [2]. One of the key reasons for this is that diverse and continuously acting factors of mechanical overload (e.g., excess weight) outweigh the positive effects that pharmacological agents can exert on joint tissues at the biochemical level.

1.3 Epidemiology of the Disease or Condition

Gonarthrosis. According to recent epidemiological studies, the prevalence of knee osteoarthritis among the adult population worldwide varies widely: from 2.0% to 42.4% when considering only clinical criteria, from 16.3% to 33.0% based on radiographic criteria, and from 1.5% to 15.9% for a combination of clinical and radiographic criteria [5, 6, 7]. Eighty-one million patients are registered in five developed countries (Germany, Italy, France, UK, Spain) and more than 380 million patients in Russia, Brazil, India, and China [4]. According to official statistics, from 2000 to 2010, the number of osteoarthritis patients in the Russian Federation increased almost 2.5-fold [5]. A recent epidemiological study showed that 13% of the population over the age of 18 suffers from gonarthrosis and/or coxarthrosis in Russia [6].

Although both the incidence and severity of osteoarthritis increase in older age groups, more than half of all patients belong to the age group under 65 years. Furthermore, regardless of age, the disease develops 1.2 to 1.7 times more frequently in women than in men [8, 9, 10, 11].

Disease progression over several years or decades leads to disability—patients with deforming arthrosis account for about one-third of all individuals with permanent disability resulting from joint diseases [12].

Epidemiology of gonarthrosis in children

The epidemiology of gonarthrosis in children is unknown due to the lack of clear clinical and radiographic criteria adapted for this age category of patients. In most cases, gonarthrosis in childhood is secondary and traditionally regarded as a consequence of an underlying disease (juvenile chronic arthritis, congenital and hereditary skeletal disorders, hemophilia) [216, 217]. Juvenile chronic arthritis is among the most frequent causes of secondary gonarthrosis in pediatric patients, although the rate of progression to gonarthrosis has decreased significantly nowadays due to advances in biologic therapy [216]. Post-traumatic gonarthrosis in children generally has the same pathogenesis and course as in adults, but its clinical and radiographic picture may dissociate—pain intensity may be less pronounced despite comparable radiographic findings.

A typical picture of primary (idiopathic) gonarthrosis in children is extremely rare due to the age-specific nature of the disease, which is characterized by progression with the patient's age, although the main etiopathogenic factors contributing to the development of osteoarthritis in adults, as listed previously, also occur in childhood.

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems

M17 – Gonarthrosis [arthrosis of the knee]

M17.0 – Primary bilateral gonarthrosis

M17.1 – Other primary gonarthrosis

M17.2 – Post-traumatic bilateral gonarthrosis

M17.3 – Other post-traumatic gonarthrosis

М17.4 – Other secondary bilateral gonarthrosis

М17.5 – Other secondary gonarthrosis

M17.9 – Gonarthrosis, unspecified

М 24.5 – Joint contracture

1.5 Classification of the disease or condition

1. By etiology:

   1. Primary gonarthrosis (idiopathic) – occurs without any obvious external causes.

   2. Secondary gonarthrosis – the history indicates one or more factors leading to the development of the disease. Most commonly, these are traumatic factors, such as intra-articular fractures of the femoral and tibial condyles, as well as the patella, healed femoral or tibial shaft fractures with residual deformity, injuries to cartilage, menisci, and knee ligaments, as well as any surgical interventions on the joint leading to post-traumatic gonarthrosis [13]. Inflammatory factors are less common—for example, acute and chronic arthritis of any etiology, hemarthrosis, and other pathological conditions disrupting the normal homeostasis of the joint synovial environment (other secondary gonarthrosis). Either one or both knee joints may be affected.

2. By severity of pathological changes:

   In clinical practice, the classifications by N.S. Kosinskaya (1961) and Kellgren & Lawrence (1963) are most frequently used [14, 15]. The Ahlbäck radiographic classification (1968) also exists, though it is currently used much less frequently [16].

N.S. Kosinskaya Classification (Clinical and Radiographic)

Stage I – radiography reveals a slight narrowing of the joint space compared to the healthy joint and mild subchondral osteosclerosis. Clinically, the disease manifests as pain occurring after or during walking, especially when going down and up stairs, which subsides at rest; sometimes pain may appear after prolonged standing, and joint movements are generally not restricted;

Stage II – the narrowing of the radiographic joint space is 2–3 times the normal value, subchondral sclerosis becomes more pronounced, and bony outgrowths (osteophytes) appear at the margins of the joint space and/or in the area of the intercondylar eminence. Clinically—moderate pain syndrome, development of restricted joint movement, muscle hypotrophy, limp, and mild frontal deformity of the limb axis;

Stage III – the clinical picture is characterized by persistent flexion-extension contractures, severe pain and limping, moderate to marked valgus or varus limb deformity, joint instability, and atrophy of the thigh and leg muscles. Radiography reveals significant deformation and sclerosis of the articular surfaces of the epiphyses with zones of subchondral necrosis and local osteoporosis, the joint space is almost completely absent, and extensive bony outgrowths and loose joint bodies are detected.

Kellgren & Lawrence Classification (Radiographic)

0 – no changes

I – doubtful: minute osteophytes;

II – minimal: definite osteophytes and minimal joint space narrowing;

III – moderate: moderate joint space narrowing and multiple osteophytes;

IV – severe: marked joint space narrowing with subchondral sclerosis, coarse osteophytes.

A significant drawback of radiography is that it does not allow visualization of early pathological changes in the joint tissues; consequently, most patients begin treatment only at the stage of "organ failure", when reparative capabilities are completely lost [17].

The most accurate assessment of cartilage, subchondral bone, menisci, ligaments, and synovial membrane can be achieved using magnetic resonance imaging (MRI) of the joints (single joint), which detects the earliest structural abnormalities before radiographic signs of the disease appear [18, 19]. Unfortunately, to date, there is no universally accepted MRI classification of knee osteoarthritis. Only a few of the published classifications are currently used to a limited extent in research studies. This explains the lack of the necessary evidence base and prevents the inclusion of such classifications in these clinical guidelines.

1.6 Clinical presentation of the disease or condition

The leading clinical symptom of knee osteoarthritis is pain that worsens with movement or joint loading, by the end of the day, upon exposure to cold, and in damp weather. In the early stages, the pain subsides after a period of rest. The intensity of the pain syndrome does not directly correlate with the stage of the disease or the degree of morphological changes in the joint. As the disease progresses, the pain becomes constant. Complaints associated with pain include claudication, the need for an additional support device such as a cane when walking, difficulty going up or down stairs, and difficulty rising from a chair or armchair. As the pathological process progresses, there is a limitation of the range of motion (contracture): initially in flexion and later in extension, crepitus, joint deformation and enlargement, and periodic synovitis.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for Establishing the Diagnosis/Condition

Historically, the diagnosis of osteoarthritis was based on the results of clinical and radiographic examinations. It should be taken into account that radiographic signs of gonarthrosis appear much later than morphological changes. Moreover, over the past decade, numerous prospective studies have demonstrated the high value of magnetic resonance imaging of the joints (single joint) for diagnosing osteoarthritis at the early "pre-radiographic" stage [17]. If magnetic resonance imaging of the joints (single joint) is not feasible, ultrasound examination (ultrasound) of the joint can be used to assess individual elements of the knee joint (cartilage on the femoral condyles, menisci, synovial membrane, ligaments, synovial fluid) and periarticular soft tissue formations (muscles, tendons, cysts, bursae, etc.), although it has lower diagnostic value compared to magnetic resonance imaging of the joints (single joint). In addition, in specific clinical situations, direct invasive visualization of joint structures—i.e., diagnostic arthroscopy—may be additionally used.

2.1 Complaints and Anamnesis

• When examining an adult patient with suspected gonarthrosis, a thorough medical history taking and a comprehensive clinical examination are recommended to establish a diagnosis [20, 21, 22, 23, 24, 25].

Limb deformities develop gradually (varus or valgus deformity of the knee joints).

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

Comments: Typical symptoms of knee OA include: onset of pain with walking, intensification of pain toward the end of the day, relief after rest, and "start-up" pain. The pain can be either diffuse or localized, accompanied by moderate swelling and mild crepitus. It subsides after rest or cyclic low-intensity exercise, such as riding a stationary bike without resistance [20]. It must be emphasized that in the early stages, the pain syndrome is intermittent and may resolve spontaneously. Nevertheless, integral indicators of pain severity are often comparable to those of the terminal stage of the disease [21]. Night pain occurs in more advanced stages of OA.

Stiffness of movement may be observed in the morning or after a period of rest: it is short-lived and resolves within a few minutes after movement begins.

Chronic pain leads to myostatic imbalance and impaired sensorimotor function, resulting in muscle atrophy that causes secondary functional impairments [22]. Proprioceptive deterioration leads to muscle weakness combined with an increased sense of joint "loosening" [23]. As a result, patients experience difficulty squatting or kneeling, going up or down stairs, and rising from a chair or armchair [24]. Gradually, claudication develops, along with the need for additional support when walking. As the disease progresses, limitation of the range of motion (contracture), crepitus, joint deformation and enlargement, and periodic synovitis occur [25].

2.2 Physical Examination

Comments: Objective examination reveals tenderness upon palpation along the joint line, most pronounced in the area of the affected compartment of the knee joint. When the process is predominantly localized in the patellofemoral joint, tenderness may predominate upon palpation and displacement of the patella. Persistent irritation of the peripheral and central nervous system is the cause of chronic pain syndrome characterized by mechanical allodynia and hyperalgesia [26, 27].

Further, as the disease progresses, frontal limb deformity (varus or valgus) and limitation of motion (contracture) appear: initially in flexion and subsequently in extension of the knee joint, the severity of which is clarified during the examination. Later, the deformity and contracture become fixed. In addition, in the presence of knee joint synovitis, the patellar tapotement (ballottement) test becomes positive.

2.3 Laboratory Diagnostics

Currently, there is no "gold standard" for the laboratory diagnosis of osteoarthritis [28, 29].

Comments: in OA, there are no pronounced inflammatory changes in the complete blood count; RF is predominantly undetectable; anti-CCP antibodies and blood uric acid levels are typically within the normal range or slightly elevated.

Comment: moderate elevation of these parameters may be observed in synovitis, while pronounced elevation indicates a different condition.

Comments: Laboratory tests are prescribed primarily to assess the condition of the patient's internal organs and systems [28, 29]. Laboratory tests of blood, urine, or synovial fluid are not required to diagnose knee osteoarthritis, but can be used to confirm or rule out other inflammatory joint diseases (pyrophosphate arthropathy, gout, rheumatoid arthritis, etc.). If knee joint synovitis is present, arthrocentesis of the synovial bursa of the joint with evacuation of the synovial fluid and its subsequent analysis is necessary. OA is characterized by a non-inflammatory nature of the synovial fluid: sterile, transparent or slightly turbid, viscous, with a leukocyte concentration of less than 2000/mm³. Higher values are typical for inflammatory joint diseases. The presence of crystals in the synovial fluid is not characteristic of OA.

2.4 Instrumental Diagnostics

Comments: Radiological signs of OA:

• joint space narrowing;

• subchondral sclerosis;

• osteophytes at the margins of articular surfaces and at ligament attachment sites;

• cysts in the epiphyses;

• changes in the shape of the epiphyses.

Knee radiography is performed in anteroposterior (frontal) and lateral projections. To additionally assess the patellofemoral joint, an axial projection of the patella in the supine position or functional radiography—an axial standing projection—is used.

In early gonarthrosis, when the pathological process is most often localized predominantly in one of the compartments of the femorotibial joint, radiographs in the supine position are of low diagnostic value. Performing weight-bearing radiography in the posteroanterior projection with an axial load in 30–45 degrees of flexion (Rosenberg or Lyon-Schuss view) helps detect joint space narrowing [14].

A significant limitation of radiography is that the articular cartilage can only be assessed indirectly—via the narrowing of the radiological joint space, the height of which in the femorotibial joint is also affected by the degree of peripheral meniscus extrusion.

To quantitatively assess the degree of deformity, full-leg tele-roentgenography of the entire lower limb can be performed with the patient standing, capturing the hip and ankle joints ("gold standard"). Computed tomography of the lower extremity can be used as an alternative to tele-roentgenography [30].

The most common radiological classifications of gonarthrosis are presented above in Section 1.5. If the above-mentioned clear radiological signs of gonarthrosis are present, further instrumental examination (magnetic resonance imaging of the joints [single joint], ultrasound examination of the joint, scintigraphy, etc.) is not required for diagnosis. Indications for magnetic resonance imaging of the joints (single joint) in gonarthrosis include suspected traumatic injury to the menisci, tendons, ligaments, muscles, or the development of osteonecrosis. In addition, magnetic resonance imaging of the joints (single joint) or ultrasound examination of the joint can be used to determine the severity of synovitis and when a Baker's cyst is suspected or ruptured.

A disadvantage of radiological classifications is that they assess the disease independently of the clinical presentation, whereas pain intensity and knee joint dysfunction do not directly correlate with the morphological changes detected on radiographs.

• A clinical and radiological approach to assessing the stage of knee osteoarthritis is recommended for adult patients to identify both the severity of complaints and functional impairments, as well as the degree of joint destruction, enabling personalized treatment selection and prognosis of disease progression in a specific patient [14, 30, 31].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: As previously noted, radiological signs of the disease appear later than the initial morphological changes in the joint, making the diagnosis of early knee osteoarthritis using this imaging method rather difficult [14, 30, 31].

• In the presence of clinical signs but the absence of radiological signs of knee osteoarthritis in adults and children, magnetic resonance imaging of the knee joint (single joint) is recommended to detect early stages of the pathological process. This allows for the identification of initial pathological changes in the articular cartilage (thinning, loss of integrity, appearance of cartilaginous and osteocartilaginous proliferations), subchondral bone (areas of edema, cystic transformation, osteonecrosis), menisci (degenerative changes), as well as the synovial membrane (hypertrophy, presence of excess synovial fluid), ligaments, tendons, and muscles [18, 19, 32, 33, 34, 132].

AGR ALEL 1Level of recommendations assessment A (Level of evidence – 1)

Comments: magnetic resonance imaging of the joints (single joint) allows visualization of all degrees of cartilage changes ranging from edema to thinning, fraying, and fissuring, the state of the subchondral bone tissue, changes in the menisci, "chondrophytes", synovial inflammation, etc. [18]. It is possible to calculate the total volume of the affected cartilage and altered subchondral bone areas, as well as to assess the condition of the knee ligaments [19].

Among the currently developed MRI systems for assessing the severity of pathological changes in osteoarthritis in adults, BLOKS, WORMS, and MOCART have gained the widest acceptance [32, 33, 34]. However, it should be emphasized that they are practically not used in routine clinical practice, nor are they validated and adapted for the Russian Federation, and therefore are not yet mandatory for domestic specialists.

• In adult patients, it is recommended to perform a two-view knee radiograph at 6 and 12 months postoperatively to assess the position of the endoprosthesis components [1].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

2.5 Other Procedures

• Among invasive diagnostic methods in adults and children, diagnostic knee arthroscopy is recommended in rare cases when other studies cannot be used and for differential diagnosis, in order to directly visualize cartilage on all articular surfaces, as well as other intra-articular structures [35, 36, 37, 38, 39, 40, 133, 134, 135].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comments: For diagnostic purposes, arthroscopy may be advisable in early knee osteoarthritis, in the absence of significant radiological signs of the disease and in situations where magnetic resonance imaging of the joints (single joint) cannot be performed, and ultrasound data are insufficient for an accurate diagnosis.

Assessment of cartilage status during arthroscopy can be performed using the criteria proposed by the International Cartilage Repair Society (ICRS) [39]. Cartilage erosion up to 50% of its thickness (superficial to middle zone) is considered the morphological boundary of early knee osteoarthritis and a kind of "point of no return", since with further progression, regeneration of the damaged collagen matrix structure of the cartilage is no longer possible, whereas proteoglycan loss is reversible [40].

Comments: Clinical and laboratory criteria for differential diagnosis are outlined in the clinical guidelines dedicated to the aforementioned nosological entities.

Features of the diagnosis of gonarthrosis in children

For the diagnosis of knee osteoarthritis in children, as well as osteoarthritis of other large limb joints, and for determining treatment tactics, it is primarily advisable to diagnose the underlying disease.

In children, the diagnosis of gonarthrosis relies on the same clinical, laboratory, and imaging methods used in adults. A specific feature of X-ray diagnostics in children is the need to account for ossification patterns; therefore, assessing the mechanical axis deviation (MAD) parameter when diagnosing axial lower limb deformities in children with hereditary skeletal disorders demonstrates better reproducibility compared to angulometric parameters [218, 219].

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

Treatment of gonarthrosis is carried out throughout the patient's life and is based on a combination of non-pharmacological, pharmacological, and surgical methods. The goals of treatment are to reduce pain, prevent the progression of functional impairment in the affected joint, improve health-related quality of life, and prevent and reduce adverse events from pharmacotherapy. A patient with gonarthrosis requires ongoing dynamic follow-up.

Treatment options include conservative (drug and non-drug) and surgical (intra-articular injections, joint-preserving, and joint-replacing) methods, the choice of which depends on the patient's complaints and expectations, severity of clinical manifestations, degree of functional limitations, and the stage of gonarthrosis [1, 80, 204].

• Conservative (non-surgical) treatment is recommended for early stages of gonarthrosis (stage I according to Kosinskaya and stages I–II according to Kellgren and Lawrence), whereas surgical treatment, along with the continuation of conservative therapy, is indicated for later stages (stages II–III according to Kosinskaya and stages III–IV according to Kellgren and Lawrence) or in cases of conservative treatment failure and severe, refractory pain in patients with earlier stages according to these classifications [1, 80, 204].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Non-surgical treatment is advisable for stages I–II of gonarthrosis according to Kosinskaya, while surgical treatment is indicated for stages II–III, as well as in cases of conservative therapy failure in patients with stage I [1, 80]. Regarding the Kellgren and Lawrence classification, conservative treatment is primarily indicated for stages I–II of gonarthrosis, and surgery for stages III and IV. However, conservative treatment should also be performed in late stages of gonarthrosis (stage III by Kosinskaya, stages III and IV by Kellgren and Lawrence): in addition to surgical treatment, or instead of it when surgery is not feasible or patients refuse it. It can also be performed after surgery on one knee joint to treat the contralateral knee joint if it is affected by gonarthrosis. On the other hand, surgical treatment in eligible patients may be performed in early stages of gonarthrosis (stages I and II by Kosinskaya, as well as stages I and II by Kellgren and Lawrence) in cases of severe and poorly controlled pain syndrome, as well as obvious failure of comprehensive conservative therapy. Indications for a particular type of surgical treatment are determined individually in discussion with the patient, taking into account their complaints, expectations, severity of clinical symptoms, degree of functional limitations, and the stage of the disease.

3.1 Conservative Treatment

Conservative treatment of gonarthrosis consists of non-pharmacological and pharmacological methods. Since the pathogenesis of gonarthrosis remains unclear to date, etiotropic therapy for this disease is lacking.

• The main goals of treatment in gonarthrosis may include: effective control of disease symptoms, primarily pain in the affected knee joints; preservation and improvement of their function; reduction in the severity of synovitis; slowing the progression of the pathological process; and prevention of articular cartilage degradation [1, 69, 80, 174, 194, 195, 204].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence Evidence – 5).

3.1.1 Non-pharmacological therapy

• All patients with osteoarthritis are recommended to modify sports/physical activities and unload the affected joint: avoid dynamic and static factors that increase axial load on the knee joint (running, prolonged walking, jumping, heavy lifting, maintaining a monotonous working posture, etc.); wear shoes with well-cushioned soles; and use additional support such as a cane or crutch in the hand opposite to the affected joint during exacerbations [42, 43, 136].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence Evidence – 5).

• All patients with osteoarthritis are recommended therapeutic exercise for joint diseases and injuries aimed at strengthening the thigh and lower leg muscles, which is the most effective method for reducing pain and improving joint function in the long term [42, 43, 136].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence Evidence – 5).

Comments: it is necessary to explain to patients who consider any form of physical activity as a factor worsening their condition that targeted exercises are an effective form of therapy. In the majority of eligible patients, an increase in the severity of gonarthrosis symptoms is not predicted during specially supervised therapeutic exercises [42, 43]. Aerobic exercises are most effective in reducing pain and improving motor activity indicators; mind-body exercises combining body movements with concentration and breathing (yoga, qigong, tai chi) have a similar effect on knee joint function; and exercises aimed at stretching and strengthening specific muscle groups are moderately effective for both. Mixed-type training is the least effective [44].

• Weight loss is strongly recommended for patients with gonarthrosis who are overweight or obese [45]. Appropriate physical exercise programs can be recommended for this purpose to relieve gonarthrosis symptoms and increase the effectiveness of weight loss [156, 157].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence – 5).

Comment: A dose-dependent response has been noted regarding the magnitude of weight loss that leads to improvement in symptoms or functional parameters in patients with osteoarthritis [18, 45]. Weight loss of ≥5% may be associated with changes in clinical and mechanical parameters. Furthermore, clinically significant benefits increase with weight loss of 5–10%, 10–20%, and >20% of body weight. The most effective weight loss strategy includes dietary optimization (reducing dietary fat and carbohydrate intake, restricting salt intake, increasing fruit and vegetable consumption) combined with therapeutic exercise.

Comments: Braces with moldable side stays and hinges make it possible to correct the altered limb axis to unload the medial or lateral compartment of the joint and, with the help of stabilizers, center the patella movement relative to the femoral condyles in the presence of its lateral subluxation [46, 48, 49]. Data from randomized controlled trials (RCTs) and a Cochrane review on the use of braces in medial gonarthrosis indicate that significant clinical or biomechanical effects are absent [26]. It should also be noted that braces with side stays capable of correcting the limb axis and unloading the affected tibiofemoral compartment are poorly tolerated by most patients, leading to low compliance. On the other hand, an RCT conducted by M.J. Callaghan et al. (2015) demonstrated that bracing in isolated patellofemoral osteoarthritis leads to a significant clinical effect and a reduction in subchondral bone lesion areas on MRI [47]. Thus, bracing should be applied differentially depending on the lesion patterns of various knee joint compartments.

• To ensure comprehensive treatment, various physiotherapy methods possessing anti-inflammatory, analgesic, and trophic-regenerative effects are recommended alongside pharmacotherapy [52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 139, 140, 141, 142, 143].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence Evidence – 5).

• For knee osteoarthritis, the following may be recommended, taking into account individual patient characteristics: transcutaneous electrical nerve stimulation, ultrasound therapy, ultra-high frequency (UHF) electric field therapy, sinusoidal modulated current therapy (SMT therapy), high-frequency electromagnetic field therapy (inductothermy), combined pulsed current therapy, medicinal ultraphonophoresis, medicinal magnetophoresis, general and local magnetotherapy [53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 157, 158, 159, 160, 161, 164, 165, 166, 167].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence Evidence – 5).

Comments: Pulsed electrotherapy methods reduce pain severity and improve the quality of life in patients with knee osteoarthritis. Contraindications for electrotherapy include implanted electronic devices, skin lesions and sensory disturbances in the area of electrode placement, and individual current intolerance.

The advantages of magnetotherapy include good tolerance, few contraindications, applicability in the presence of synovitis, and the availability of portable equipment for home procedures.

Comment: The advantage of shock wave therapy is its defibrosing effect due to the mechanical nature of this physical factor, alongside a pronounced analgesic effect in chronic pain syndromes. The course prescribes 5 to 6 procedures at a frequency of 1 to 2 times a week. It should be noted that pain intensification may occur at the beginning of treatment, of which patients should be warned. If pain intensifies after several procedures, it is advisable to discontinue shock wave therapy.

Comments: Eleven randomized controlled trials (494 subjects) support this recommendation, indicating adequate quality. The use of manual therapy makes a positive contribution to the treatment of patients with knee osteoarthritis by reducing pain and improving functionality.

Comment: A systematic review and meta-analysis with low or moderate GRADE quality of evidence, including 12 RCTs with 737 participants, and a systematic review including 26 RCTs with 2634 participants showed that standard massage therapy 1 to 4 weeks after its initiation contributes to a significant reduction in pain scores and improvement in motor function in patients with knee osteoarthritis in the short term.

Comment: Clinical studies conducted utilized various methodological approaches using ice packs or air/gas cryotherapy devices.

Comment: high- and moderate-level evidence studies comparing acupuncture with placebo, standard therapy, or other types of non-pharmacological treatment demonstrated neither clinically significant differences nor potential harm [63, 64].

Comment: Sanatorium-resort treatment programs include the combined use of natural therapeutic factors, therapeutic exercise, hardware physiotherapy, and medical massage. The efficacy of sanatorium-resort treatment has been proven in the form of partial or complete relief of pain syndrome, significant improvement in clinical symptoms, and an increase in patients' quality of life. The achieved remission persists on average for 6 months after the completed sanatorium-resort treatment.

• To increase the range of motion, reduce pain, and enhance motor activity, physical exercises are recommended for adult patients with knee osteoarthritis [220, 221].

Leveled Grade CLevel of Evidence 4Level of recommendation evidence C (level of data reliability – 4).

3.1.2 Drug therapy

Etiotropic pharmacotherapy for knee osteoarthritis has not yet been developed, so medical treatment is symptomatic in nature.

• For patients predominantly in the early stages of knee osteoarthritis, regardless of the severity of the pain syndrome, the prescription of symptomatic slow-acting drugs in osteoarthritis (SYSADOA) is recommended:

• Chondroitin sulfate, glucosamine, and their combinations for adult patients administered orally or parenterally as solutions in accordance with the instructions for use of these drugs for the effective relief of knee osteoarthritis symptoms and obtaining a structure-modifying effect with long-term use [81, 174, 175, 182].

Leveled Grade ALevel of Evidence 2Level of recommendation evidence A (level of data reliability – 2).

• A drug based on avocado and soybean oil unsaponifiables (INN: avocado and soybean oils unsaponifiable fractions) for the relief of knee osteoarthritis symptoms in patients aged 18 years and older at a dose of 300 mg per day [78, 176].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

• Diacerein for the relief of knee osteoarthritis symptoms in patients aged 18 years and older [186, 198, 199, 206].

Leveled Grade BLevel of Evidence 1Level of recommendation evidence B (level of data reliability – 1).

• Preparations from the M09AX group "Other drugs for disorders of the musculoskeletal system" based on a bioactive concentrate from small marine fish or a glycosaminoglycan-peptide complex to reduce the severity of knee osteoarthritis symptoms in patients aged 18 years and older [177, 178].

Leveled Grade BLevel of Evidence 2Level of recommendation evidence B (level of data reliability – 2)

Comments: currently, chondroitin sulfate, glucosamine and their combinations, as well as preparations based on avocado and soybean oil unsaponifiables (INN: avocado and soybean oils unsaponifiable fractions) in adult patients, and diacerein in adult patients, are singled out into a separate group of symptomatic slow-acting drugs in osteoarthritis (SYSADOA), which, according to the ATC (Anatomical Therapeutic Chemical) drug classification, belong to group M01AX – "Other non-steroidal anti-inflammatory and antirheumatic products" and are considered basic therapy for osteoarthritis [73, 174, 179, 194, 195]. It should be especially emphasized that these drugs have varying evidence bases for their efficacy in osteoarthritis.

The most studied drugs in terms of efficacy and safety in osteoarthritis are chondroitin sulfate, glucosamine, and their combinations. These drugs possess not only analgesic and anti-inflammatory effects but are also capable of slowing down the progression of knee osteoarthritis and delaying knee arthroplasty surgeries. A pronounced symptomatic effect from SYSADOA usage develops 8 – 12 weeks after the start of administration, but for the structure-modifying effect of the drugs, the duration of treatment should be at least two years [179, 180, 181, 182, 185, 197]. The daily therapeutic doses are 1500 mg for glucosamine and more than 800 mg for #chondroitin sulfate. At the same time, the calculation of the therapeutic dose for glucosamine was performed based on studies conducted with glucosamine sulfate. The standard regimen for oral administration of chondroitin sulfate is 500 mg twice daily, but in randomized clinical trials compared with celecoxib (contraindicated under 18 years of age), this drug showed comparable efficacy at a dose of #800 mg [228] or #1200 mg [185] every 24 hours. At the beginning of therapy to increase bioavailability and achieve a faster analgesic effect, chondroitin sulfate-based drugs, glucosamine, and other drugs from the SYSADOA group can be prescribed to patients aged 18 and older parenterally, for example, in the form of intramuscular injections, in accordance with the current instructions for their use [196].

Unlike NSAIDs, drugs of the SYSADOA group have a carry-over effect for two to four months after treatment is discontinued. Recent systematic reviews and meta-analyses of randomized clinical trials have confirmed the efficacy of drugs of this group in the treatment of patients with osteoarthritis [174, 175], which led to the inclusion of these drugs in international clinical guidelines [80]. However, the results of recent meta-analyses indicate that positive data on the efficacy of original standardized medicinal products from the SYSADOA group cannot be extrapolated to generics, dietary supplements, and other substances not registered as pharmacological agents [81, 183].

According to meta-analysis data, crystalline glucosamine sulfate significantly reduced pain, improved joint function, and reduced pain syndrome in osteoarthritis, while other forms showed no significant difference in these parameters compared to placebo [184]. This drug also demonstrated comparable efficacy to ibuprofen** in relieving pain and improving joint function as early as the second week of use [80]. In other studies, it was shown that glucosamine sulfate slowed joint space narrowing and reduced the need for joint arthroplasty in patients with osteoarthritis over 8 years of follow-up [179, 180, 182]. In a two-year randomized controlled trial, a significant reduction in articular cartilage volume loss according to quantitative MRI was proven when taking #chondroitin sulfate at a dose of 1200 mg/day in patients with knee osteoarthritis [185].

A recent meta-analysis of the efficacy and safety of a drug based on avocado and soybean oil unsaponifiables (INN: avocado and soybean oils unsaponifiable matters) demonstrated a significant symptomatic effect in terms of reducing pain syndrome with an incidence of adverse events comparable to placebo [176]. However, there is no convincing data on its structure-modifying effect.

Drugs based on a bioactive concentrate from small marine fish, as well as glycosaminoglycan-peptide complex drugs indicated for use in knee osteoarthritis, have also demonstrated symptomatic efficacy regarding pain reduction in placebo-controlled RCTs [177, 178].

Diacerein is also classified as a SYSADOA; its efficacy in reducing pain severity and preventing joint space narrowing in osteoarthritis, including knee osteoarthritis, was until recently considered questionable [186]. However, a 2019 international multicenter double-blind comparative study of celecoxib and diacerein confirmed the analgesic and anti-inflammatory efficacy of the latter in osteoarthritis [198]. There is also evidence of the structure-modifying effect of diacerein on articular cartilage in hip osteoarthritis, obtained during a long-term three-year study [199]. The efficacy and safety of diacerein in knee osteoarthritis were also confirmed in a meta-analysis summarizing the results of 12 randomized clinical trials involving 1732 target patients [206]. Therefore, diacerein can be an alternative to NSAIDs in the treatment of knee osteoarthritis, especially in patients with contraindications to such therapy, since it does not cause adverse events typical of NSAID use. However, it should be borne in mind that taking this drug can cause gastrointestinal adverse events: diarrhea, flatulence, epigastric pain.

In the absence of a clinical effect within three months in patients receiving drugs from the SYSADOA group, it is advisable to consider replacing them with other drugs of the specified group or additionally prescribing drugs from other pharmacological groups, taking into account the feasibility of a final assessment of SYSADOA efficacy after the completion of a full treatment course, which usually lasts 5 – 6 months

• In adult patients with knee osteoarthritis presenting with moderate to severe pain syndrome for rapid and effective pain reduction in the affected knee joints, it is recommended to prescribe non-steroidal anti-inflammatory and antirheumatic drugs (NSAIDs), taking into account patient comorbidity [66, 68, 70].

Leveled Grade ALevel of Evidence 1Level of recommendation evidence A (level of data reliability – 1).

• To relieve moderate pain in knee osteoarthritis prior to prescribing oral NSAIDs, adult patients are recommended to use transdermal (topical) forms of NSAIDs [65, 80].

GOM ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comments: A recent meta-analysis showed that etoricoxib at a dose of 60 mg/day and diclofenac** at a dose of 150 mg/day are highly effective oral NSAIDs for pain relief and functional improvement in patients with knee and hip osteoarthritis [66]. However, such therapy is not suitable for patients with comorbidities or for long-term use due to an increased risk of adverse events (AEs), especially when using diclofenac**. Topical application of diclofenac (in patients over 12 years of age) for knee osteoarthritis at a dose of 70–81 mg/day is an effective and safe treatment strategy [66]. In addition, topical forms of other NSAIDs exert a pronounced analgesic effect in knee osteoarthritis, have good tolerability, and practically do not cause systemic side effects, since their concentration in the systemic bloodstream does not exceed 5 – 15% compared to oral administration of the same NSAIDs [65, 66, 168].

• Adult patients with pain syndrome are recommended to be prescribed a continuous course of NSAIDs, which provides better symptom control in knee osteoarthritis than "on-demand" NSAID intake [68, 149, 153].

LoE BGoE 2Level of Recommendation B (level of evidence – 2).

Comments: The use of non-steroidal anti-inflammatory and antirheumatic drugs (NSAIDs), which possess anti-inflammatory and analgesic effects, is considered the mainstay of drug therapy for patients with knee osteoarthritis. NSAIDs in medium and maximum therapeutic doses in the treatment of chronic pain are not inferior in efficacy to tramadol** (contraindicated under 14 years of age) [1]. At the same time, it should be considered that the clinical efficacy of the recommended doses of NSAIDs is approximately the same, and the main difference lies in the individual response of patients to a specific drug. Therefore, the choice of a drug from this group for therapy in target patients should be made individually, taking into account the pharmacological characteristics of each drug and the comorbidity (concomitant diseases) of a particular patient [69]. All NSAIDs in medium and maximum therapeutic doses with prolonged use have equal analgesic potential. The decision to modify NSAID therapy is advisable 5 – 7 days after the start of treatment with drugs of this group (in case of ineffectiveness of previous analgesic therapy).

NSAID use can lead to serious adverse events (AEs), the most common of which are erosive and ulcerative lesions of the gastrointestinal (GI) tract, cardiovascular complications, and renal dysfunction [68]. It should be noted that most side effects are mild and transient. Nevertheless, GI lesions may occasionally result in bleeding and perforations (incidence rate 0.25%–1.58%). The main risk factors for GI AEs include age >65 years, a history of gastric and duodenal ulcers or upper GI bleeding, and concomitant use of antithrombotic agents [61]. The main risk factors for cardiovascular AEs are cardiovascular diseases (CHD, hypertension, CHF, etc.) as well as high cardiovascular risk [68].

The duration of use and dosing regimen of NSAIDs depend on the clinical presentation of knee osteoarthritis and the need for joint pain control. There is no clear evidence supporting the long-term use of NSAIDs in knee osteoarthritis. These drugs should be used solely for pain control and discontinued once significant improvement is achieved. Depending on the clinical situation, NSAIDs can be used in prolonged or short courses, as well as on an "as-needed" basis to manage disease exacerbations [148, 149]. However, as noted above, scheduled course therapy with NSAIDs provides better pain relief than an "as-needed" regimen [68, 149, 153].

• In adult patients with peptic ulcer disease and a risk of perforations, bleeding, and other serious gastrointestinal adverse events, it is recommended to use NSAIDs whose mechanism involves preferential COX-2 inhibition [144].

GOM ALOE 1Grade of Recommendation A (Level of Evidence – 1).

• In adult patients with dyspeptic symptoms, it is recommended to prescribe non-selective NSAIDs in combination with proton pump inhibitors (PPIs) [144].

GOM ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comments: The choice of optimal treatment for pain relief, inflammation control, and gastrointestinal protection must be individualized based on the patient's risk profile. NSAIDs whose mechanism involves preferential COX-2 blockade are the drugs of choice in the presence of the following risk factors for adverse events: age over 65 years, history of peptic ulcer disease or gastrointestinal bleeding, concurrent use of systemic corticosteroids or antithrombotic agents, and presence of severe comorbidities.

• For patients aged 18 years and older with a moderate risk of cardiovascular complications, short-term use of propionic acid derivatives (naproxen, ibuprofen**, or low doses of celecoxib) is recommended [68, 145].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1).

• It is not recommended to prescribe NSAIDs to adult patients with OA and a very high risk of cardiovascular complications [70, 145].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comments: The frequency of mild gastrointestinal and cardiovascular complications associated with NSAID use steadily increases, becoming clinically significant as early as 4 weeks into therapy [68]. Therefore, when prescribing NSAIDs, one should consider the potential early appearance of minor adverse events, as well as drug tolerability and patient preferences. During long-term NSAID use, it is advisable to monitor the gastrointestinal tract, liver and renal function, and measure peripheral blood pressure in relevant patients [69, 154].

• Paracetamol** is recommended for adults and children in accordance with its current product labeling when NSAIDs are ineffective or contraindicated [71, 231].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: Paracetamol** was long considered the drug of choice for mild to moderate pain in osteoarthritis (OA) without signs of marked inflammation, as its analgesic efficacy was thought to be comparable to NSAIDs. However, subsequent studies demonstrated not only its low analgesic efficacy (comparable to placebo in knee OA) but also frequent gastrointestinal and cardiovascular adverse events [66, 71]. Therefore, it may currently be used when NSAIDs are ineffective or contraindicated at a daily dose not exceeding 3.0 g, provided a satisfactory clinical effect is achieved. Furthermore, the drug should not be prescribed to patients with liver disease and chronic alcoholism.

• For patients aged 18 years and older when previous conservative therapy is ineffective or contraindicated, it is recommended to use tramadol** to control severe pain, taking into account the risks of gastrointestinal and central nervous system adverse events with its long-term use [169, 170].

Recommendation Grade AEvidence Level 1Level of recommendation evidence A (level of data reliability – 1).

Comment: Tramadol** is an opioid analgesic that also acts as a selective serotonin reuptake inhibitor (SSRI). This drug exerts a moderately dose-dependent analgesic effect in knee osteoarthritis. The absence of direct ulcerogenic and prothrombotic effects of tramadol** allows its administration in patients with high gastrointestinal and cardiovascular risk. The mechanism of action of tramadol** differs from NSAIDs, making its use appropriate when the latter are ineffective. However, a large number of AEs (nausea, constipation, sleep disturbances, dizziness, potential for habituation, etc.) and social issues related to the non-medical use of opioids limit the applicability of this drug [169, 170].

• Duloxetine is recommended for patients aged 18 years and older to control severe chronic pain associated with osteoarthritis when previous conservative therapy is ineffective and there are signs of central sensitization, neuropathic pain, and/or depression [72, 171, 172].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

Duloxetine is an antidepressant from the N06AX group "Other antidepressants" according to the ATC classification, which possesses properties of selective serotonin and norepinephrine reuptake inhibition, and also weakly inhibits dopamine reuptake. The analgesic effect of duloxetine is related to its influence on central nociceptive mechanisms, which determines its efficacy in fibromyalgia and neuropathic pain [171, 172].

A meta-analysis on its use in osteoarthritis indicates a significant reduction in pain, stiffness, functional disability, and an improvement in quality of life [72].

Duloxetine can cause various adverse events, so its administration requires careful medical monitoring and a gradual dose titration starting from the minimum dose of 30 mg/day [173].

Comments: Drugs of this group, by causing local skin irritation, produce both reflex (cutis-visceral) and analgesic pharmacological effects (distraction through additional afferent impulses). Pain attenuation may also occur due to the activation of antinociceptive mechanisms in the central nervous system.

3.1.3 Intra-articular injections

• In adult patients with osteoarthritis presenting with pain syndrome and functional impairment in the knee joints, it is recommended to administer intra-articular hyaluronic acid-based synovial fluid substitutes*** (synovial fluid prostheses) [187, 188].

Recommendation Grade BEvidence Level 1Level of recommendation evidence B (level of data reliability – 1).

Comments: Intra-articular administration of sodium hyaluronate derivatives can lead to a positive clinical effect of varying severity, with an average duration of 4 to 6 months or more, varying widely depending on the physicochemical characteristics of a particular medical device and the clinical characteristics of the patient [92]. After the clinical effect wears off, the injection can be repeated. The use of synovial fluid substitutes*** (synovial fluid prostheses) based on hyaluronic acid has a more favorable safety profile than NSAIDs and can be an alternative to the latter in the treatment of knee osteoarthritis, especially in elderly patients and individuals with high comorbidity. The treatment is well tolerated, comparable to placebo: pain resembling a pseudogout attack occurs very rarely. The results of comparative studies of intra-articular administration of synovial fluid substitutes*** (synovial fluid prostheses) based on hyaluronic acid and glucocorticoids show approximately equal efficacy at 4 weeks post-injection and a significantly greater effect of synovial fluid substitutes*** (synovial fluid prostheses) based on hyaluronic acid at 5 to 13 weeks post-injection [187, 189, 190]. Preparations of synovial fluid substitutes*** (synovial fluid prostheses) based on hyaluronic acid should be injected into the knee joint only in the absence of synovitis (into a "dry" joint).

• In cases of persistent severe joint pain and synovitis in adult patients that are not relieved by other methods of conservative therapy, intra-articular administration of glucocorticoids is recommended, but no more than once every 3 months, and course-based use of these drugs should be excluded [93, 95].

LoE BGoE 2Level of Recommendation B (level of evidence – 2).

Comments: Intra-articular administration of glucocorticoids produces a strong anti-inflammatory effect, but is associated with a high risk of secondary osteonecrosis and exacerbation of articular cartilage degradation. Therefore, their use is possible in situations where synovitis cannot be controlled with adequate doses of NSAIDs, but no more than once every 3 months [93, 95].

• Adult patients may be recommended platelet-rich plasma injection into the knee joint area upon the patient's initiative [191].

Leveled Grade BLevel of Evidence 1Level of recommendation evidence B (level of data reliability – 1).

Comments: A recent meta-analysis of 30 RCTs demonstrated the superiority of intra-articular platelet-rich plasma injections compared to glucocorticoids, hyaluronic acid, and placebo in patients with knee OA at 3, 6, and 12 months of follow-up [191].

• Adult patients may be recommended the administration of autologous stromal-vascular fraction into the joint cavity and/or autologous bone marrow cells upon the patient's initiative [99, 192].

Level of Recommendation VLevel of Evidence 3Level of Recommendation V (Level of Evidence – 3).

Comments: Currently, there is no conclusive evidence regarding the efficacy of autologous stromal-vascular fraction into the joint cavity and/or autologous bone marrow cells as a treatment method for gonarthrosis. Risk factors for adverse events during this procedure include: active infection in the knee joint area; inflammatory process at the adipose tissue harvest site; the patient's hematopoietic system disorders; pregnancy and breastfeeding periods.

Features of drug therapy for gonarthrosis in children

• To select medical treatment for gonarthrosis in children, it is recommended to take into account age and the presence of contraindications according to the instructions [221].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence – 5).

Comments: There is no specific drug treatment for gonarthrosis in children. For symptomatic treatment of pain in children, NSAIDs are used, the choice of which is limited for patients under 18 years of age. The most widely used drugs are paracetamol** and ibuprofen**. Paracetamol** is approved for use in children over 3 months of age, and ibuprofen** orally from 1 year). In general, special attention should be paid to contraindications for the use of certain pharmacological drugs in children, as well as their dosages specified in the instructions for the respective drugs [221].

3.1.4 Future of therapy for knee osteoarthritis

Among potential new treatments for patients with gonarthrosis, the efficacy of which is currently being studied but not yet confirmed enough to recommend them for wide clinical use, are protease inhibitors that cause chondrocyte apoptosis and cartilage matrix degradation, autologous blood plasma protein concentrates or platelet-rich plasma (according to ATC: plasma substitutes and plasma protein fractions), cultures/concentrates of auto- or allogeneic mesenchymal stem cells, as well as gene-cell therapy (e.g., allogeneic chondrocytes overexpressing TGF-$\beta$1 via retroviral vectors) [100].

3.2 Surgical Treatment

• Surgical treatment is recommended for adults and children, predominantly patients with gonarthrosis of stages II–III according to Kosinskaya and stages III–IV according to Kellgren and Lawrence, with an unsatisfactory effect of complex conservative therapy (pain syndrome is not relieved by complex non-pharmacological and pharmacological treatment), or in situations where initial medical consultation reveals pronounced degenerative-dystrophic changes in the joint accompanied by persistent functional disorders [35, 36, 37, 38, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: Currently, the most effective methods of surgical treatment for gonarthrosis are corrective periarticular osteotomies of the femur and/or tibia and partial or total knee arthroplasty (joint replacement). Indications for endoscopic interventions (arthroscopy) in patients with gonarthrosis have narrowed sharply in recent years.

3.2.1 Joint-sparing surgeries

• Arthroscopic treatment may be recommended for adult patients with stages I–II of the disease according to Kosinskaya and stages I–II according to Kellgren and Lawrence with moderately pronounced restriction of knee joint function, pain duration of more than three months, ineffectiveness of complex conservative therapy, normal lower limb axis or its deviation of less than 5 degrees, and the presence of complaints and symptoms indicating concomitant meniscus injury or loose intra-articular bodies, provided there are no indications for periarticular osteotomies or partial/total knee arthroplasty [35, 37, 38, 102, 105, 110, 207, 208].

強BLeveled 2Level of recommendation evidence B (level of data reliability – 2).

Comments: The positive clinical effect of arthroscopic lavage or joint flushing (arthroscopic joint debridement) affected by a degenerative-dystrophic process was first indicated by M. Bircher (1921) in a work devoted to the arthroscopic diagnosis of deforming arthrosis of the knee joint, and the lavage effect was first described by M. Burman et al. (1934), believing that the clinical effect is achieved due to abundant flushing of the joint cavity and removal of debris (free fragments of articular cartilage, fibrin, enzymes, cytokines, and other inflammatory mediators) irritating the synovial membrane. However, to date, questions regarding the impact of arthroscopic surgeries on the course of the pathological process, the ratio of their positive clinical action to the placebo effect, and possible mechanisms of pain reduction remain unanswered. A number of studies have shown that simple joint flushing, both through a regular needle and during arthroscopy, is not effective in patients with gonarthrosis [37, 102, 105, 110, 207]. Performing arthroscopic lavage and rational debridement is not advisable in patients with radiologically confirmed gonarthrosis and/or full-thickness cartilage loss on adjacent surfaces of the femur, tibia, and/or patella detected on MRI, as well as in the presence of signs of meniscus extrusion and aseptic necrosis of the femoral and tibial condyles.

Another hypothesis postulating that the main importance is the elimination of mechanical obstacles hindering joint movement, i.e., performing arthroscopic debridement, which may include resection of unstable, detached, and damaged cartilage fragments, degeneratively altered areas of the menisci, hypertrophied sections of the synovial membrane, smoothing of cartilage fibrillation areas, removal of loose intra-articular bodies and osteophytes causing soft tissue impingement, has also not been confirmed in randomized controlled trials [35, 38, 207].

Tunneling, microfracture, or abrasive chondroplasty for localized full-thickness cartilage defects of degenerative etiology on the femoral condyles can be used only in patients with a normal limb axis and minimal signs of gonarthrosis. They are contraindicated in widespread pathological processes, severe contractures, deformities, and knee joint instability. They should be avoided in patients who are unable or unwilling to offload the operated joint for two months.

Arthroscopic meniscal resection is indicated only when complex non-pharmacological and pharmacological conservative treatment (NSAIDs, therapeutic exercise, physical therapy) is ineffective and symptoms persist for 3 months under a number of conditions [208]:

• extra-articular causes of pain are excluded;

• functional radiography shows no marked joint space narrowing;

• MRI signs of grade 3 or higher meniscal injury are present [111].

During arthroscopy, the core principle should be the minimum possible meniscal resection to preserve its function and prevent extrusion, which is associated with pain due to emerging overload of the cartilage and underlying subchondral bone and directly correlates with the progression of gonarthrosis.

Currently, the most important goal of knee arthroscopy in a joint affected by a degenerative-dystrophic process can be considered the confirmation of the diagnosis and refinement of the further treatment plan when it is impossible to obtain the necessary information through radiography, MRI, or other non-invasive methods.

In stage III gonarthrosis, arthroscopy including lavage and rational debridement is unable to provide a sufficient therapeutic effect and stabilize the pathological process.

• Adult patients may be recommended periarticular osteotomy of the femur and/or tibia for stage I–II gonarthrosis according to the Kosinskaya classification and stage I–II according to the Kellgren and Lawrence classification with predominant involvement of the medial compartment and varus deformity or the lateral compartment and valgus deformity of the knee joint in case of ineffective non-surgical treatment [103, 112, 113, 150].

GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).

Comments: The choice of the osteotomy site—the distal metaphysis of the femur and/or the proximal metaphysis of the tibia—depends on the severity of the deformity in the individual limb segment, taking into account the slope of the joint line in the frontal and sagittal planes to minimize its change. When performing a tibial osteotomy, an additional fibular osteotomy or mobilization of the proximal tibiofibular joint is often required [103]. The biomechanical concept of corrective femoral and/or tibial osteotomies consists in restoring the altered lower limb axis, which helps to offload the affected compartment of the knee joint [112]. The exact mechanism of pain relief after osteotomy remains not fully understood; it is believed that in addition to reducing the load on the most altered parts of the articular surface, contributions may also be made by the return of the meniscus to its normal position from being luxated to the periphery of the joint, normalization of intraosseous pressure, and possible proliferation of fibrocartilage in the affected joint compartment. The clinical outcome of osteotomy depends on compliance with indications and contraindications for surgery, thorough preoperative planning, and precision of surgical technique. After a correctly performed osteotomy, regression of subchondral sclerosis and restoration of radiological joint space height are observed, which is clinically accompanied by a decrease in pain syndrome and preservation of an adequate range of motion [113].

Periarticular osteotomies are most promising in patients younger than 50–55 years, as they allow delaying knee arthroplasty for up to 8–12 years.

• Adult patients may be recommended tibial tubercle osteotomy for its ventralization or ventromedialization in isolated stage I–II gonarthrosis according to the Kosinskaya classification and stage I–II according to the Kellgren and Lawrence classification with predominant involvement of the patellofemoral joint [106, 108].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comments: General mandatory conditions for the use of corrective periarticular osteotomies of the femur and tibia are a frontal deformity of no more than 15–20 degrees, a range of motion in the knee joint of at least 90 degrees, extension restriction of no more than 10–15 degrees, a satisfactory condition of the hyaline cartilage and meniscus in the adjacent joint compartment (based on MRI or endoscopic examination data), and the absence of class 3–4 obesity [108].

Contraindications to these osteotomies include total involvement of the knee joint by the pathological process, obesity (BMI >35), decompensated chronic venous or arterial insufficiency, the presence of a bone defect of the medial or lateral condyle of the femur or tibia, subluxation of the lower leg in the frontal plane, a sedentary lifestyle, systemic connective tissue diseases, and age over 65 years [106].

3.2.1.1 Specifics of joint-sparing surgical treatment in children with knee osteoarthritis

• For injuries to the internal structures of the knee joint (ligaments, menisci, articular cartilage) in children, arthroscopic surgeries may be recommended: removal and/or repair of damaged structures, which is preferable given the minimally invasive nature of such interventions [229].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence – 5).

• For the correction of lower limb deformities in children that underlie the pathogenesis of gonarthrosis, temporary epiphysiodesis (guided growth) methods of the lower limb segments forming the knee joint [223], as well as various options for extra-articular corrective osteotomies of the femur and/or tibia, including those using external fixation devices [230], may be recommended.

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence – 5).

Comments: Autologous cartilage transplantation can be used for significant articular cartilage defects in children. However, despite isolated scientific publications with positive outcomes of such treatment, a clear formulation of indications, uniformity of surgical techniques, and evaluation of treatment results are lacking [225].

3.2.2 Total knee arthroplasty

• Surgical treatment in the scope of knee arthroplasty is recommended for adult patients with stage III gonarthrosis according to the Kosinskaya classification and stage III–IV according to the Kellgren and Lawrence classification, as well as in rare cases when other treatment options are ineffective at earlier stages of the disease [101, 104, 107, 109, 114, 115, 205, 209].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comments: Knee arthroplasty allows for rapid pain relief, restoration of the biomechanics of the affected joint, and prompt domestic and professional rehabilitation of the patient. Depending on the extent of the pathological process, one (partial or unicompartmental), two (bicompartmental), or all three (total) compartments of the knee joint can be replaced during arthroplasty. Partial arthroplasty has a number of proven advantages compared to total arthroplasty; in particular, recovery is twice as fast, a larger proportion of patients achieve excellent functional outcomes, the rates of infectious, thromboembolic, and cardiovascular complications are significantly lower, and if revision is necessary, standard implants and instrument systems for primary total knee arthroplasty can be used in most cases [210, 211]. Partial arthroplasty is indicated for full-thickness cartilage wear on the articulating surfaces in one compartment of the joint, functionally competent stabilizers, full cartilage thickness, and an intact meniscus in the adjacent femorotibial compartment [211]. It is contraindicated in fixed frontal deformity (usually exceeding 15 degrees) and fixed contracture (extension restriction of more than 15 degrees and flexion restriction of more than 90 degrees), as well as significant involvement of other knee compartments in the pathological process.

• After knee arthroplasty, to check the quality of placement of the implanted structures, it is recommended to perform radiography of the knee joint in two projections before discharge from the hospital in an adult or pediatric patient [1, 101, 115].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Principles for correcting fixed flexion and extension contractures in total knee arthroplasty.

In flexion contracture, when knee extension is limited, the primary pathogenetic focus is located in its posterior compartment. The pathophysiological basis of flexion contracture is a mismatch between the gaps formed after bone cuts: the extension gap is smaller than the flexion gap; therefore, to eliminate this imbalance, sequential manipulations on both bone and soft tissues are necessary. Following arthrotomy, removal of accessible osteophytes, and exposure of the femoral and tibial condyles, the first stage involves a standard distal cut of the femoral condyles (8–10 mm), corresponding to the thickness of the femoral component, and a cut of the tibial plateau — 8–10 mm from the articular surface of the less damaged condyle. Next, to correct the flexion contracture, it is necessary to thoroughly remove all osteochondral proliferations from the posterior parts of the femoral and tibial condyles, as well as any intra-articular bodies located behind them. Then, the contracted areas of the posterior capsule in the medial and/or lateral compartments of the joint are resected, which are easily palpable during joint extension and gentle traction on the lower leg. If the surgical technique involves performing an anteroposterior resection of the femoral condyles prior to the distal cut, for example, during the implantation of designs with a mobile polyethylene insert, a preliminary resection of the posterior parts of the femoral condyles with a thickness of 3–5 mm can be performed after the plateau cut to facilitate access to the posterior parts of the knee joint. Next, if necessary, mobilization of the capsule from the posterior parts of the femoral condyles and release of the femoral attachment of the gastrocnemius muscle heads are performed.

Having completed the medial-lateral balancing of the extension gap by releasing the contracted structures on the concave side of the deformity, gap spacers are used to check the completeness of lower leg extension and the stability of the extension gap. If full extension of the lower leg cannot be achieved with the smallest gap spacer, additional release of the posterior capsule, posterior cruciate ligament, or an additional distal resection of the femoral condyles (+3 mm) is performed. Exceeding this value leads to proximal displacement of the joint line during extension, the formation of patella baja with subsequent restriction of lower leg flexion, and the development of joint instability at mid-flexion angles due to disruption of collateral ligament isometry. Next, anteroposterior and oblique cuts of the femur are performed, and the symmetry and equality of the flexion and extension gaps are verified. If full extension of the lower leg cannot be achieved while maintaining a stable flexion gap, an additional distal resection of the femoral condyles (+3 mm) is performed following the standard initial 8–10 mm distal cut, which selectively increases the extension gap. Following the additional distal resection, oblique cuts must be repeated.

If the gaps are symmetrical but stabilized by inserts of different heights (usually a high gap spacer is required in flexion, whereas a significantly smaller height is needed for full lower leg extension), it is permissible to increase the femoral component by one size (it must not protrude beyond the femoral epicondyles in the frontal plane) and achieve joint stabilization and full extension with a lower polyethylene insert height. It should be kept in mind that by slightly increasing extension, PCL resection can lead to an increase in the flexion gap by 2–4 mm, once again causing a discrepancy in size and an imbalance between the flexion and extension gaps.

Much less frequently, limitation of full lower leg extension is caused by massive osteophytes forming on the anterior surface of the femoral groove and contacting osteophytes of the anterior margin of the tibia during knee joint extension. In this situation, the removal of these osteophytes leads to the restoration of the full range of motion [227].

Extension contracture, referred to in foreign literature as a "stiff knee," implies a limitation of lower leg flexion to less than 50°. The pathophysiological basis of this condition is scarring changes in the capsular-ligamentous apparatus, the formation of massive osteophytes and connective tissue or bony adhesions between the articular surfaces, and the subsequent contraction of the knee joint extensor mechanism.

Main stages of surgical correction of extension contracture:

1. Synovectomy, excision of scars and adhesions from the joint cavity (arthrolysis), and resection of the scar-altered Hoffa's fat pad.

2. Removal of all osteophytes: both posterior femoral and tibial osteophytes, which can contact each other and limit flexion, and bony proliferations on the anterior surface of the lower third of the femoral diaphysis.

3. Tenolysis and, if necessary, myolysis of the quadriceps femoris muscle.

4. Excision of the scar-degenerate vastus intermedius muscle.

5. The surgery begins with standard arthrotomy; however, to mobilize the articular surfaces, it is often necessary to use extended approaches to the knee joint: transection of the quadriceps tendon (a "quadriceps snip" according to J.N. Insall) or osteotomy of the tibial tubercle [227].

Comments: Arthrodesis eliminates pain syndrome and restores limb load-bearing capacity, but is usually accompanied by limb shortening. Subsequently, due to biomechanical disruption, degenerative-dystrophic changes develop and progress in the lumbosacral spine and adjacent hip and ankle joints. Other potential complications of knee arthrodesis include delayed union and nonunion [117].

Knee arthroplasty in children with knee osteoarthritis is extremely rare. One study reported 11 cases of knee arthroplasty in children (under 18 years of age) for non-oncological reasons (primarily juvenile chronic arthritis), noting a significant reduction in pain scores and functional improvement [226].

3.3 Other Treatment

• Adult patients are recommended to undergo deep vein thrombosis (DVT) and pulmonary embolism (PE) prophylaxis using pharmacological and non-pharmacological methods following limb-sparing surgeries on the knee joint, as well as knee arthroplasty, based on relevant clinical guidelines for thromboprophylaxis [115, 213].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Venous thrombosis prophylaxis should aim to accelerate blood flow in major veins (nonspecific prophylaxis) and correct hemostasis (specific anticoagulant prophylaxis) [115, 212]. Nonspecific prophylaxis methods are aimed at preventing venous stasis; they do not increase the risk of bleeding and enhance the efficacy of pharmacological thromboprophylaxis. These include early postoperative mobilization of patients, therapeutic exercise (leg exercises, use of a "foot pedal" providing passive contraction of the calf muscles), and mechanical prophylaxis (elastic compression of the lower extremities, sequential intermittent pneumatic compression, calf muscle electrical stimulation, etc.) [212, 213].

Comments: Knee arthroplasty is classified as a clean surgery in which the development of complications is accompanied by a high risk of harm to the patient's health and life. The choice of drugs for perioperative antibiotic prophylaxis (PAP) must be based on their activity against the most likely causative agents of surgical site infection for a specific procedure; cefazolin** or cefuroxime** are most commonly used [119].

In cases of a high risk of infectious complications (immunocompromised patient, history of infections, antibiotic use within 2 months prior to surgery, etc.), it is advisable to consult the patient with a clinical pharmacologist, if available in the medical institution. It is also possible to use antiseptics and disinfectants after surgery, such as dressings with silver ions (sterile alginate wound dressing) [214].

• Adult patients are recommended to receive adequate analgesia during and after knee surgery, taking into account the patient's individual tolerability [115, 215].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

• For adequate analgesia, adult patients are recommended to use multimodal analgesia with a combination of drugs having different mechanisms of action, or monomodality if the former cannot be prescribed [115, 215].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence – 5).

Comments: Multimodal analgesia, defined as the use of various analgesics and methods targeting different mechanisms of action in the peripheral and/or central nervous system, may provide additive or synergistic effects and more effective pain relief compared to monomodal methods. For example, clinicians may offer local anesthesia based on local anesthetics (ropivacaine**, bupivacaine** (in patients older than 12 years), lidocaine**, etc.) combined with opioids and NSAIDs as part of a multimodal approach to perioperative pain. Various multimodal combinations and regimens are possible for each specific situation, depending on the scope of the specific surgery and the patient's individual characteristics [115].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

This section presents the principles and approaches to medical rehabilitation of patients with gonarthrosis who have undergone surgical treatment. Corresponding rehabilitation approaches for relevant patients receiving conservative treatment are presented in these clinical guidelines in Section 3.1.1 – Non-pharmacological therapy.

The goal of rehabilitation for patients both after organ-sparing surgeries and after knee arthroplasty is full functional, social, domestic, and occupational recovery. Rehabilitation includes medical rehabilitation, or restorative treatment; social rehabilitation aimed at social and domestic adaptation; and occupational rehabilitation, which consists of vocational orientation, vocational education, and vocational-production adaptation [120].

Patient rehabilitation is based on well-known principles: early initiation once the patient achieves an adequate level of analgesia through the multimodal use of both various pharmacological agents and non-pharmacological methods, continuity, consistency, comprehensiveness, and an individualized approach to therapeutic measures [115, 121].

Comments: Thoracic and diaphragmatic breathing exercises and exercise therapy are prescribed starting on days 1–2 (isometric exercises, movements in the joints of the upper extremities and the healthy leg); starting from day 1 under the guidance of an exercise therapy instructor, the patient is taught to sit up in bed using their hands and an overbed frame; getting up and walking without weight-bearing on the operated limb with additional support from crutches is permitted a few hours after surgery. After drain removal, walking with additional support from crutches and partial weight-bearing on the operated limb is advisable. During the same timeframe, treatment with an ultra-high-frequency electric field (UHF therapy) or ultraviolet irradiation of the wound, and electrical muscle stimulation of the healthy leg (5 sessions) may be prescribed, and after suture removal, also of the operated leg.

• Rehabilitation measures for adult patients are recommended to begin in the hospital immediately after surgery and continue throughout the entire hospitalization (first stage of rehabilitation). After discharge from the hospital, if necessary, continue restorative treatment (if possible) in rehabilitation departments (second stage of rehabilitation), and finish in day hospital medical rehabilitation departments, sanatoriums, out-patient medical organizations, or at home (third stage of rehabilitation) [56, 115].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence – 5).

Comments: The entire course of postoperative restorative treatment consists of 2 periods (early and late postoperative periods), which are subdivided into 5 motor regimes: 1) sparing regimen from days 1–2 to days 5–7 (acute postoperative reactive inflammation), 2) tonic regimen from days 5–7 to day 15 (healing of the postoperative wound), 3) early recovery regimen from day 15 to 6–8 weeks (dominance of resorption processes in destroyed bone structures), 4) late recovery regimen from 6–8 to 10 weeks (dominance of bone tissue regeneration processes), 5) adaptation regimen from 10–12 weeks to 12 months (bone tissue remodeling).

• Medical rehabilitation for adult patients planning or having received surgical treatment for gonarthrosis, especially elderly and senile patients, is recommended to begin in the preoperative period for early mobilization in the postoperative period [56, 57, 58, 59, 60, 61, 62, 120, 121].

Leveled Grade BLevel of Evidence 2Level of recommendation evidence B (level of data reliability – 2)

Comments: Preoperative period: electrical muscle stimulation (EMS) of the gluteal muscles, muscles of both thighs, and lower legs; medical massage of both lower extremities; exercise therapy for joint diseases and injuries (isometric exercises).

Early postoperative period (up to 15 days after surgery): thoracic and diaphragmatic breathing exercises; physical therapy (ultra-high-frequency electric field (UHF therapy) or UV irradiation of the wound, EMS of the healthy leg (N 5), and after suture removal – of the operated leg, massage starting from 2–3 weeks after surgery); exercise therapy starting from days 1–2 (isometric movements, movements in the upper extremity joints and the healthy leg); starting from day 1 under the guidance of an exercise therapy instructor, the patient is taught to sit up in bed using their hands and an overbed frame; getting up and walking without weight-bearing on the operated limb with additional support from crutches is permitted a few hours after surgery. After drain removal, walking with additional support from crutches and partial weight-bearing on the operated limb is advisable.

Late postoperative period (from the third week after surgery): partial weight-bearing on the leg is permitted (walking stairs with crutches), using a cane for 3–4 weeks; exercise therapy (ET) and physical therapy: electrophoresis of analgesics.

• Adult patients may be recommended to use physical therapy as part of rehabilitation in the postoperative period in the absence of contraindications for a specific category of patients [56, 57, 58, 59, 60, 61, 62, 151].

GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).

Comments: The tasks of physical therapy in the early period involve the application of physical factors to achieve analgesic, anti-inflammatory, anti-edematous, and reparative-regenerative effects in the affected tissues of the operated limb. For this purpose, if clinically necessary, a wide range of modern physical therapy methods can be used, taking into account the patient's comorbidity factors.

5. Prevention and Dispensary Observation

Preventive measures for gonarthrosis development include the elimination of modifiable risk factors (overweight, muscle weakness) and the avoidance of potential injuries or chronic microtrauma to the knee joint.

• For adult patients, it is recommended to carry out follow-up dispensary observation on an outpatient basis 2–3 months after the start of treatment (clinical examination) and then annually (follow-up examination and radiography or magnetic resonance imaging (MRI) of the joints (one joint)). Subsequently, as deemed necessary by the physician or the patient based on existing symptoms. After organ-sparing surgeries, serial MRI may be used to monitor the progression of the pathological process, and after joint replacement, radiography at 6 and 12 months, and then once every five years [1].

GРR CLeE 5Level of Recommendations Reliability C (Level of Evidence Evidence – 5).

6. Organization of Medical Care

Indications for hospitalization in a medical organization:

1. Patients with knee joint pathology

   • severe pain syndrome or intensification of pain during treatment;

   • change in the character of pain syndrome in the joint(s) during ongoing therapy;

   • synovitis or recurrent synovitis;

   • marked functional impairment affecting the patient's motor activity.

Indications for patient discharge from a medical organization:

1. achieved clinically significant improvement in the treatment of knee joint diseases

Type of care

Diagnostic and therapeutic measures for patients with primary gonarthrosis are elective in nature.

Conditions for the provision of medical services

Diagnostic procedures at the stage of establishing a diagnosis may be carried out in an outpatient setting. Rehabilitation measures may be carried out in a day hospital setting and on an outpatient basis.

7. Additional Information

• After knee joint replacement, patients are not recommended to perform heavy physical labor or excessive sports activities involving running, jumping, lifting, and carrying heavy loads, as this may shorten the lifespan of the endoprosthesis components and lead to the need for revision arthroplasty.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. L.I. Alekseeva, MD, PhD, Head of the Department of Metabolic Bone and Joint Diseases, Nasonov Research Institute of Rheumatology, Professor at the Department of Rheumatology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health

2. N.G. Badalov, MD, PhD, Chief Researcher, Federal Research and Clinical Center of Medical Rehabilitation and Balneology of the FMBA, Professor at the Department of Rehabilitation Medicine, Balneology and Physiotherapy, Sechenov First Moscow State Medical University of the Russian Ministry of Health

3. R.A. Bodrova, MD, PhD, Head of the Department of Rehabilitology and Sports Medicine, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health

4. S.V. Bozhkova, MD, PhD, Head of the Scientific Department of Prevention and Treatment of Wound Infection and Department of Clinical Pharmacology, Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health

5. T.V. Buylova, MD, PhD, Director of the Institute of Rehabilitation and Human Health, Lobachevsky National Research State University of Nizhny Novgorod

6. A.E. Karateev, MD, PhD, Head of the Department of Inflammatory Joint Diseases, Nasonov Research Institute of Rheumatology

7. V.M. Kenis, MD, PhD, Deputy Director for Innovative Development and Regional Collaboration, Turner National Medical Research Center for Children's Orthopedics and Trauma of the Russian Ministry of Health

8. N.N. Kornilov, MD, PhD, Professor at the Department of Traumatology and Orthopedics, Head of Traumatology and Orthopedics Department No. 17, Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health

9. A.Yu. Kochish, MD, PhD, Professor, Deputy Director for Research and Education, Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health

10. T.A. Kulyaba, MD, PhD, Head of the Scientific Department of Knee Pathology, Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health

11. A.M. Lila, MD, PhD, Professor, Corresponding Member of the RAS, Director of Nasonov Research Institute of Rheumatology, Head of the Department of Rheumatology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health

12. A.I. Petukhov, MD, PhD, Head of Traumatology and Orthopedics Department No. 10, Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health

13. A.V. Saraev, MD, PhD, Researcher at the Department of Knee Pathology, Orthopedic Surgeon at Traumatology and Orthopedics Department No. 17, Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health

14. R.M. Tikhilov, MD, PhD, Professor, Corresponding Member of the RAS, Director of Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health

Conflict of interest none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Trauma and orthopedic surgeons

2. Healthcare facility administrators

3. Lawyers

4. Patients

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

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 were developed taking into account the following regulatory legal documents:

1. The procedure for providing medical care in the profile of "traumatology and orthopedics" was approved by Order of the Ministry of Health of the Russian Federation No. 901n of November 12, 2012.

2. Order on Approval of Quality Assessment Criteria for Medical Care No. 203n of May 10, 2017

To assess the stages of knee joint involvement, it is advisable to use the classifications by N.S. Kosinskaya or Kellgren & Lawrence.

Kosinskaya Classification

Stage I – radiography reveals a slight narrowing of the joint space compared to the healthy joint and mild subchondral osteosclerosis. Clinically, the disease manifests as pain occurring after or during walking, especially when going down and up stairs, which subsides at rest; sometimes pain may appear after prolonged standing, and joint movements are generally not restricted;

Stage II – the narrowing of the radiographic joint space is 2–3 times the normal value, subchondral sclerosis becomes more pronounced, and bony outgrowths (osteophytes) appear at the margins of the joint space and/or in the area of the intercondylar eminence. Clinically—moderate pain syndrome, development of restricted joint movement, muscle hypotrophy, limp, and mild frontal deformity of the limb axis;

Stage III – the clinical picture is characterized by persistent flexion-extension contractures, severe pain and limping, moderate to marked valgus or varus limb deformity, joint instability, and atrophy of the thigh and leg muscles. Radiography reveals significant deformation and sclerosis of the articular surfaces of the epiphyses with zones of subchondral necrosis and local osteoporosis, the joint space is almost completely absent, and extensive bony outgrowths and loose joint bodies are detected.

Kellgren & Lawrence Classification

0 – no changes

I – doubtful: minute osteophytes;

II – minimal: definite osteophytes;

III – moderate: definite joint space narrowing;

IV – severe: marked joint space narrowing with subchondral sclerosis.

Key (interpretation): Corresponds to the content.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Rehabilitation exercises: the patient must follow the doctor's prescriptions, adhere to the basic principles of postoperative rehabilitation, and follow recommendations in the long-term period after surgical treatment:

• walk with crutch support for 2–12 weeks;

• on days 12–14, visit the local outpatient clinic for suture removal;

• after suture removal, undergo a rehabilitation course (exercise therapy, massage, exercise machines, swimming pool, etc.);

• perform follow-up radiography of the joint 3 months after surgery to determine the further weight-bearing regimen for the limb;

• subsequently, avoid heavy impact and static loads on the joint;

• undergo courses of conservative rehabilitation treatment.

Knee arthroplasty is a reconstructive surgical procedure involving the replacement of damaged femoral and tibial surfaces (and in some cases the patella) with artificial ones to reduce pain intensity, restore range of motion in the knee joint, and restore lower limb weight-bearing capacity.

The advantages of knee arthroplasty over other types of surgical treatment include rapid patient mobilization, early weight-bearing on the operated limb and restoration of joint motion, as well as predictable positive long-term outcomes. The survival rate of modern knee arthroplasty models is 90–95% at 10 years, over 80–90% at 15 years, and 75–80% at 20 years postoperatively.

Unfortunately, many patients with knee joint diseases unnecessarily delay this type of treatment due to fear of surgery and lack of information. They have to endure daily pain, limit their active lives, and experience emotional suffering. Joint replacement surgery is a real opportunity to restore lost limb function and stop feeling constant pain in the joint.

Knee arthroplasty is performed under spinal or general anesthesia (endotracheal anesthesia). Spinal anesthesia is optimal and well-tolerated. It is used in somatically healthy patients and patients with mild to moderate concomitant diseases. If there are contraindications to spinal anesthesia, most commonly in patients suffering from severe concomitant diseases, general anesthesia (endotracheal anesthesia) is used. Modern medications used during anesthesia minimize the risk of complications and smooth out unpleasant sensations during the operation and upon emergence from anesthesia. The duration of the operation ranges from 1 to 2 hours (sometimes longer) and is determined by the severity of pathological changes in the knee joint.

Postoperative period. After the operation, you will be taken to the intensive care unit, where you will stay until the evening of the current day or the morning of the next day. There, anesthesiologists-reanimatologists and nurses will monitor your body's condition, performing necessary therapeutic measures: administration of painkillers, blood and blood substitute transfusions if necessary, and so on. In the presence of severe postoperative anemia, replenishment of blood loss without transfusion of blood components is impossible!

During the operation, surgeons restore movement in the knee joint, but after the operation, pain may limit flexion and extension. Your main task in the postoperative period is to control the pain syndrome by taking prescribed medications in a timely manner and, with the help of special exercises (see below) and recommendations given by the attending physician and exercise therapy doctor, to achieve full flexion and extension in the operated knee joint.

On the first day after the operation, bed rest is usually recommended. Movements of the operated limb are permissible in full. If your general condition is satisfactory, you can sit up in bed, dangle your legs, and get up with additional support on crutches. Before sleep and as needed, you will be given analgesics, sleeping pills, and sedatives. You will be examined by an exercise therapy doctor. Based on the specifics of the surgical intervention, they will select an individual postoperative rehabilitation program. You will be taught each exercise prescribed by the exercise therapy doctor by an exercise therapy instructor. They will work with you once a day throughout the entire postoperative period; the rest of the time during the day, you must exercise independently. You must move around the ward and department using crutches.

Rehabilitation exercises

Follow these simple rules: movements in the operated joint must be smooth and uniform, and the range of motion should increase gradually.

1. Exercises to strengthen the muscles of the lower limb.

   1. Tighten your thigh muscles by straightening the lower limb at the knee joint. Hold it in this state for 5 - 10 seconds. Repeat this exercise 10 times, rest, and repeat the exercise until the thigh muscles feel fatigued.

   2. Straight leg raise. Lying on the bed, tighten your thigh muscles, completely straighten the lower limb, and lift your leg a few centimeters above the bed. Hold it in this position for 5 - 10 seconds. Lower it carefully. Repeat this exercise 10 times, rest, and repeat the exercise until the thigh muscles feel fatigued. This exercise can be done from a lying or sitting position.

   3. Rhythmically raise and lower your foot, tensing your calf muscles. Perform this exercise for 2 - 3 minutes 2 - 3 times an hour.

2. Exercise for extending the lower limb at the knee joint.

   Roll up a towel and place it under your heel so that it does not touch the bed. Tightening your thigh muscles, try to completely straighten your lower leg and touch the bed with the back surface of your knee joint. Repeat this exercise until your thigh muscles feel fatigued.

3. Exercises for knee flexion.

   1. Supine flexion with support. Flex the lower limb at the knee joint as much as possible. The foot should slide along the bed. Hold the lower limb in the flexed position for 5 - 10 seconds, then straighten it. Repeat this exercise several times.

   2. Seated flexion with support. Sit on the edge of the bed or on a chair (the thigh must be supported). Place the foot of the healthy leg under the heel of the operated lower limb. Bend the lower limb in the operated knee joint as slowly as possible. Hold the lower limb in the flexed position for 5 - 10 seconds. Repeat this exercise until fatigue sets in.

   3. Seated flexion without support. Sit on the edge of the bed or on a chair, the thigh must be supported. Bend the lower limb in ڤ the operated knee joint as slowly as possible. Hold the lower limb in the flexed position for 5 - 10 seconds. Repeat this exercise until fatigue sets in.

4. Walking. Walking on a flat surface and stairs is an exercise to develop strength and endurance. Soon after the operation, you will start moving around the ward. Early activity will promote your rapid recovery and help restore muscle strength and range of motion in the knee joint.

   1. Using a walker. Walkers help maintain balance. Initially, when walking, you should try to put as little body weight as possible on the operated lower limb.

      Rules for moving with a walker

      Stage 1. Lift and place the walker 10 - 15 cm in front of you with both hands. Make sure all four legs of the walker are firmly supported on the floor.

      Stage 2. Lean on the walker and shift most of your body weight onto it.

      Stage 3. Step forward with the operated lower limb (inside the walker). Make sure that your foot does not catch on the leg of the walker.

      Stage 4. Grasping the walker firmly with both hands, take a step forward (inside the walker) with the unoperated lower limb.

   2. Using crutches. When the muscles of the knee joint and lower limb are strong enough, crutches can be used instead of a walker.

      1. Walking on a flat surface using crutches:

         Stage 1. Grasp the handles of the crutches firmly. The main weight must be supported by your hands, not your armpits.

         Stage 2. Move the operated leg and both crutches forward simultaneously.

         Stage 3. Move the unoperated leg forward.

      2. Going down stairs using crutches:

         Stage 1. Place the crutches and the operated leg on the lower step.

         Stage 2. Maintaining balance with the crutches, lower the unoperated leg onto the step.

      3. Going up stairs using crutches:

         Stage 1. Place the crutches vertically on the floor and lean on them securely.

         Stage 2. Lift the unoperated leg and place it on the step.

         Stage 3. Leaning forward on the crutches, step up to the step where the unoperated leg is standing.

         Body weight should be distributed between the crutches and the unoperated leg. Always start moving up with the healthy leg and down with the operated leg. Remember: up with the healthy, down with the sick.

   3. Moving with a single crutch. When you can walk and stand for more than 10 minutes (usually patients achieve this 2 - 4 weeks after surgery), it is advisable to switch to walking with a cane or a single crutch. Always hold the cane in the hand opposite to the operated leg. When going up or down stairs, always use additional support on the handrail. Always start moving up with the healthy leg and down with the operated leg. Remember: up with the healthy, down with the sick.

After discharge from the hospital:

Physical therapy (PT). Objective: to strengthen the thigh and calf muscles of the operated limb; to increase the range of motion in the operated joint, preventing stiffness and contractures; to reduce body weight; to decrease pain in the operated knee joint.

Independently at home, continue to perform the set of exercises taught to you by the physical therapy doctor daily. In an outpatient clinic, sanatorium, or rehabilitation center, modern rehabilitation methods (mechanotherapy, massage, and physiotherapy) will be added to the standard exercise routine.

Mechanotherapy involves the use of devices for passive joint mobilization. Flexion and extension in the knee joint occur without the patient's active participation. Mechanotherapy is used to increase the range of motion, develop muscle strength, improve tissue trophism, coordinate movements, and form a correct motor stereotype. Training on mechanotherapy devices is carried out by selecting the angle of flexion and extension, the force, and the frequency of exposure.

Shower and bathing: For the first six weeks after surgery, it is preferable to take a warm shower.

1. Taking a shower while standing. In the shower stall: when entering the shower, put the healthy leg in first, followed by the sore leg. When exiting the shower, follow the reverse sequence: take the sore leg out first, then the healthy one.

2. Taking a shower while sitting. When entering the shower, sit down on the edge of the bath, holding onto it firmly with your hands. Transfer your legs into the bath one by one, shifting all your weight onto your arms. Then smoothly lower yourself into the bath, bending the healthy leg at the knee joint while keeping the operated leg straight. In some cases, a low bench may be needed. When exiting the shower, lean your body forward, press both hands against the edges of the bath, and bend the healthy leg at the knee joint (with the operated leg straightened). Simultaneously straightening your arms and the healthy leg, rise and sit on the edge of the bath. Transfer your legs out of the bath one by one, shifting all your weight onto your arms.

Technique for getting into a car: 1. Sit on the front seat after tilting the backrest and pushing the seat back as far as possible to provide maximum space for the affected leg. 2. Place a pillow on the seat to make it higher. 3. To facilitate movement during boarding and inside the car, place a smooth, slippery fabric on the seat to reduce friction against the seat upholstery. 4. First, the patient sits on the seat, holding firmly onto the car frame. 5. The affected leg remains straight while the healthy leg is moved into the interior. 6. Assistance may be needed to move the affected leg.

Technique for getting out of a car. 1. With your legs bent at a right angle (90 degrees), move both legs outward simultaneously. 2. With your feet supported, hold onto the edges of the car door frame and stand up. 3. Then ask for your crutches to be handed to you.

1. Wear special stockings (compression knitwear) for 4 to 12 weeks after surgery to provide a toning effect and reduce the risk of thromboembolic complications.

2. During the first year, skin temperature in the area of the operated joint may be elevated, and there may be swelling and mild tenderness.

3. If there is an unexplained fever, increased pain, and increased swelling in the operated knee joint, or discharge in the area of the postoperative scar against a background of overall well-being, you must immediately consult your attending physician.

4. Continue to perform the exercises described above independently every day.

5. Use additional support such as crutches or a cane until the weight-bearing capacity of the operated lower extremity is fully restored.

6. Follow these rules to maximize the lifespan of the endoprosthesis: avoid lifting heavy objects and prolonged stair climbing; do not gain excess weight, but strive to normalize it; avoid sports that place high stress on the joint, such as running, jumping, weightlifting, and sports aerobics.

7. The operated joint after arthroplasty is more susceptible to infection than a healthy one. In case of any colds or infections accompanied by a fever above 38 degrees, before visiting a dentist or undergoing surgical procedures, systemic antibacterial drugs in average therapeutic doses must be taken as a prophylactic measure.

In conclusion, we would like to emphasize that without your active participation, it is impossible to achieve a surgical result that would satisfy both you and your attending physician. Remember that while you are in the hospital, the department staff will create conditions for your comfortable rehabilitation treatment and provide all necessary assistance. We urge you to make maximum efforts in the postoperative period to restore the range of motion in the knee joint and normal function of the lower extremity.

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

Assessment scales, questionnaires, and other patient status evaluation tools are absent.