Sarcoidosis: Clinical Guidelines

List of Abbreviations

BAL – bronchoalveolar lavage

VATS – video-assisted thoracoscopic surgery

TB LN – intrathoracic lymph nodes

RF – respiratory failure

ILD – interstitial lung diseases

CT – computed tomography

PH – pulmonary hypertension

LU – lymph node

MTX – methotrexate**

TLC – total lung capacity

FEV₁ – forced expiratory volume in 1 sec

TST – intradermal test with recombinant tuberculosis allergen

RCTs – Randomized Controlled Trials

RPS – Russian Phthisiatricians Society

RRS – Russian Respiratory Society

SCS – Systemic corticosteroids

RS – respiratory sarcoidosis

TBLB – transbronchial needle and surgical lung biopsy

PFT – pulmonary function testing

FVC – forced vital capacity

6MWT – 6-minute walk test

DL_CO – diffusing capacity of the lungs for carbon monoxide

FAS – Fatigue Assessment Scale

IGRA (Interferon-Gamma Release Assays) – in vitro immunological tests

mMRC – modified Medical Research Council dyspnea scale

WASOG – World Association for Sarcoidosis and Other Granulomatous Disorders

Terms and Definitions

Granuloma – a focus of productive inflammation in the form of a dense nodule, an accumulation of inflammatory cells: mononuclear cells (monoblasts, promonocytes, monocytes, resident macrophages), some of which show incomplete phagocytosis, T-helper cells, cytotoxic T-suppressor cells, in a delayed-type hypersensitivity reaction.

Sarcoid granuloma – (g. sarcoideum) occurring in lymph nodes and internal organs in sarcoidosis; consists predominantly of epithelioid cells mixed with lymphoid cells, Pirogov-Langhans giant multinucleated cells, and foreign body giant cells. Necrotic and non-necrotic granulomas are distinguished. A non-necrotic granuloma may consist of histiocytes, epithelioid cells, Pirogov-Langhans cells, and foreign bodies. In a necrotic granuloma in sarcoidosis, there is a small fibrinoid necrosis in the center, surrounded by the same cellular composition.

Sarcoid granuloma typically has a punched-out appearance.

Löfgren's syndrome – a variant of acute sarcoidosis presenting with intrathoracic lymphadenopathy, erythema nodosum, joint syndrome, and fever.

Heerfordt-Waldenström syndrome – a variant of acute sarcoidosis presenting with uveitis, parotitis, fever, and in some cases accompanied by facial nerve palsy (Bell's palsy).

Sarcoid-like reaction – the formation in various organs and tissues of localized groups of epithelioid-cell non-caseating granulomas of the sarcoid type in response to exogenous factors of various origins (e.g., implants, tattoos, fillers), the use of interferons, as well as perifocally in malignant tumors and parasitic diseases. It differs from sarcoidosis by the presence of only local changes without involvement of other organs and systems.

Pulmonary hypertension – a clinical syndrome characterized by an elevation of mean pulmonary arterial pressure ≥25 mm Hg at rest, measured by transvenous cardiac catheterization.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Sarcoidosis is a systemic inflammatory disease of unknown etiology characterized by the formation of non-caseating granulomas, multisystem involvement of various organs, and T-cell activation at the site of granulomatous inflammation with the release of various chemokines and cytokines [1,2].

International definition: Sarcoidosis is a multisystem disorder of unknown origin that typically affects young and middle-aged adults and frequently presents with bilateral hilar lymphadenopathy, pulmonary infiltration, and ocular and skin lesions. The liver, spleen, lymph nodes, salivary glands, heart, nervous system, muscles, bones, and other organs may also be involved. Frequently observed immunological features include depressed cutaneous delayed-type hypersensitivity and an enhanced Th1 immune response at disease sites. Circulating immune complexes and evidence of B-cell hyperactivity may also be detected [3,4].

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

Risk factors and potential etiological factors

Environmental exposure acting on a genetically predisposed organism plays a decisive role in the development of the disease [1; 4; 5]. Genome-wide association studies have identified hereditary factors influencing the likelihood of developing sarcoidosis and the variety of its clinical manifestations. Candidate genes for single nucleotide polymorphisms of host susceptibility to the development of sarcoidosis have been identified. An increased risk of sarcoidosis is associated with single nucleotide polymorphisms in genes with various functions, such as genes encoding major histocompatibility complex class I and II molecules, IL1A, IL12B, IL18, BTNL2, CCDC88B, CCR2, CCR5, MST1, MST1R, IFN-γ, XAF1, SLC11A2, or TNFα, as well as ANXA11, BAG2, RAB23, BEND6, CFTR, FAM117B, KCNK4, KIAA1586, NOTCH4, OS9, PRDX5, RAGE, RAS23, SCGB1A1, VEGFA, and ZNF415. Alleles of HLA (-DRB1, -DPB2, and -DQA2), ZNF184, ADCY3, and LRR16A are associated with specific clinical manifestations of sarcoidosis. In Löfgren's syndrome, mutations in the CC10, MMP9, and FCGR3A genes are identified. The severity of sarcoidosis may depend on mutations in Fas genes. Single nucleotide polymorphisms of NOD2 receptor genes have been identified in early-onset pediatric sarcoidosis [1, 4, 6, 7, 8].

Probable external factors (triggers) for the development of sarcoidosis include the presence of certain bacteria: altered forms of Mycobacterium tuberculosis (revertants) that do not cause tuberculosis, propionibacteria (Propionibacterium acnes, Propionibacterium granulosum), and the Lyme disease agent Borrelia burgdorferi. Other pathogens are currently being investigated [9-12].

A factor in the development of a sarcoid reaction or sarcoidosis is the use of interferons and interferonogenesis inducers. Interferons are immunomodulators used in hepatitis C, multiple sclerosis, and oncological diseases, and in Russia for the treatment of colds and viral diseases, including herpes infections. The use of targeted biologic therapy may be accompanied by the development of sarcoid granulomas [13, 14, 15].

Many observations indicate that the onset of sarcoidosis was preceded by stressful life events (death of a loved one, divorce, work problems, etc.) [16,17].

Pathogenesis

Formation of epithelioid-cell non-caseating granulomas

Both innate and adaptive immunity factors are involved in the pathogenesis of sarcoidosis. These include innate immunity receptors—NOD-like and Toll-like receptors—as well as cellular factors such as dendritic cells and macrophages. The main effector cells of adaptive immunity in the pathogenesis of sarcoidosis are Th1 and Th17 lymphocytes, regulatory T cells (Treg), and B lymphocytes. Sarcoidosis is a polygenic, multifactorial disease in which genetic predisposition to hypersensitivity reactions of the immune system to unknown etiological factors plays an important role. Sarcoidosis is characterized by a combination of hyperactivation of T-cell immune responses at inflammatory sites with marked peripheral anergic suppression [18, 19, 20, 21].

A hallmark of active sarcoidosis is the predominant expression of interferon-gamma in affected organs due to Th1 polarization of T helpers with the participation of IL-12 from antigen-presenting cells. Hyperactive immune reactions at inflammation sites persist even after the potential antigen/trigger has disappeared. A decrease in sarcoidosis activity is usually combined with a reduction in the severity of alveolitis. Sarcoidosis is characterized by the formation of compact, non-caseating epithelioid-cell granulomas, which are sterile and located predominantly along lymphatic drainage pathways in lung tissue [22]. Clinical research findings regarding the etiology and pathogenesis of sarcoidosis have recently been confirmed in model experiments as well [23]. Heat shock proteins are involved in the pathogenesis of sarcoidosis and can trigger sarcoid granuloma formation in response to both infectious and non-infectious factors in genetically predisposed individuals [24]. Oxidative stress may also play a certain role in this chain of events as a potential therapeutic target [25]. The role of oxidative stress has also been demonstrated in cardiac sarcoidosis [27].

In addition, activated macrophages and granuloma cells can produce 1,25-(OH)2-D3 (calcitriol), leading to hypercalcemia in (2–10% of patients) or hypercalciuria in (6–30% of cases) and, consequently, nephrolithiasis and renal failure [2, 19]. Paradoxically, blood levels of vitamins D and D3 are decreased in many patients.

Impairment of organ and system functions

The pathogenesis of pulmonary function impairment in sarcoidosis involves various mechanisms. Bronchoobstructive syndrome and increased airway aerodynamic resistance may result from the thickening of bronchial and bronchiolar walls or their compression by enlarged lymph nodes [28, 29, 30]. When bronchoobstructive syndrome is detected, comorbid conditions such as COPD and bronchial asthma should be ruled out. Restrictive changes in sarcoidosis can be driven not only by pulmonary fibrosis and "honeycomb lung", but also at the stage of granuloma formation with the development of "sarcoid alveolitis". A reliable correlation has been established between forced vital capacity (FVC) values and the severity of pathological changes according to open biopsy data (pneumonitis, fibrosis) [31]. The localization of granulomas in the myocardium, less commonly in the peri-, epi-, and endocardium, interventricular septum, and papillary muscles, leads to cardiac arrhythmias and conduction blocks, decreased myocardial contractility, and sudden cardiac death [32]. Granuloma localization in the brain, meninges, and medulla oblongata leads to a wide spectrum of neurological disorders—ranging from mild to severe—that result in patient disability [33, 34].

Pulmonary hypertension

The pathogenesis of pulmonary hypertension in sarcoidosis is associated with granulomatous infiltration of pulmonary vessels, including capillaries and veins (leading to the development of occlusive venopathy), or with hypersensitivity to vasoactive substances and compression of the pulmonary artery by enlarged mediastinal lymph nodes. In the terminal stage of sarcoidosis, pulmonary hypertension is associated with hypoxic vasoconstriction and vascular bed reduction due to fibrotic changes [35, 36].

1.3 Epidemiology of the Disease or Condition

Sarcoidosis occurs worldwide and affects both sexes, all races, and all ages. According to data from Moscow for 2012, the male-to-female ratio was 1:2.8, the mean age of men was 42 years, and that of women was 53 years. The prevalence of sarcoidosis was 2.85 per 100,000 population, ranging from 8.2 to 1.8 per 100,000 population across the administrative districts of the capital. Among men, the highest prevalence rate was 9.0 per 100,000 male population, and among women, 7.8 per 100,000 female population [37]. Between 1998 and 2008, the incidence and prevalence of respiratory sarcoidosis in Saint Petersburg varied from 2.6 to 3.9 and from 16.5 to 25.1 per 100,000 population, respectively. Sarcoidosis was predominantly diagnosed in young and middle-aged women (66%). Löfgren's syndrome was observed in 22.0% of patients [38]. In Omsk, between 2003 and 2011, there were 295 patients with sarcoidosis, all with verified diagnoses; the prevalence was 24.6 per 100,000 population, and the female-to-male ratio was 1.95. Stage I radiographic disease was diagnosed in 10.6% of patients, stage II in 75.3%, stage III in 9.3%, and stage IV in 4.8%. Classical Löfgren's syndrome (intrathoracic lymphadenopathy, erythema nodosum, arthralgia, fever) was noted in 11 (3.73%) cases [39]. In the Republic of Tatarstan in 2014, the prevalence of sarcoidosis was 51.35 per 100,000 population, and the incidence was 2.72 per 100,000 population. Women accounted for 71.1%, were significantly older than men, had a predominance of radiographic stage I, and Löfgren's syndrome occurred 3 times more frequently. Over the past 20 years, the proportion of verified sarcoidosis cases has increased from 29.2 to 58.2% [39]. In Tatarstan, from 1967 to 2023, 3,037 cases of sarcoidosis were registered, including 2,094 women (68.9%) and 943 men (31.1%). The median age was 45 [34;55] years, with a peak incidence at 36–55 years. Men were significantly younger than women. A peak in detection occurred in 2017 with 161 patients, followed by a decline during the COVID-19 pandemic and recovery in subsequent years. Radiographic stage 0 was observed in 18 patients (0.6%), stage I in 1,162 (38.3%), stage II in 1,527 (50.3%), stage III in 302 (9.0%), and stage IV in 28 (0.9%). Löfgren's syndrome was present in 387 (12.7%), and extrathoracic manifestations in 576 (19.0%). Case detection across various districts of Tatarstan correlated with population size. Biopsies were performed in 44.7% of cases overall, 47.3% before the COVID-19 pandemic, and 72.5% after [40]. The incidence of sarcoidosis in Northern Europe ranges from 7 to 19 per 100,000 per year, with the highest incidence reported in the Scandinavian countries. Data from the Swedish National Patient Register estimate the incidence at 11.5 per 100,000, while in the Danish National Patient Register, the incidence varied from 11.3 to 14.8 per 100,000 per year from 2001 to 2015. Conversely, the lowest frequencies of sarcoidosis have been reported in Asian countries; estimates from South Korea, Malaysia, Taiwan, and Japan range from 0.47 to 5 per 100,000. Incidence estimates in North America are 6.8 per 100,000 in Canada and 7.6–11 per 100,000 per year in the US. There remain numerous countries with no available information on sarcoidosis [4]. Familial sarcoidosis occurs with a mean frequency of 9.5% (ranging from 4.6% to 16.1%), with the highest frequency among the French, African Americans, Dutch, and Irish [41]. In Iceland, from 1981 to the end of 2021, 282 extended families and seven pairs of siblings with sarcoidosis were identified. Twenty-seven families had five or more affected members. The most common sarcoidosis phenotypes were pulmonary sarcoidosis (47.6%), ocular-cardiac-cutaneous and central nervous system (OCCC) sarcoidosis (21.6%), and musculoskeletal-cutaneous (MSC) sarcoidosis (20.9%) [42]. In the Republic of Tatarstan, the frequency of familial sarcoidosis cases was 3.1% [43].

1.4 Features of Coding the Disease or Condition

D50-D89 CHAPTER III. Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism.

D86 Sarcoidosis

D86.0 Pulmonary sarcoidosis

D86.1 Sarcoidosis of lymph nodes.

D86.2 Pulmonary sarcoidosis with sarcoidosis of lymph nodes

D86.3 Sarcoidosis of skin

D86.8 Sarcoidosis of other specified and combined sites

Iridocyclitis in sarcoidosis +(H22.1*)

Multiple cranial nerve palsies in sarcoidosis +(G53.2*)

Sarcoid:

arthropathy +(M14.8*)

myocarditis +(I41.8*)

myositis +(M63.3*)

D86.9 Sarcoidosis, unspecified.

In the presented ICD-11 draft, sarcoidosis belongs to the chapter:

Disorders of the immune system/Certain disorders involving the immune system

4B20.0 Pulmonary sarcoidosis

4B20.1 Lymph node sarcoidosis

4B20.2 Digestive system sarcoidosis

4B20.3 Neurosarcoidosis

4B20.4 Ocular sarcoidosis

4B20.5 Cutaneous sarcoidosis

4B20.Y Other specified sarcoidosis

4B20.Z Sarcoidosis, unspecified

1.5 Classification of the disease or condition

Classification of intrathoracic sarcoidosis based on imaging data

Computed tomography (CT) of the chest characterizes the extent and nature of pathological changes more precisely than radiography. CT findings of intrathoracic sarcoidosis supplement the radiological stage of the disease. When formulating the diagnosis, all organs and systems where signs of sarcoidosis were detected are listed. The radiological classification cannot be considered as the staging of the clinical course of sarcoidosis.

Phenotypes (clinical and pathogenetic variants) of sarcoidosis

1. By localization

a. Classic, with predominant intrathoracic (pulmonary) involvement

b. With predominant extrathoracic involvement

c. Generalized (clinically significant multi-system involvement)

2. By course characteristics

a. With acute onset (Löfgren syndrome, Heerfordt-Waldenström syndrome, etc.)

b. With initially chronic course.

c. With fibrotic progression

d. Relapse.

e. Sarcoidosis in children under 5 years of age.

f. Sarcoidosis refractory to systemic corticosteroid therapy.

Comment

Generalized sarcoidosis is defined as the involvement of 2 or more organs and systems accompanied by a clinically significant impairment of their structure and/or function. Sarcoidosis is always multi-organ, but these changes are not always clinically significant. Severity is determined by the development of organ or system failure. An acute course of sarcoidosis presenting as Löfgren syndrome does not indicate a generalized process.

Variants of the course of sarcoidosis

Course variants: spontaneous regression; regression during treatment; stabilization of the condition (spontaneous, during, or after therapy); progression; undulating course; exacerbation; relapse; fibrotic progression.

Exacerbation is a reactivation of the process within one year after completing the main course of treatment that resulted in the disappearance of activity signs or regression of the process;

Relapse is the recurrence of sarcoidosis manifestations 1 year or more after the completion of the main course of treatment that resulted in the resolution of the process, or after spontaneous regression of the process [1].

Progression is the worsening of clinical symptoms, increase in lung lesions against the background of an increase or decrease in the size and number of intrathoracic lymph nodes on CT, appearance/intensification of extrathoracic manifestations of sarcoidosis, decrease in FVC by 10% or more, decrease in DLco by 15% within 1 year, development of pulmonary hypertension, increased ACE level, hypercalciuria and/or hypercalcemia [1, 2, 4, 45, 46, 47].

The diagnosis is formulated as follows:

1. Localization (list the organs and systems whose involvement was diagnosed during the examination). If signs of intrathoracic sarcoidosis are detected on the chest X-ray, indicate the radiological stage (0-IV)

2. Potency

   Grade 0 (inactive) – asymptomatic course, no laboratory signs of inflammation;

   Grade 1 (active) – presence of clinical and laboratory signs of inflammation; in the presence of a full clinical picture, "Löfgren syndrome" or "Heerfordt-Waldenström syndrome" may be indicated instead of activity.

3. Course: stable, progressive, regressive, fluctuating, exacerbation, relapse.

4. Complications: functional impairment (indicating the affected organ) and/or persistent structural changes (fibrosis, calcification, cysts, etc.) [1, 39].

5. Confirmation of the diagnosis at the cellular or tissue level.

Examples of diagnosis formulation

Example 1:

Sarcoidosis of intrathoracic lymph nodes and lungs, stage II (ICD-10 D86.2), active, progressive course. Confirmed by VATS biopsy.

Example 2.

Generalized sarcoidosis (D86.8) with involvement of the lungs (stage III), eyes, hypercalciuria, and skin. Active, progressive. Confirmed by skin biopsy.

1.6 Clinical presentation of the disease or condition

Symptoms depend on the predominant localization of the lesion and the course variant – acute or chronic. Most often, sarcoidosis presents with a mild, chronic course of the disease. General symptoms characteristic of all forms of sarcoidosis and symptoms of specific organ and system involvement are distinguished [48, 49, 50].

The symptoms of patients with Löfgren syndrome (fever, erythema nodosum, bilateral periarthritis with predominant involvement of the ankle joints, and bilateral hilar lymphadenopathy, usually lasting no more than 2 months) and with "uveoparotid fever" – Heerfordt-Waldenström syndrome (enlargement of the parotid glands, anterior uveitis, and facial nerve palsy (Bell's palsy as an optional symptom)) are the most pronounced and dynamic [51, 52].

General symptoms characteristic of all localizations of sarcoidosis.

- Non-organ-specific manifestations such as fatigue, anxiety, depression, pain, cognitive dysfunction, and small fiber neuropathy are common in patients with sarcoidosis [41].

- Fatigue, asthenia. The frequency varies from 30% to 80% depending on age, gender, and race; it is an independent sign and may not directly correlate with granulomatous involvement of various organs. The level of fatigue can be objectified using the FAS fatigue scale (Appendix G2). It should be remembered that anemia, chronic heart failure, and vitamin D deficiency can also occur in patients with sarcoidosis, determining the presence of fatigue and asthenia; studies are necessary to exclude them [1, 4, 17].

- Fever is characteristic of the acute course of Löfgren syndrome or Heerfordt-Waldenström syndrome, but prolonged low-grade fever is also possible. The frequency of fever in sarcoidosis varies from 20% to 60%.

Symptoms of sarcoidosis characteristic of specific organ and system involvement

Pulmonary and intrathoracic lymph node sarcoidosis

- Chest pain and discomfort are not always clearly explained by the nature and extent of changes detected even on chest CT. Discomfort in the back, burning sensation in the interscapular region, heaviness in the chest, and the inability to "take a full breath" have been noted. Pain may be localized in bones, muscles, and joints without any specific characteristics.

- Dyspnea can be of pulmonary, central, metabolic, and cardiac origin. Most often it is of a mixed nature and reflects progressive mixed disorders of external respiration and a decrease in the diffusing capacity of the lungs. Obstructive disorders are most often caused by compression or deformation of the bronchi and are rarely reversible. Objective assessment of the severity of dyspnea is carried out using the modified mMRC scale (Appendix G1).

Cough in sarcoidosis is usually dry and caused by enlargement of intrathoracic lymph nodes, which is accompanied by increased pressure on the bronchial wall, or by irritation of nerve endings in the airway walls by sarcoid granulomas. In late stages, cough is a consequence of extensive interstitial changes in the lungs and relatively rarely a consequence of pleural involvement [1, 4, 40, 53].

Clinical manifestations of extrapulmonary sarcoidosis

Skin lesions in sarcoidosis occur with a frequency of 10% to 56% (in Russia, 10–15%).

Erythema nodosum is a vasculitis with a primary destructive-proliferative lesion of arterioles, capillaries, and venules. Perivascular histiocytic infiltration and signs of septal panniculitis are observed in the dermis. The septa of subcutaneous fat are thickened and infiltrated by inflammatory cells extending to the periseptal areas of fat lobules. The thickening of the septa is due to edema, hemorrhage, and neutrophil infiltration. A histopathological marker of erythema nodosum is the presence of the so-called Miescher radial granulomas – a variant of lipoid necrobiosis – which consist of well-defined nodular clusters of small histiocytes arranged radially around a central cleft. Erythema nodosum does not contain sarcoid granulomas, and biopsy of its elements has no diagnostic value. Erythema nodosum can accompany certain tumor processes, so cancer screening remains relevant in differential diagnosis.

Skin sarcoidosis occurs with a frequency of 10–30%. Specific lesions include nodules, plaques, maculopapular changes, lupus pernio, and scar sarcoidosis. Manifestations of sarcoidosis are likely in areas of skin that have previously sustained injuries where foreign bodies could have entered (scars, tattoos, etc.). Special attention should be paid to this localization of sarcoidosis (as well as to peripheral lymphadenopathy), since in this case biopsy avoids more invasive procedures. Lupus pernio manifests as indurated plaques with discoloration on the nose, cheeks, lips, and ears, and often coexists with bone cysts and pulmonary fibrosis. Other skin changes in sarcoidosis include angiolupoid of Brocq-Pautrier; subcutaneous sarcoids of Darier-Roussy; macular, lichenoid, psoriasiform sarcoids; small-nodular and large-nodular forms; rarely psoriasiform and ulcerative forms, ichthyosis, alopecia, hyper- and hypopigmented spots, and nail involvement. As a rule, chronic cutaneous sarcoid changes are not accompanied by pain or itching and do not ulcerate.

The following forms of skin sarcoidosis are distinguished: clinically typical – Besnier-Boeck skin sarcoid. Sarcoidosis can also manifest as annular, indurated plaques – granuloma annulare. The histological picture of skin sarcoidosis is characterized by the presence of well-demarcated epithelioid cell granulomas without surrounding inflammatory reaction and without caseation (fibrinoid necrosis may occur); the presence of a varying number of Pirogov-Langhans giant cells and foreign body giant cells; and unchanged or atrophic epidermis. These features are used in the differential diagnosis of skin sarcoidosis and lupus vulgaris [1, 4, 54].

Lupus pernio – a chronic recurrent lesion of the skin of the nose, cheeks, auricles, and fingers, less commonly the forehead, extremities, and buttocks, causing severe cosmetic defects. It is often a component of chronic sarcoidosis with involvement of the lungs, bones, and eyes; it does not resolve spontaneously and is often resistant to therapeutic and surgical interventions. Affected skin areas are indurated and colored red, purple, or violet. Relapses are more common in winter [1, 4, 55].

Specific cutaneous manifestations in patients with sarcoidosis include the "revived scar" phenomenon, which includes increasing hyperemia, induration, and tenderness of long-standing postoperative scars and traumatic skin scars, and may be one of the earliest signs of sarcoidosis. The formation of sarcoid granulomas is observed in tattooed skin areas, sites of gel injections, etc. [56]. The installation of breast implants can act as a trigger for the formation of a sarcoid reaction [57].

Ocular involvement in sarcoidosis is classified as a dangerous condition requiring medical attention and treatment, as it can lead to a significant decrease in vision and blindness. Decreased visual acuity and/or blurred vision may be important signs of sarcoid uveitis, which requires a mandatory ophthalmological examination and active treatment. Ocular involvement occurs in approximately 5–25% of sarcoidosis cases, of which 70–75% are anterior uveitis, 25–30% are posterior uveitis, and conjunctival, scleral, and iris involvements are less common. Uveitis is a component of Heerfordt-Waldenström syndrome. Optic nerve involvement in sarcoidosis is uncommon, but it is an indication for long-term systemic glucocorticosteroid (SGCS) therapy. In children under 5 years of age, the characteristic clinical triad consists of uveitis, skin lesions, and arthritis without pulmonary involvement [1, 4, 58].

Sarcoidosis of peripheral lymph nodes (LNs), accessible by palpation, occurs in 10–25% of cases. Most commonly, the posterior and anterior cervical, supraclavicular, epitrochlear, axillary, and inguinal lymph nodes are involved. LNs have a dense, elastic consistency, do not soften, and do not form fistulae. Abdominal lymph nodes, predominantly in the hepatic hilum, may also be involved, which is detected by lymph node ultrasound and/or computed tomography of the chest organs. The detection of epithelioid cell granulomas upon histological examination of a removed LN requires correlation with clinical presentation and other organ involvement for the differential diagnosis of sarcoidosis, sarcoid reaction, and other granulomatoses [59].

Splenic involvement in sarcoidosis (10% to 40%) presents as splenomegaly and hypersplenism (1–5% of cases), which is an enlargement of the spleen combined with an increased number of cellular elements in the bone marrow and a decrease in formed elements in the peripheral blood (erythrocytes, leukocytes, and/or platelets). Splenomegaly is detected by ultrasound of the spleen, computed tomography of the abdominal cavity and retroperitoneal space, and differential diagnosis is performed with neoplastic and infectious diseases. Focal lesions or nodules may also be present in the spleen. Splenic involvement may manifest clinically as abdominal discomfort and pain, thrombocytopenia with purpura, and agranulocytosis. CT- or ultrasound-guided fine-needle biopsy of the spleen is highly informative, but the procedure can be hazardous if the lesion is located close to the hilum or peripherally. Moderate splenomegaly does not worsen the course of sarcoidosis, whereas massive splenomegaly is a life-threatening condition, and splenectomy is performed in cases of pronounced systemic manifestations [1, 4, 60, 61].

Sarcoidosis of the hematopoietic system is rare and is confirmed by the presence of epithelioid cell granulomas in the bone marrow. One of the manifestations of non-caseating bone marrow granulomas can be fever of unknown origin combined with lymphopenia and cytopenia. Hematopoietic system involvement is most frequently detected in multi-organ sarcoidosis [1, 4].

Kidney involvement in sarcoidosis occurs in 5–30% of patients, ranging from subclinical proteinuria to severe nephrotic syndrome and renal failure; it may be caused by granuloma formation and a non-specific inflammatory process (microcirculatory disturbances, edema, vasculitis), as well as electrolyte imbalances. Granulomas in the kidneys are most frequently localized in the cortical layer. The cause of nephropathy in sarcoidosis can be calcium metabolism disorders, hypercalcemia, and hypercalciuria. Calcium nephrolithiasis is detected in 2–10% of patients with sarcoidosis [1, 4]. The most frequent variant of renal involvement in sarcoidosis is granulomatous tubulointerstitial nephritis; mesangioproliferative glomerulonephritis, membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and amyloidosis are less common [62, 63].

Musculoskeletal involvement in sarcoidosis frequently presents as joint syndrome, whereas isolated bone and muscle lesions are significantly less common. Joint syndrome is prominent in Löfgren's syndrome, but it can also be an independent syndrome [1, 4].

Joint involvement (ankle, knee, and elbow joints) in sarcoidosis is most commonly observed as part of Löfgren's syndrome, reaching 88% in the acute course of sarcoidosis. Along with arthritis, periarthritis (swelling of the soft tissues adjacent to the joint), tenosynovitis, dactylitis, bone lesions, and myopathies have been described in sarcoidosis.

Acute arthritis in sarcoidosis often resolves spontaneously without sequelae. Chronic arthritis, although less typical, can progress and cause joint deformities. Differential diagnosis is performed with rheumatoid arthritis [64].

Bone sarcoidosis (1% to 39%) most frequently manifests as asymptomatic cystic osteitis of the small bones of the hands and feet. Lytic lesions are rare, localized in the vertebral bodies, long bones, pelvic bone, and scapula, and are usually accompanied by visceral lesions. Only a bone biopsy allows for a definitive diagnosis of epithelioid cell granulomatosis. Involvement of the finger bones manifests as bone cysts of the terminal phalanges and nail dystrophy, and is a sign of chronic sarcoidosis. The scintigraphic picture is similar to multiple bone metastases of malignant tumors.

Multiple cyst-like osteitis of Jüngling (Morozov-Jüngling disease) is distinguished by its typical localization in the phalanges of the hands and feet. Bone involvement in the fingers manifests as bone cysts of the terminal phalanges and nail dystrophy, and is a sign of chronic sarcoidosis. In most cases, there are no clinical manifestations. The diagnosis of bone sarcoidosis is based on characteristic radiological signs, typical localization, and a combination with manifestations of sarcoidosis in other organs.

Skull bone involvement is rare and presents as cyst-like formations of the mandible, and extremely rarely of the cranial vault bones.

Spine involvement manifests as back pain, lytic and destructive changes in the vertebrae, and bears similarity to ankylosing spondylitis.

Muscle sarcoidosis manifests as nodule formation, granulomatous myositis, and myopathy. The diagnosis is confirmed by muscle biopsy [1, 4, 65].

Sarcoidosis of the ENT organs and oral cavity accounts for less than 1% of sarcoidosis cases. Most often, these are incidental findings. Sinonasal sarcoidosis presents with non-specific symptoms: nasal congestion, rhinorrhea, crusting on the mucosa, epistaxis, nasal pain, and olfactory disturbances. Endoscopy reveals a picture of chronic rhinosinusitis with nodules on the septum and/or nasal turbinates, with crust formation; small sarcoid nodules may be found, most frequently on the nasal septum and superior nasal turbinate. The diagnosis requires histological verification.

Tonsillar sarcoidosis may present as asymptomatic unilateral or bilateral enlargement of the palatine tonsils, in the tissue of which non-caseating granulomas were detected after tonsillectomy.

Laryngeal sarcoidosis leads to dysphonia, dysphagia, and cough. Mucosal edema and erythema, papules, and nodules are detected. The diagnosis is confirmed by biopsy. Laryngeal sarcoidosis can lead to life-threatening airway obstruction.

Ear sarcoidosis belongs to particularly rare localizations of the disease and is usually combined with other disease localizations. It manifests as hearing loss, tinnitus, deafness, and vestibular disorders. Sarcoidosis can cause sensorineural hearing loss of varying severity. Cases with middle ear involvement and conductive hearing loss have been noted [4, 66, 67].

Sarcoidosis of the oral cavity and tongue is uncommon and manifests as swelling and ulceration of the oral mucosa, tongue, lips, and gums. Oropharyngeal sarcoidosis can be the cause of obstructive sleep apnea as the sole manifestation of the disease [1, 4].

Cardiac sarcoidosis (2–18%) is a life-threatening manifestation of sarcoidosis; it is characterized by a certain autonomy, not coinciding with the phases of the process in the lungs and intrathoracic lymph nodes. Monitoring and treatment of these patients should be carried out in tertiary medical institutions or federal centers.

Complaints of discomfort in the cardiac region, palpitations, or bradycardia, and a sensation of skipped beats may be a sign of granulomatous heart disease and require an ECG, Holter heart rhythm monitoring, as well as echocardiography and contrast-enhanced cardiac magnetic resonance imaging.

According to clinical manifestations, three main syndromes are distinguished: pain (cardialgic), arrhythmic (manifestations of rhythm and conduction disturbances), and heart failure syndrome. The course variants of cardiac sarcoidosis are fulminant (sudden cardiac death, myocardial infarction-like variant, cardiogenic shock), rapidly progressive (with increasing severity of manifestations to a critical level within a maximum of 1–2 years), and slowly progressive (chronic, with relapses and improvements). The diagnosis of cardiac sarcoidosis should be based on the results of instrumental examinations and, if possible, endomyocardial biopsy. Laboratory markers specific for cardiac sarcoidosis currently do not exist. The most informative are the determination of blood troponin T level, blood N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, blood creatinine level, and blood levels of angiotensinogen, its derivatives, and angiotensin-converting enzyme [1, 4, 68, 69].

The detection rate of ECG abnormalities reliably depends on the nature of the granulomatous cardiac involvement and the development of postsarcoidosis sclerosis: 42% for the microscopic type and 77% for extensive granulomatous infiltration. To clarify the diagnosis, myocardial scintigraphy with perfusion radiopharmaceuticals (radiopharmaceuticals for diagnosing cardiovascular diseases), cardiac MRI with late gadolinium enhancement, and positron emission tomography combined with contrast-enhanced myocardial computed tomography are performed [1, 4, 70].

Nervous system involvement in sarcoidosis – neurosarcoidosis occurs in 5–10% of cases; management is recommended at tertiary-level healthcare facilities or federal centers. Neurological manifestations of sarcoidosis include not only granulomatous involvement, but also non-granulomatous disorders such as small fiber neuropathy (SFN) and headache.

Granulomatous involvement of the nervous system is clinically manifested in 5–10% of patients with sarcoidosis and can be divided into manifestations of the central nervous system (CNS; brain, spinal cord, cranial nerves) and the peripheral nervous system. In more than 50% of cases, this can be the first symptom of sarcoidosis, and in some cases, it may remain the only manifestation. Recent studies have shown that isolated neurological involvement is observed in 10–20% of cases. Neurosarcoidosis affects women more often than men.

CNS neurosarcoidosis. CNS involvement occurs due to the spread of leptomeningeal inflammation along perivascular spaces, which are the largest and most numerous at the base of the brain and provide communication between the lymphatic fluid and the parenchyma.

Cranial neuropathy. The most common manifestation of neurosarcoidosis is cranial nerve involvement, accounting for 50% of cases, most frequently affecting the facial nerve, followed by the optic nerve. While facial nerve palsy usually resolves within a few months even without treatment, optic neuropathy, especially when bilateral, can have a poorer prognosis, leaving the patient with residual visual impairment. Hearing loss (involving cranial nerve VIII) and facial pain/sensory changes (cranial nerve V) have been described.

Aseptic meningitis, manifesting as leptomeningeal and less commonly pachymeningeal inflammation, is usually accompanied by headache and cranial neuropathies, although seizures, cognitive impairment, and gait disturbances may also occur. In severe cases complicated by hydrocephalus, patients may present with a blunted level of consciousness, requiring urgent evaluation and possibly shunt placement if the patient is unresponsive to medical therapy.

Intracranial parenchymal lesions may occur with or without meningeal involvement and can manifest as headache, seizures, cognitive changes, gait disturbance, and focal sensorimotor deficits depending on the lesion location. Involvement of basal neuroendocrine structures can lead to hypothalamic-pituitary dysfunction, which is frequently permanent. Stroke is rare and can be caused by perivascular inflammation with vessel wall invasion, vasculitis (rarely), or direct granulomatous compression of an intracranial artery.

Spinal cord involvement is one of the most severe clinical manifestations of neurosarcoidosis, as it frequently leads to residual paraparesis, sensory dysesthesia, and bowel/bladder dysfunction. Patients typically present with subacute sensory changes, walking difficulties, and subjective weakness, although muscle strength is often only mildly reduced or normal.

Peripheral nervous system neurosarcoidosis, affecting muscular or large (myelinated) peripheral nerve fibers, is rare (although subclinical granulomatous muscle inflammation has been reported postmortem) and accounts for <2% of all neurological complications. Sarcomatous myopathy typically presents as progressively worsening weakness in a proximal-to-distal distribution with periodic involvement of cervical, facial, bulbar, and respiratory muscles. Less common muscular manifestations include nodular myopathy, acute myositis, and a distal predominant presentation resembling inclusion body myositis.

Non-granulomatous manifestations are poorly understood and may potentially be driven by a range of factors, including active inflammation, cytokine release, and drug side effects. SFN is a disorder of thin-myelinated Aδ and unmyelinated C fibers, which has been objectively confirmed in a third of patients with systemic sarcoidosis, although the reported symptom frequency is 40–90%. SFN frequently leads to disabling pain and/or autonomic dysfunction symptoms that interfere with daily life. Symptoms are predominantly sensory (e.g., pain, numbness, burning, paresthesias).

Headache is common in granulomatous CNS involvement of the brain parenchyma and meninges, and may also be the sole neurological symptom in patients with systemic sarcoidosis. In these cases, the clinical presentation resembles tension-type headache that is refractory to steroid treatment and is described as a severe global headache occurring daily or almost daily. In those presenting with morning headaches, the diagnosis of obstructive sleep apnea should be considered, as a higher prevalence of obstructive sleep apnea has been reported among sarcoidosis patients [1, 4, 34, 71].

Digestive system involvement.

Sarcoidosis of the salivary glands (6%) manifests as bilateral swelling of the parotid glands and occurs as part of Heerfordt-Waldenström syndrome. It should be differentiated from changes in chronic sialadenitis, tuberculosis, cat-scratch disease, actinomycosis, and Sjögren's syndrome. Esophageal sarcoidosis is an extremely rare localization. Traction diverticula develop due to granulomatous inflammation of mediastinal lymph nodes, and secondary achalasia resulting from esophageal sarcoidosis has been described. Gastric sarcoidosis presents as granulomatous gastritis, can cause ulcer formation and gastrointestinal bleeding, as well as polyp-like lesions upon gastroscopy. Histological verification is indicated. Intestinal sarcoidosis of both the small and large intestine is represented in the literature by case reports confirmed by histological examination of biopsy specimens. It may be combined with localized and massive abdominal lymphadenopathy. Differential diagnosis with tuberculous and non-tuberculous mycobacteriosis is necessary.

Hepatic sarcoidosis occurs with a frequency of 10–80% according to various sources and is frequently asymptomatic. In clinically significant involvement, laboratory signs of cholestasis syndrome, hepatomegaly, and, somewhat less commonly, cytolysis syndrome are detected. Morphological examination of liver tissue obtained by biopsy reveals granulomatous hepatitis, and in a small proportion of patients, nonspecific reactive hepatitis. Granulomas typically form in the portal tracts, central necroses are minimal, and the focal fibrosis forming in their place is insignificant and virtually never (in no more than 1% of cases) leads to liver cirrhosis. Hepatic sarcoidosis leads to cirrhosis and portal hypertension in only 1% of cases. The primary sign of liver involvement in sarcoidosis is cholestasis syndrome, often combined with hepatomegaly and relieved by glucocorticosteroids [63]. Abdominal contrast-enhanced computed tomography reveals multiple low-density focal lesions in the liver and spleen.

The pancreas is rarely affected, and the changes may resemble cancer. In two-thirds of patients with pancreatic sarcoidosis, abdominal pain is present. One of the earliest signs may be a chronically elevated lipase level. In isolated cases, diabetes mellitus may develop due to sarcoid infiltration of the pancreas [1, 4, 72].

Sarcoidosis of the endocrine system. Involvement of the hypothalamohypophyseal region occurs in 2–8% of patients with neurosarcoidosis and is accompanied by signs of neuroendocrine dysfunction. The clinical picture of hypopituitarism is determined by the degree of reduced production of follicle-stimulating and luteinizing hormones, thyroid-stimulating hormone, growth hormone, and adrenocorticotropic hormone. In addition, some patients develop hyperprolactinemia. Typically, hypothalamic disorders are accompanied by thirst, polyuria (which may indicate the onset of diabetes insipidus), impaired thermothermoregulation, appetite, and sleep, and decreased libido. Such patients may develop clinical symptoms of thyroid, adrenal, and gonadal dysfunction. Galactorrhea and amenorrhea may also occur [1, 4].

Urogenital sarcoidosis in women is extremely rare. Sarcoidosis of the urinary tract manifests as a decrease in urinary stream force. Sarcoidosis of the external genitalia is a very rare condition, manifesting as nodular lesions of the vulva and perianal skin. Uterine sarcoidosis most dangerously manifests as postmenopausal bleeding. The diagnosis is made incidentally following histological examination of material obtained by curettage or hysterectomy. Fallopian tube involvement in sarcoidosis is extremely rare and occurs in women with multiorgan disease [1, 4].

Urogenital sarcoidosis in men is extremely rare.

Sarcoidosis of the testis and epididymis resembles or may be combined with oncopathology of the same localization; a granulomatous reaction may accompany the tumor process without being a sign of sarcoidosis.

Prostatic sarcoidosis has no specific features and creates difficulties in differential diagnosis with prostate cancer, as it may be accompanied by an elevated PSA level [1, 73].

Breast sarcoidosis is detected during evaluation for suspected breast cancer. It is diagnosed via biopsy of a dense, painless breast mass based on the detection of multiple noncaseating granulomas. Differential diagnosis with tuberculosis is required [1, 4].

Sarcoidosis and pregnancy. Sarcoidosis should not be considered a condition that frequently and severely impairs a woman's reproductive function. In most cases, pregnancy can be carried to term, but the issue must be addressed individually in each case, and pregnant patients should be managed jointly by obstetrician-gynecologists and sarcoidosis specialists. The main concerns are the teratogenicity of the therapy and the degree of organ and system impairment in the mother.

For women with severe restrictive/obstructive ventilatory defects, reproductive organ sarcoidosis, or renal involvement, pregnancy planning, antenatal care, and delivery in specialized multidisciplinary facilities are advisable [1, 74].

Sarcoidosis in children and adolescents

In children and adolescents older than 4 years, in most cases the manifestations of sarcoidosis do not differ from those in adults, with a predominance of intrathoracic changes, most often in adolescents aged 13 years and older. The so-called "early-onset sarcoidosis" is distinguished in children aged 4 years and younger, in whom intrathoracic lesions are extremely rare, while the triad of arthritis, uveitis, and skin lesions dominates. This distinction is crucial in the diagnosis and differential diagnosis of sarcoidosis in the two age groups [1, 4, 75].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

The diagnosis of sarcoidosis is established based on the patient's complaints and history, the results of imaging, functional, laboratory, and morphological examination methods, and requires the exclusion of sarcoid-like reactions and diseases with manifestations similar to sarcoidosis.

The diagnosis of sarcoidosis is verified based on morphological tissue examination data by detecting non-caseating granulomas in at least one organ or tissue in a patient with characteristic clinical and radiological symptoms. However, certain clinical scenarios (Löfgren syndrome, Heerfordt syndrome, lupus pernio, and asymptomatic bilateral intrathoracic lymphadenopathy) are so specific that they allow a presumptive diagnosis of sarcoidosis without morphological tissue examination [1, 4, 76, 77].

2.1 Complaints and Anamnesis

Complaints depend on the disease course variant and the localization of the process. Complaints and history are described in the "Clinical Presentation" section.

2.2 Physical Examination

• All patients with sarcoidosis are recommended to undergo a physical examination to detect impairment of all organs and systems [1, 4].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: During the examination, attention is paid to skin changes, especially in the area of old scars and tattoos. Palpation may reveal painless, mobile, enlarged peripheral lymph nodes (most commonly supra- and infraclavicular, cervical, and inguinal, less commonly epitrochlear), as well as subcutaneous nodules – Darier-Roussy sarcoids (sometimes quite painful). Examination of the conjunctiva and iris of the eye allows suspecting uveitis and episcleritis. Upon percussion and auscultation, changes are found in approximately 20% of patients with sarcoidosis. It is important to evaluate the size of the liver and spleen. Obvious clinical signs of respiratory and cor pulmonale failure are relatively rarely detected in respiratory sarcoidosis, as a rule, when pronounced pneumosclerotic changes develop at stage IV [1, 4].

2.3 Laboratory Diagnostics

• A complete blood count (CBC) is recommended for all patients with sarcoidosis to assess the activity of the process and the white blood cell response [1, 4].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: In acute variants of sarcoidosis, it reveals an elevated ESR. Fluctuating changes in ESR or a moderate increase are observed for a long time during the chronic and asymptomatic course of the disease. Peripheral blood leukocytosis occurs in the acute and subacute courses of sarcoidosis, as well as during systemic glucocorticosteroid therapy. Signs of activity include lymphopenia and monocytosis, and an increased neutrophil-to-lymphocyte ratio (Krebs index).

Thrombocytopenia in sarcoidosis occurs with liver, spleen, and bone marrow involvement, and requires differential diagnosis with autoimmune thrombocytopenic purpura [1, 4].

• Assessment of renal function is recommended for all patients to evaluate potential renal involvement in granulomatosis and changes associated with calcium metabolism disorders during initial diagnosis and during follow-up at least once every 6 months; it includes a urinalysis, blood creatinine level determination, blood urea level determination, and calculation of the glomerular filtration rate using formulas [1, 4].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: The normal range for serum ACE activity at the age of 6-18 years is 29-112 ACE units, and over the age of 18 years is 20-70 ACE units. A clinically significant finding is an increase in serum ACE activity of more than 150% of the upper limit of normal. ACE activity should not be used as a differential diagnostic criterion, but only as a marker of sarcoidosis activity. Subsequently, it can be measured dynamically to assess activity when sarcoidosis progression is suspected. In young children, ACE levels fluctuate significantly, and this test is generally not used [1, 4].

Comments: C-reactive protein, an acute-phase inflammatory protein, has low reliability as an indicator of epithelioid-cell granulomatosis activity. The normal range is less than 5 mg/L. A moderate elevation is typical for Löfgren syndrome and other acute presentations of sarcoidosis. It is recommended in acute sarcoidosis [1,112,113,114].

• Measurement of total blood calcium and 24-hour urine calcium levels is recommended upon initial detection and during follow-up as one of the criteria for an active granulomatous process [1, 78].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: Hypercalcemia (5%) in sarcoidosis is considered a manifestation of active sarcoidosis. Hypercalciuria (25%) occurs much more frequently and is a more accurate method for detecting calcium metabolism disorders. In most patients, blood calcium is normal or may be reduced, which must be considered when prescribing glucocorticoids, which induce osteoporosis [1, 78].

• Measurement of blood immunoglobulin A, M, G levels. Immunoglobulins A, M, G are a special type of proteins produced in response to antigens that have the ability to bind to them specifically. Measurement of blood immunoglobulin levels is recommended during initial evaluation for differential diagnosis with immunodeficiency states accompanied by granuloma formation, such as CVID [79, 80, 115,116].

LeR CLoE 4Level of Recommendation C (Level of Evidence — 4)

• Intradermal tuberculin test with tuberculin allergen (PPD-L) is recommended at the initial diagnostic stage of sarcoidosis in children under 7 years of age to rule out tuberculosis [1, 4].

GCR CLEL 5Level of Grading of Recommendations  C (Level of Evidence - 5)

Comments: The intradermal test with tuberculin allergen (Mantoux test with 2 TU) in active sarcoidosis is negative in at least 80–85% of cases who have not received systemic glucocorticosteroids (SGCS). During SGCS treatment of sarcoidosis patients previously infected with Mycobacterium tuberculosis, the Mantoux test with 2 TU may become positive. Tuberculin anergy in sarcoidosis is not related to tuberculin sensitivity in the general population. Positive sensitivity to tuberculin based on the Mantoux test with 2 TU (papule of 5 mm or more) in suspected sarcoidosis requires very careful differential diagnosis and exclusion of tuberculosis in children [1, 4].

• Intradermal test with recombinant tuberculosis allergen (Diaskintest, Recombinant Tuberculosis Allergen in standard dilution**) is recommended for all patients as mandatory during the initial diagnosis of sarcoidosis to rule out active tuberculosis infection [1, 85].

GCR CLEL 5Level of Grading of Recommendations  C (Level of Evidence - 5).

Comments: Interpretation of the Diaskintest has the following values:

• negative – with the complete absence of infiltrate and hyperemia or in the presence of a "needle reaction" up to 2-3 mm (possibly in the form of a "bruise");

• doubtful – hyperemia of any size;

• positive – in the presence of an infiltrate (papule) of any size.

Note: performing the Diaskintest is not recommended if the patient is receiving immunosuppressive therapy.

• Measurement of blood interferon-gamma response to Mycobacterium tuberculosis complex antigens (QuantiFERON test and T-SPOT.TB/ELISPOT) is recommended if skin tests are refused or cannot be performed for medical reasons as an alternative to intradermal tuberculin tests [117,118,119]

GCR CLEL 4Level of Grading of Recommendations  C (Level of Evidence - 4).

Comments: In most cases, the results of the intradermal test with recombinant tuberculosis allergen and interferon-gamma release assays are negative [4]. Sarcoidosis activity does not affect the results of IGRA tests and the Diaskintest [86]. IGRA is generally preferred for screening for latent tuberculosis because patients with sarcoidosis frequently do not react to the intradermal Mantoux test [87]. If positive results are obtained for tuberculin tests and/or interferon-gamma release assays (IGRA), the patient is indicated for an in-depth evaluation by a phthisiatrician. If local tuberculosis is ruled out, the result is interpreted as latent tuberculosis infection, which must be taken into account when prescribing immunosuppressive therapy.

2.4 Instrumental Diagnostics

• Chest X-ray is recommended for all patients for initial diagnosis and staging (according to the intrathoracic sarcoidosis classification). The use of X-ray for follow-up and treatment efficacy assessment is appropriate only when CT is unavailable [1, 4, 81, 82].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: The chest X-ray of a patient with intrathoracic sarcoidosis typically reveals more or less symmetrical enlargement of the tracheobronchial and mediastinal lymph nodes and/or bilateral focal-interstitial changes in the lungs. A discrepancy between the patient's relatively satisfactory condition and the extent of the pathological process is characteristic. In rare cases, an atypical picture is possible – unilateral enlargement of intrathoracic lymph nodes (ITLN), unilateral dissemination, foci, consolidation areas, or cavities [1, 4, 47, 81].

• Computed tomography of the chest is recommended for all patients for initial diagnosis and follow-up in intrathoracic sarcoidosis [1, 4, 81, 82].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: Intrathoracic lymph node involvement. Sarcoidosis is characterized by enlargement of lymph nodes in the central mediastinum, located along the trachea and main bronchi, and the pulmonary hila. On a posteroanterior chest X-ray, this manifests as bilateral widening of the mediastinal and hilar shadows with polycyclic contours. Anterior and posterior mediastinal lymph nodes are usually not involved, which is clearly visible on lateral views. On computed tomography, the lymph nodes are spherical or ovoid, homogeneous, with smooth, distinct contours, and without perifocal infiltration or sclerosis. With intravenous contrast enhancement, the lymph nodes uniformly and moderately accumulate the contrast agent, distinguishing these changes from tuberculosis. Bronchial patency impairment due to external compression by lymph nodes is uncharacteristic for sarcoidosis. With marked lymph node enlargement leading to external bronchial compression, areas of hypoventilation and even atelectasis may very rarely appear in the lungs. In chronic long-term cases, one-third of patients develop calcifications within the lymph nodes, appearing as multiple, bilateral, monolithic, irregularly shaped calcium deposits located far from the bronchi in the center of the lymph nodes.

Lung involvement. A characteristic sign of sarcoidosis is mixed, focal, and interstitial dissemination with polymorphism of focal changes. On chest CT, multiple small foci are located along the bronchovascular bundles, interlobar fissures, costal pleura, and interlobular septa, causing their uneven ("beaded") thickening. This distribution of foci on chest CT is defined as perilymphatic. Changes classically predominate in the middle lung zones, often in the perihilar region, and are combined with thickening of the segmental bronchial walls.

One of the rare manifestations of sarcoidosis on chest CT can be areas of ground-glass opacification of varying extent and localization. Their frequency is 18–83%, and they are observed more often at diagnosis than at later stages of the disease. The morphological substrate of the ground-glass opacity sign is numerous tiny foci that cannot be resolved on CT as independent entities or, in rarer cases, true ground-glass opacity is observed as a manifestation of diffuse thickening of the interalveolar septa. Over time, changes may resolve (inflammatory granulomas), remain stable, or progress due to the development of fibrosis. In this case, reticular changes and traction bronchiectasis form within the ground-glass areas.

The development of fibrotic changes in sarcoidosis is characterized by an increase in reticular changes, the formation of soft-tissue conglomerates with visible bronchial lumens located around the upper lobe bronchi and inseparable from the anatomical structures of the root. Distinctive features of the final fibrotic stage of intrathoracic sarcoidosis are traction bronchiectasis and honeycombing in the upper lobes of the lungs, combined with distorted pulmonary angioarchitecture [1, 4, 82].

Currently, it is customary to distinguish variant patterns of sarcoidosis on chest computed tomography by subdividing them into non-fibrotic and fibrotic phenotypes. Non-fibrotic phenotypes (second and third radiological stages of the disease) include: multiple peribronchovascular, perifissural, and subpleural small nodules; bilateral areas of consolidation, usually of peribronchovascular localization, as the main (in combination with nodules) or sole feature; multiple large peribronchovascular nodules; scattered large nodules without peribronchovascular changes. Fibrotic variants of the HRCT pattern include: bronchocentric (peribronchial) distribution of reticular changes, sometimes combined with areas of consolidation, without air cavities; bronchocentric (peribronchial) distribution of reticular changes combined with areas of consolidation and the presence of air cavities within them; large bronchocentric conglomerates or pathological tissue-density formations in the root regions. All fibrotic phenotypes of respiratory sarcoidosis are combined with pulmonary angioarchitecture distortion, volume reduction (usually of the upper lobes), traction bronchiectasis in areas of altered lung tissue, and, rarely, honeycombing [82].

Cavities are rarely observed in sarcoidosis (3.4–6.8% of cases), usually indicating severe and active sarcoidosis arising either as a result of ischemic necrosis or vasculitis. Cavities are often multiple and bilateral, located in the root regions of the lungs, typically in the area of the upper lobe bronchi. In most cases, they appear as thin-walled cysts or cavities within areas of consolidation. The presence of a cavity upon imaging in a patient with sarcoidosis requires the exclusion of concomitant infection, as primary cavitary sarcoidosis is rare [1, 4, 83].

• Magnetic resonance imaging (MRI) of the heart and great vessels and/or brain MRI are recommended for patients suspected of having cardiac and central nervous system sarcoidosis in order to clarify the diagnosis [1, 4].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• Among radionuclide imaging methods for respiratory sarcoidosis with lymph node involvement in specialized centers, it is recommended to perform lung perfusion scintigraphy with gallium [⁶⁷Ga] citrate, which is important for characterizing the involvement of the pulmonary microcirculation and the function of lymph nodes, both in the localization zone of the process and in intact lung areas [1, 4, 120-124, 126-132].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

• Whole-body positron emission tomography with tumorotropic radiopharmaceuticals (18-fluorodeoxyglucose [18F]) is recommended to clarify the localization of the process. Interpretation of these data requires caution, because 18-fluorodeoxyglucose uptake in lymph nodes in sarcoidosis can mimic a malignant neoplasm, and does not allow differentiating sarcoidosis from a malignant neoplasm or infection [1; 4; 84, 159, 160].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: PET in certain cases provides additional information about the activity of the process, and in combination with anatomical imaging methods (CT, MRI) helps identify the localization of increased metabolic activity, i.e., the topography of previously established active sarcoidosis or locations for biopsy, including in cardiac sarcoidosis [1, 4, 84].

• Transesophageal mediastinal endoscopic ultrasonography and endoscopic ultrasonography of the trachea and bronchi are recommended during the initial examination of patients with changes in intrathoracic lymph nodes as an imaging method for various groups of mediastinal lymph nodes, determining their size and structural features [1, 4].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: The endoscopic sonographic picture of lymph nodes in sarcoidosis has certain distinctive features: the lymph nodes are well demarcated from each other; the node structure is isoechoic or hypoechoic with atypical blood flow, and septa and vessels are often identified in large nodes. Nevertheless, these features do not allow differentiating lymph node involvement in sarcoidosis from tuberculosis or tumor.

• Appropriate instrumental diagnostic methods are recommended for patients suspected of having generalized or extrapulmonary sarcoidosis for the purpose of diagnosing the disease: complex ultrasound examination of the abdominal cavity, brain MRI, MRI of the heart and great vessels, echocardiography, radiography of the affected limb, bone MRI, soft tissue MRI [1, 4].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: Complex ultrasound examination of the abdominal cavity helps detect splenomegaly, hepatomegaly, and multiple hypoechoic formations located in both the liver and the spleen. On abdominal computed tomography with intravenous bolus contrast enhancement, small low-density foci may be identified within the liver structure. Splenomegaly and enlargement of lymph nodes in the hepatoduodenal ligament, the porta hepatis and spleen, and peripancreatic adipose tissue may also be detected. CT changes in granulomatous diseases are nonspecific and require morphological verification.

In sarcoidosis, echocardiography reveals solitary foci in the myocardium, including the interventricular septum, measuring 3–5 mm. Cardiac foci may calcify over time. On magnetic resonance imaging of the heart and great vessels, the affected area of the heart may exhibit increased signal intensity on T2-weighted images and, following contrast administration (contrast-enhanced cardiac magnetic resonance imaging), on T1-weighted images. In rare cases on contrast-enhanced cardiac computed tomography, cardiac sarcoidosis may manifest as areas of myocardial thickening that weakly take up the contrast agent.

In neurosarcoidosis, brain MRI reveals hydrocephalus, enlargement of the basal cisterns, and single or multiple lesions that are isoechoic on T1-weighted scans and hyperintense on T2-weighted images with good signal enhancement following contrast administration (contrast-enhanced brain MRI). Typical localizations of sarcoids are the hypothalamus and the optic chiasm region. Vascular thromboses with microstrokes are possible. Brain MRI is especially sensitive in detecting meningeal involvement.

Bone and joint sarcoidosis manifests on radiography of the affected part of the skeletal system and on bone and/or joint computed tomography as cystic or lytic changes. On MRI of soft tissues, the muscular system, bone tissue (one region) and/or joints (one joint) in the presence of musculoskeletal symptoms, infiltration in small and large bones, signs of osteonecrosis, arthritis, soft tissue infiltration, space-occupying lesions of various localizations, myopathy, and nodular formations in muscles are detected [1; 4].

2.4.1 Functional diagnostic methods

• All patients at the stage of initial diagnosis of sarcoidosis (regardless of localization) and during follow-up to assess the severity of lung damage are recommended spirometry (measurement of unforced respiratory volumes and flows) (FVC, FEV₁, and the FEV₁/FVC% ratio). The key parameters are FVC and FEV₁/FVC%. If FEV₁/FVC% < 70%, a short-acting bronchodilator test is performed. Spirometry should be performed at least once every 3 months during the active phase of the process and annually during subsequent follow-up [1, 30, 86]. Measurement of diffusing capacity of the lungs by the single-breath carbon monoxide uptake method (DLco) is recommended only in pulmonology or diagnostic centers. DLco expressed as a percentage of predicted values is one of the most informative parameters in determining the management tactics for patients with sarcoidosis and their follow-up. It is important when prescribing treatment and for assessing the effectiveness of ongoing therapy. The significance of performing spirometry and assessing the diffusing capacity of the lungs has been demonstrated in studies where a 24-month decline in lung function may be a risk factor for mortality in sarcoidosis, independent of other severity criteria. It should be emphasized that the assessment of unforced respiratory volumes must be performed in all newly diagnosed patients regardless of the primary localization, since subsequent involvement of the lungs in the process cannot be excluded [1, 30, 86].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• Gas exchange disorders in sarcoidosis are assessed at the time of detection and during follow-up based on blood oxygen saturation (SaO₂) via pulse oximetry at rest, and if it is necessary to clarify the development of respiratory failure—during the 6-minute walk test (6MWT); this is recommended at all stages of patient detection and monitoring. Blood gas analysis and acid-base status assessment are recommended only in ICU settings [1, 4, 86, 87].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• Electrocardiography is recommended as a mandatory component of the initial examination, and if rhythm disturbances are detected, Holter monitoring of the cardiac rhythm is performed [1, 4, 125].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

2.5 Other Procedures

2.5.1 Invasive diagnostic methods

• Bronchoscopic methods are recommended for all patients at the stage of primary diagnosis, verification of the diagnosis, and during follow-up. Bronchoscopy includes visualization of the bronchial tree to detect typical endoscopic signs of sarcoidosis and harvesting biopsy material using the most optimal method: direct biopsy of bronchial lesions, transbronchial lung biopsy, fine-needle aspiration biopsy of intrathoracic lymph nodes, ultrasound-guided biopsy, and cryobiopsy [1, 4]. All patients should be screened to rule out tuberculosis, which involves a pathomorphological examination of the biopsy (surgical) material and/or bronchial washings for Mycobacterium tuberculosis (microscopy, liquid culture using an automated growth detection system (Bactec MGIT 960, USA), and solid Löwenstein-Jensen and Finn-II media), as well as detection of Mycobacterium tuberculosis complex DNA in sputum, bronchoalveolar lavage fluid, or bronchial washings by PCR.

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• Surgical diagnostic operations are recommended for all patients (children and adults) when transbronchial diagnostics is not feasible for diagnosis verification; the decision should be made by the attending physician in cooperation with an endoscopic surgeon and a surgeon [1, 4].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• If endoscopic methods yield non-informative results or cannot be performed, a decision may be made in cooperation with an endoscopic surgeon and a surgeon to perform surgical diagnostic operations to verify the diagnosis. It is recommended to prioritize minimally invasive methods (video-assisted thoracoscopic lung resection and biopsy of intrathoracic lymph nodes) [1, 4].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• Invasive diagnostics of extrapulmonary sarcoidosis (biopsy of a lymph node (peripheral), skin, tumors, tumor-like soft tissue formations (subcutaneous formations), liver, and other organs in accordance with the lesion) is recommended for patients with sarcoidosis to obtain material from the affected organ. The choice of the method for obtaining material should be determined by the attending physician together with a surgeon [98-102, 126-132].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

The scope of laboratory and instrumental examinations and consultations by medical specialists is presented in Table 1 [1, 4].

Table 1

Scope of laboratory and instrumental examinations during initial diagnosis of sarcoidosis depending on localization

2.5.2 Differential Diagnosis

• Differential diagnosis of sarcoidosis is recommended at the initial diagnostic stage, in case of relapse, or unrelenting disease progression, and is determined by the localization of the process, which can involve any organ and system of the human body; therefore, sarcoidosis is considered a "great mimicker" [1, 88]. In most cases, sarcoidosis manifests with intrathoracic signs.

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

The diagnosis of sarcoidosis is established and formulated by a pulmonologist at a level 2–3 medical organization following diagnostic evaluations.

Comments:

Differential diagnostic series in the detection of intrathoracic lymphadenopathy

• Tuberculosis

• Sarcoidosis

• Nontuberculous mycobacteriosis

• Brucellosis

• Toxoplasmosis

• Granulomatous histiocytic necrotizing lymphadenitis (Kikuchi disease)

• Cat scratch disease

• Sarcoidal reaction of regional lymph nodes in carcinoma

• Hodgkin lymphoma

• Non-Hodgkin lymphoma

• Acute lymphoblastic leukemia

• GLUS syndrome (Granulomatous lesions of unknown significance)

• IgG4-related disease

• Common variable immunodeficiency (CVID)

Differential diagnostic series in the detection of disseminated pulmonary process

• Tuberculosis

• Sarcoidosis

• Nontuberculous mycobacteriosis

• Cryptococcosis

• Aspergillosis

• Tumor-related dissemination

• Histoplasmosis

• Coccidioidomycosis

• Blastomycosis

• Pneumocystis carinii

• Mycoplasma spp.

• Hypersensitivity pneumonitis

• Pneumoconiosis: beryllium (chronic beryllium disease), titanium, aluminum

• Drug-induced reactions

• Langerhans cell granulomatosis (histiocytosis X)

• Aspiration of foreign materials

• Granulomatosis with polyangiitis (Wegener's) (sarcoid-like granulomas are rare)

• Chronic interstitial pneumonia, usual interstitial pneumonia, and lymphocytic interstitial pneumonia

• Necrotizing sarcoidal granulomatosis

• Common variable immunodeficiency (CVID)

  [1,4, 88].

• In children under 5 years of age, differential diagnosis is recommended to be performed with uveitis, parotitis, arthritis, and skin lesions of various etiologies [1, 4, 133, 134].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

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

3.1 Pharmacotherapy

The goal of sarcoidosis treatment is to prevent or reduce tissue damage, alleviate symptoms, and improve patients' quality of life. There is no etiotropic therapy for sarcoidosis. In all cases, it is recommended to weigh the necessity of prescribing treatment against the severity of consequences from modern corticosteroid, cytostatic, or biological ("targeted") therapy.

• All existing regimens are recommendations, and in each case, the attending physician assumes knowledge-based responsibility for the prescribed treatment [1, 3, 4, 89]. For a morphologically verified diagnosis of sarcoidosis, in the absence of life-threatening conditions, decreased organ and system function, or obvious data for rapid disease progression, active surveillance is recommended [1, 3, 4, 91].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Pharmacological classes of drugs used in the treatment of sarcoidosis are presented in Table 1.

Table 1. Pharmacological classes of drugs used in the treatment of sarcoidosis

Note: medications marked with "#" are used off-label; therefore, the dosage regimens used in clinical studies are indicated below in the corresponding recommendation statements — sources are cited in square brackets "[]".

• Since the rate of spontaneous remission is high, asymptomatic patients (children and adults) with a confirmed diagnosis of sarcoidosis in the absence of organ or system failure are recommended active monitoring with status evaluation after 3 months [1, 2, 3, 4, 89, 91].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• For adult patients with an asymptomatic course and no functional impairments, as an alternative, the prescription of #alpha-tocopherol acetate 200 mcg twice daily for at least 6 months or the use of #alpha-tocopherol acetate 200–400 mcg twice daily combined with #pentoxifylline** at a daily dose of 400–2000 mcg (depending on tolerability) for at least 6 months may be recommended. The risk of adverse reactions to #pentoxifylline** is moderate [1, 92, 93, 135–139].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Systemic corticosteroids

• SCS are recommended as first-line drugs in patients with a progressive disease course (for progression criteria, see above) according to radiological and pulmonary function tests, only in the presence of severe symptoms, extrathoracic manifestations disrupting organ function, development of lupus pernio, life-threatening conditions, or a sharp decline in quality of life. The risk of adverse events is high. The administration of oral prednisolone** (or an equivalent dose of another SCS) to adults is recommended daily in the morning at an initial dose of 20–40 mg per day for 4 weeks (0.5 mg/kg), then the dose is tapered by 5 mg per month (stepwise) to the minimum maintenance dose (helping to control symptoms and prevent disease progression) taken for 12–24 months. After 3 months from the start of treatment, the effect of SCS must be evaluated. If there is no effect, switch to alternative therapy [1, 2, 3, 4, 89, 90, 94].

GCR BLOE 3Grade of Recommendation B (Level of Evidence 3).

Comments: patients who received SCS and finished their course develop relapses more frequently (30–80%) than those who did not receive hormonal therapy. In asymptomatic patients receiving SCS, developing adverse events may impair the patient's quality of life to a greater extent than the manifestations of sarcoidosis. There is no convincing data proving that SCS use improves the long-term prognosis of patients with sarcoidosis or reduces the likelihood of fibrosis development. It should be borne in mind that resistance to SCS is possible [1, 2, 3, 4, 89, 90, 94]. The use of SCS may be accompanied by serious adverse events, such as arterial hypertension, elevated blood glucose, weight gain, osteoporosis, and adrenal insufficiency [1, 4, 89]. If systemic corticosteroid-induced osteoporosis develops, the use of bisphosphonates is recommended for the treatment of osteoporosis and fracture prevention. Immunosuppressants (mainly corticosteroids) are used for the treatment of cardiac sarcoidosis in combination with implantable electrical devices, such as a cardioverter-defibrillator, which is primarily justified to prevent sudden death due to ventricular arrhythmias [4].

Cessation of treatment. SCS drugs should be used for at least 10–12 months; the risk of relapse increases by 6–36 months after discontinuation of therapy, especially in patients with a worse prognosis and a need for SCS at the time of diagnosis. Complete remission of the disease can only be claimed 3 years after discontinuation of therapy. If there is no treatment effect after 3–6 months and in case of progression, it is important to re-evaluate the diagnosis and exclude an infectious, mainly tuberculous, nature of the changes. In case of sarcoidosis relapse after a full course of SCS, second-line drugs are recommended, among which preference is given to methotrexate [1, 2, 3, 4, 89, 90, 94].

Inhaled glucocorticoids

• Inhaled glucocorticoids are not recommended as primary therapy in the treatment of sarcoidosis, because sarcoidosis is a systemic disease rather than solely pulmonary. Inhaled glucocorticoids may be prescribed for severe cough syndrome [1, 4], as well as for laryngeal sarcoidosis [1, 4]. The combination of inhaled glucocorticosteroids with bronchodilators (drugs from ATC groups R03AK adrenergics in combination with glucocorticoids or other drugs, except anticholinergics, and R03AL adrenergics in combination with anticholinergics, including triple combinations with corticosteroids according to ATC classification codes) is recommended only for bronchoobstructive syndrome proven by spirometry to be reversible after a short-acting bronchodilator or in concomitant bronchoobstructive diseases. Their effect on the course of sarcoidosis has not been proven, whereas they themselves can cause adverse events [140].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

#Methotrexate**

• Before starting treatment with #Methotrexate** (MTX**) it is recommended to perform a general clinical biochemical blood test: determination of alanine aminotransferase, aspartate aminotransferase activity in the blood, blood creatinine level, and a complete blood count. During treatment, a general clinical biochemical blood test is recommended to be repeated every 1–3 months. The use of MTX** is accompanied by risks of hepatotoxicity, interstitial lung changes, leukopenia, and infections. The drug is teratogenic and contraindicated during pregnancy [1, 4, 144].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• #Methotrexate** (MTX**) – a structural antagonist of dihydrofolate reductase – is recommended (for children and adults) as second-line treatment for resistance to systemic corticosteroids, for adverse reactions caused by systemic corticosteroids, as a means to reduce the dose of systemic corticosteroids, and as first-line treatment as monotherapy or in combination with systemic corticosteroids for verified sarcoidosis. Oral administration at a dose of 10–15 mg once a week is recommended. It is teratogenic and contraindicated in pregnancy [141–144].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

• For adults with neuro- and cardiosarcoidosis, the administration of #methotrexate** up to 25 mg per week is recommended [161–164].

LeveL of Recommendation BGrade of Evidence 2LeveL of Recommendation B (Grade of Evidence - 2).

• Simultaneously with MTX** administration, oral intake of #folic acid** at a dose of 5 mg once a week or 1 mg daily (no earlier than 24 hours after MTX** intake) is recommended. Duration of therapy is 6 months or more [95, 96, 97].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

#Azathioprine**

• #Azathioprine** is recommended for patients aged 3 years and older as a second-line drug at a dose of 100–200 mg daily for at least 6 months. Adverse events include hepatotoxicity, leukopenia, infections, and an increased risk of lymphoma and leukemia [1,4, 145-150].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

#Leflunomide**

#Mycophenolate mofetil**

#Cyclophosphamide**

#Hydroxychloroquine**

#Pentoxifylline**

Comments: dosing regimens:

• in international practice, 1200 mg in 3 divided doses per os is recommended for pulmonary sarcoidosis [4];

• for steroid-sparing therapy – up to 2000 mg daily [137];

• 600 mg daily per os for pulmonary sarcoidosis with pulmonary hypertension [172];

• in combination with #vitamin E for newly diagnosed stage I-III pulmonary sarcoidosis per os at a dose of 600 mg once daily or in 3 divided doses, #vitamin E at a dose of 400 IU daily in 2 divided doses [103, 171],

• in combination with #vitamin E and #hydroxychloroquine – per os at a dose of 600 mg once daily, vitamin E at a dose of 600 mg daily, and hydroxychloroquine per os at a dose of 200 mg daily for stage I-II respiratory sarcoidosis [170]

Non-steroidal anti-inflammatory and antirheumatic drugs

#Alpha-tocopherol acetate (vitamin E)

Tumor necrosis factor-alpha (TNF-alpha) inhibitors

• Antifibrotic therapy is recommended only in adults (contraindicated in children) in cases of ineffectiveness of systemic corticosteroids and second-line drugs, worsening respiratory symptoms, progression of fibrotic changes on chest computed tomography (traction bronchiectasis or "honeycomb lung"), deterioration of functional parameters during 1 year of follow-up (with an absolute decrease in FVC ≥5% and an absolute decrease in DLco (adjusted for Hb level) ≥10%), and development of pulmonary hypertension [2, 4]. Recommendations for the use of antifibrotic agents of various classes [173–175] (ATX: Other protein kinase inhibitors, Other immunosuppressants, Mucolytic agents) are based on generalized data from patients with progressive pulmonary fibrosis in various diseases [104].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

3.2 Efferent therapy methods

• Plasmapheresis is recommended for chronic, systemic corticosteroid-refractory sarcoidosis. The method improves microcirculation, unblocks cellular receptors, and stabilizes cell membranes, which leads to increased sensitivity of "target cells" to pharmacological agents. The procedure consists of removing 500–1000 ml of plasma from the bloodstream per session with replacement by 1:1 isotonic sodium chloride solution**. A course consists of 3–4 plasmapheresis sessions with a 1-week interval between procedures [1, 2, 105, 106, 166].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

3.3 Transplantation

• Heart transplantation is recommended for cardiac sarcoidosis in adults with myocardial involvement and/or refractory arrhythmias, as well as liver transplantation for severe hepatic involvement [1, 4, 107, 108, 155–157].

GCR CLOE 4Grade of Recommendation C (Level of Evidence - 4).

3.4 Other treatment methods

• Respiratory failure. A differentiated approach is recommended for the management of patients with respiratory failure based on spirometry and pulse oximetry data. Bronchodilator therapy can be recommended only in the presence of proven bronchoobstructive syndrome [168].

GCR CLOE 4Grade of Recommendation C (Level of Evidence - 4).

• In sarcoidosis complicated by respiratory failure, restrictive ventilation disorders, and desaturation, low-flow oxygen therapy is recommended, and in severe cases – non-invasive mechanical ventilation until SpO₂ >90% is achieved [1, 4, 169].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

• Pulmonary hypertension. In sarcoidosis complicated by pulmonary hypertension not associated with hypoxemia, the use of drugs such as iloprost, bosentan**, and sildenafil (with caution in proven or suspected veno-occlusive venopathy) is recommended [2,4,122] in accordance with the clinical guidelines for pulmonary arterial hypertension.

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

• Non-pharmacological treatments are recommended for all patients and include physical activity programs in gyms and swimming pools, general physical and psychological rehabilitation programs, patient support group sessions, multidisciplinary pain and sleep disorder management programs, as well as consultations and follow-up by a medical psychologist [1,2,4].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

• Fasting therapy (FT) is recommended for patients in the early stages of sarcoidosis in the presence of obesity. The method by A.N. Kokosov and S.G. Osinin provides for a preparatory period of 3-7 days, therapeutic fasting of 7-14 days, and a recovery period of 7 days. The FT method, by activating self-regulation processes in the patient's body through the mechanism of eustress, has a sanogenetic effect. Under the influence of a 14-day course of FT, the majority of patients with pulmonary sarcoidosis show an improvement in the clinical and radiological picture and correction of their immune status. Against the background of FT, an increase in antioxidant levels is noted. A competent combination of fasting therapy (FT) with evidence-based medicine methods makes it possible to optimize the final treatment outcomes of sarcoidosis [1, 109, 110]

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• An approved and validated medical rehabilitation program for patients with sarcoidosis has not been developed. For patients who have undergone sarcoidosis, the following rehabilitation components are recommended: therapeutic regimen, diet therapy, physical rehabilitation (active and passive), respiratory physiotherapy, psychodiagnostics and psychocorrection, prevention and correction of comorbid pathology, and patient education (enhancing motivation for treatment and a healthy lifestyle). Maintaining the maximum possible physical activity is recommended [1, 2, 4, 17, 111, 158].

GCP CLEL 3Level of Evidence C (Level of Likelihood of Evidence - 3).

5. Prevention and Dispensary Observation

Measures for the prevention of sarcoidosis are unknown, since the etiology of the disease is unknown. Prevention of the development of complications and consequences of sarcoidosis consists of its early detection and rational treatment. Clinical follow-up (dispensary observation) of patients with thoracic localization of sarcoidosis is carried out by a pulmonologist; in generalized forms and/or isolated extrathoracic localizations, clinical follow-up is carried out by a pulmonologist and a specialist physician for the corresponding localization of sarcoidosis.

• All patients with sarcoidosis are recommended to undergo lifelong clinical follow-up, taking into account the course of the disease, the extent of the lesion, and the presence of complications in the patient [1,2,4].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

Comments: The regimen of clinical follow-up for patients with sarcoidosis is determined by the physician individually, depending on the course of the disease, the extent of the lesion, and the presence of complications. Medical examinations and health check-ups (dispensarization) in the established manner, the appointment of additional medical measures based on their results, if necessary, including the establishment of clinical follow-up, are carried out by a general practitioner (therapist) and other specialists as indicated, taking into account the extent of the lesion, the presence of complications, and comorbid pathology.

The procedure for clinical follow-up is proposed by the authors of these guidelines.

Newly diagnosed patients in the first year of the disease and while process activity persists are recommended to undergo follow-up every 3 months; if the process stabilizes in the 2nd year – every 6 months, and in subsequent years – once a year.

In the presence of relapses, the recommended follow-up regimen is every 3 months for 2 years, and in subsequent years upon stabilization, once a year.

In the case of a progressive course, follow-up is recommended every 3 months for 2 years, then, upon stabilization of the process, every 6 months for 2 years, and then once a year.

Clinical follow-up does not preclude active visits by the patient in case of deterioration or the development of adverse events during treatment.

Patients with sarcoidosis are subject to lifelong medical monitoring

5.1 Vaccination

Patients with sarcoidosis belong to the immunocompromised group, and in order to prevent/reduce the likelihood of a severe (complicated) course of infections, routine, emergency, and post-exposure vaccination is carried out in accordance with the National Immunization Schedule and the Schedule of Preventive Vaccinations by Epidemiological Indications [Order of the Russian Ministry of Health No. 1122n dated December 6, 2021 'On Approval of the National Immunization Schedule and the Schedule of Preventive Vaccinations by Epidemiological Indications' and methodological guidelines MU 3.3.1.1095-02 'Medical Contraindications to Preventive Vaccinations with National Immunization Schedule Preparations'] and other regulatory documents of the Russian Ministry of Health taking into account the period of the disease and the therapy received .

6. Organization of Medical Care

Indications for hospital admission to a medical organization:

Planned hospitalization of patients with sarcoidosis is indicated at the stage of primary complex, including invasive, diagnostics, for the selection of initial therapy.

Emergency and/or urgent hospitalization is indicated for patients with acute progressive sarcoidosis and the development of complications (respiratory failure, cardiac arrhythmias) and other conditions of the patient requiring urgent therapeutic and diagnostic measures and/or round-the-clock monitoring to provide emergency care and intensive therapy.

3) In most cases, the monitoring and treatment of patients with sarcoidosis is carried out on an outpatient basis [1; 4].

Indications for patient discharge from a medical organization

1) Completion of the diagnostic process and establishment of the clinical diagnosis

2) Prescription of treatment taking into account the clinical diagnosis, the patient's condition, the features of the disease course, the presence of comorbidities, complications of the disease, and the results of the treatment being administered

3) Compensation of the acute condition and complications of sarcoidosis that were the cause of hospitalization has been achieved [1,4].

7. Additional Information

No additional information available

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Conflict of interest:

There is no conflict of interest among the developers of the clinical guidelines.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. general practitioner (family physician);

2. pulmonologist;

3. internist;

4. district general practitioner;

5. phthisiatrician

6. radiologist

7. pediatrician

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

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) 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

Current instructions for medicinal products mentioned in these clinical guidelines can be found at http://grls.rosminzdrav.ru.

Medical and legal framework for the management of patients with sarcoidosis and working capacity assessment

In accordance with Federal Law of the Russian Federation No. 77-FZ dated June 18, 2001, "On Prevention of the Spread of Tuberculosis in the Russian Federation", Government Decree of the Russian Federation No. 892 dated December 25, 2001, "On Implementation of the Federal Law 'On Prevention of the Spread of Tuberculosis in the Russian Federation'", Order of the Ministry of Health of the Russian Federation No. 109 dated March 21, 2003, and Order of the Ministry of Health of the Russian Federation No. 312 dated July 14, 2003, "On Declaring Invalid Orders of the Ministry of Health and Medical Industry of the Russian Federation and the Ministry of Health of the Russian Federation No. 324 dated November 22, 1995 and No. 33 dated February 2, 1998", the VIII group of dispensary registration for patients with sarcoidosis in tuberculosis medical facilities has been abolished in the Russian Federation.

Currently, patients with sarcoidosis are managed by general practitioners, family physicians/district pediatricians with consultative support from pulmonologists, phthisiologists, and specialists in other fields, depending on the primary organ involvement.

Approximate criteria for assessing the work capacity of patients with sarcoidosis.

Criteria for determining disability group III include:

• moderate clinical and radiological changes in the respiratory system in the form of pneumosclerosis and fibrosis;

• stage I and II respiratory failure, if the patients' main occupation involves contra-indicated factors, and recommended employment is accompanied by a significant decrease in skill level and reduction in production activities;

• limited employment opportunities for low-skilled workers.

Criteria for determining disability group II:

• significant clinical and radiological changes in the respiratory system;

• development of cor pulmonale;

• stage II respiratory failure;

• generalized sarcoidosis involving the heart, eyes, and nervous system, poorly responsive to effective treatment;

• loss of profession and qualification as a result of a prolonged disease course.

Criteria for determining disability group I:

• significant irreversible clinical and radiological changes in the respiratory system (stage IV of the disease with pronounced morphological and significant functional changes in the respiratory organs);

• cor pulmonale in the decompensation phase;

• stage III respiratory and cardiovascular failure;

• generalized process involving the heart, eyes, nervous system, and kidneys, refractory to effective treatment;

• chronic or progressive relapsing course of corticosteroid-dependent sarcoidosis.

The presented criteria can serve as a reference when referring patients for medical and social expertise.

Sarcoidosis and military registration

According to the Decree of the Government of the Russian Federation No. 565 dated July 4, 2013 "On Approval of the Regulation on Military Medical Expertise (as amended on April 17, 2024)", Appendix No. 1, Section II "Schedule of Diseases", column 10, article 51 of the schedule of diseases, citizens upon initial military registration, conscription for military service, those entering military service under a contract, as well as conscripts undergoing conscription military service in the event of stage III-IV sarcoidosis diagnosis, as well as in the case of generalized sarcoidosis – fitness category D – unfit for military service. In the case of stage I and II sarcoidosis confirmed by histological examination results (if the patient refuses diagnostic puncture, the diagnosis is established based on a combination of clinical and laboratory data) in individuals called up for military service, conscripts – fitness category V – limited fit for military service (not subject to conscription).

Spirometry methodology

Spirometry without a bronchodilator (selective beta2-adrenergic agonist or anticholinergic agent for inhalation) is indicated at every patient visit for intrathoracic sarcoidosis. Spirometry with a bronchodilation test is indicated at the initial diagnosis stage in patients with an FEV₁/FVC ratio <70% and/or FEV₁ less than 80% of the predicted value. Spirometry is performed in patients aged 4 years and older. The spirometer must have a calibration log.

During the spirometric study, it is recommended to perform at least three technically correct forced vital capacity (FVC) breathing maneuvers until reproducible results are obtained: the maximum and subsequent highest values of FVC and FEV₁ must not differ by more than 150 ml. In cases where the FVC value does not exceed 1000 ml, the maximum allowable difference for both FVC and FEV₁ must not exceed 100 ml.

If reproducible results are not obtained after 3 attempts, breathing maneuvers must be continued up to 8 attempts. A greater number of breathing maneuvers may lead to patient fatigue and, in rare cases, a decrease in FEV₁ or FVC. If values drop by more than 20% from baseline, further testing should be discontinued in the interest of patient safety, and the trend in values should be reflected in the report. The report must present graphical results and numerical values of at least the three best attempts. Results of technically acceptable attempts that do not meet the reproducibility criterion may be used in writing the conclusion with an indication that they are not reproducible.

The bronchodilator test is performed with a SABA (salbutamol**) at a single dose of 400 mcg via a MDI with a spacer (for children, the dose is 200 mcg). A repeated spirometric study should be performed 15–30 minutes after inhalation of the β₂-agonist.

Formula for calculating BDR:

Absolute increase (ml) = FEV_{1 post}(ml) - FEV_{1 base}(ml),

where FEV_1base is the value of the spirometric parameter before bronchodilator inhalation, and FEV_{1 post} is the value of the parameter after bronchodilator inhalation.

When evaluating the bronchodilation test, it is recommended to consider adverse cardiovascular reactions (tachycardia, arrhythmia, increased blood pressure), as well as the appearance of symptoms such as agitation or tremor.

Indications for long-term oxygen therapy

Appendix B. Physician Action Algorithms

Appendix B1

TREATMENT ALGORITHM FOR PATIENTS WITH SARCOIDOSIS

Where: SGKS – systemic corticosteroids, MTT – #methotrexate**, AZA – #azathioprine**, LEF – #leflunomide**, GHH – #hydroxychloroquine**, vit. E – vitamin E, pentoxifylline – pentoxifylline**, Infliximab/adalimumab – Infliximab** or adalimumab**

Appendix C. Patient Information

Sarcoidosis can have an acute or chronic course. The causes of its occurrence are unknown. Sarcoidosis is not a tumor disease and is not a variant of tuberculosis, therefore treatment is provided by general practitioners, general practice physicians, pulmonologists, or specialists dealing with specific organ involvement (neurologists, cardiologists, dermatologists). The disease is not contagious and is not dangerous to others. A patient cannot be legally forced into hospitalization and treatment (as happens with tuberculosis), but cooperation with doctors and treatment is in the patient's interest, since untreated progressive sarcoidosis leads to respiratory failure, paralysis and paresis, blindness, cardiac arrest, and disfiguring skin changes.

The diagnosis of sarcoidosis is made based on a comprehensive examination. To confirm the diagnosis, an examination of the affected tissue sample—a biopsy (in some countries, a biopsy of two organs)—is often required. This will avoid the so-called "trial therapy" sometimes carried out in anti-tuberculosis institutions. Any invasive (surgical) procedure can be performed only with your consent.

With asymptomatic and non-progressive sarcoidosis, only regular monitoring by a physician will be required, often without treatment. It is important to undergo regular examinations (at least once every 3 months) and visit your doctor.

If the disease progresses, hormonal drugs such as prednisolone will be prescribed first of all. During this time, it is necessary to limit carbohydrates in the diet, monitor blood pressure, blood sugar, vision status, and bone density. In most cases, sarcoidosis treatment is carried out on an outpatient basis, except for severe cases and progression (no more than 10%).

Sarcoidosis in most cases is not a contraindication to pregnancy and childbirth, but sarcoidosis treatment can adversely affect the mother's body and be dangerous for the fetus.

A person suffering from sarcoidosis should maintain physical activity, take walks, and do exercises with light dumbbells, as far as their condition allows.

In terminal stages of sarcoidosis (rare), low-flow home oxygen therapy, non-invasive ventilation, and, if indicated, lung transplantation will be required.

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

Appendix G1. Dyspnea Assessment Using the mMRC Scale

Russian title: Modified Medical Research Council Dyspnea Scale

Original title: mMRC (The Modified Medical Research Council Dyspnea Scale)

Source (validation study): § Nena Milačić, Bojan Milačić, Olivera Dunjic et al. Validity of CAT and mMRC – dyspnea score in evaluation of COPD severity. Acta Medica Medianae 2015, Vol.54(1)

Type (underline):

- rating scale

- index

- questionnaire

- other (specify)

Purpose: assessment of the severity of dyspnea experienced by the patient

Content (template):

Appendix G2. Fatigue Assessment Scale (FAS) [125]

Russian title: Fatigue Assessment Scale

Original title: Fatigue Assessment Scale (FAS)

Source (validation study): § De Vries J, Michielsen H, Van Heck GL, Drent M. Measuring fatigue in sarcoidosis: the Fatigue Assessment Scale (FAS). Br J Health Psychol. 2004 Sep;9(Pt 3):279-91. doi: 10.1348/1359107041557048. PMID: 15296678.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify)

Purpose: assessment of the degree of fatigue experienced by the patient

Content (template):

Key (Interpretation)

• FAS scores 10-21: no fatigue (normal)

• FAS scores 22-50: substantial fatigue

fatigue: scores 22-34; extreme fatigue: scores ≥35

Explanations

1 = Never, 2 = Sometimes (about once a month or less), 3 = Regularly (about a few times a month), 4 = Frequently (about weekly) and 5 = Always (about every day).