Sarcoidosis recommendations. Sarcoidosis: clinical manifestations, treatment recommendations. Hematological and immunological changes

Alexander Andreevich Vizel
Department of Phthisiopulmonology, Kazan Medical University, Ministry of Health of the Russian Federation
Marina Elisovna Guryleva
Department of Biomedical Ethics and Medical Law with a course in the History of Medicine, Kazan Medical University, Ministry of Health of the Russian Federation

For three centuries, doctors have been making efforts to understand the essence of the disease, which the Norwegian dermatologist Caesar Beck called sarcoidosis. We know that this is caseless granulomatosis, we can recognize it with a high degree of probability during an X-ray examination, we have studied Löfgren's syndrome well... However, we do not know what causes this disease, so all therapeutic interventions are aimed at the effect, and not at the cause. In such a situation, any medicinal or other medical intervention should first of all be guided by the principle of “do no harm.” Therefore, it is necessary to determine where and when patients with sarcoidosis should be treated.

Where to treat?

If the leading role of the TB service in the early detection of intrathoracic sarcoidosis is to retain its importance, then the stay of these patients in TB hospitals should be reconsidered. At the very least, it is inhumane to treat a patient without tuberculosis with hormones and cytostatics in the same clinic with patients from whose sputum in 30–50% of cases mycobacteria resistant to anti-tuberculosis drugs are cultured. In anti-tuberculosis institutions, patients with sarcoidosis are often prescribed tuberculostatic drugs for preventive or differential diagnostic purposes, which creates new problems.

If a TB doctor wants to protect himself from a lawsuit from a patient, then he should obtain the informed consent of the patient, which clearly states the risk of contracting tuberculosis.

Quite a long time ago, phthisiopediatricians proposed keeping records of children with sarcoidosis in anti-tuberculosis dispensaries during the period of differential diagnosis (registration group 0), and then observing them with a local pediatrician, conducting repeated courses of treatment in children's hospitals. It is also proposed to cancel the 8th group of dispensary registration in anti-tuberculosis institutions, and transfer information about patients with sarcoidosis to the clinic at the place of residence.

This question remains open, in reality, some patients are still under the patronage of phthisiatricians and receive isoniazid along with prednisolone, while the other part is observed in pulmonology centers or institutes.

Our experience shows the advisability of monitoring patients in multidisciplinary diagnostic centers, where all necessary non-invasive studies can be carried out within 2–3 days in day hospitals. Cytological and histological verification of the diagnosis is best carried out in the thoracic departments of oncology dispensaries.

Pulmonology departments in modern conditions are often filled with patients with severe destructive pneumonia, and the stay of non-infectious patients there is no less dangerous than in anti-tuberculosis institutions.

Treatment of patients with sarcoidosis, in our opinion, is best carried out on an outpatient basis, concentrating these patients in regional (regional, regional, republican) centers under the supervision of 1–2 specialists per region. In exceptional cases (less than 10%), patients should be hospitalized in specialized departments: for neurosarcoidosis - in the neurological department, for cardiac sarcoidosis - in the cardiological department, for nephrosarcoidosis - in the nephrological department, etc. These patients require highly qualified care and expensive monitoring methods, which are available only to such “organ” specialists. Thus, we observed 3 patients with cardiac sarcoidosis who underwent Holter monitoring, and a teenager with neurosarcoidosis who was treated in the neurosurgical department under the control of magnetic resonance imaging (MRI) of the brain. In this case, a phthisiopulmonologist, who constantly deals with sarcoidosis, served as a leading consultant. It should be recalled once again that, according to ICD_10, sarcoidosis is classified in the class “Diseases of the blood, hematopoietic organs and certain disorders involving the immune mechanism.”

When to start treatment?

Worldwide and domestic experience in monitoring patients with sarcoidosis indicates that up to 70% of newly identified cases can be accompanied by spontaneous remission. Therefore, it is advisable to adhere to the 1999 international agreement, according to which monitoring of patients with sarcoidosis should be most intensive during the first two years after diagnosis in order to determine the prognosis and the need for treatment. For stage I, observation once every 6 months is sufficient. For stages II, III, IV, this should be done more often (every 3 months). Therapeutic intervention is indicated for patients with severe, active or progressive disease. After cessation of treatment, all patients, regardless of radiological stage, should be observed for at least 3 years.

Late monitoring will not be required until new symptoms arise (old ones worsen) or extrapulmonary manifestations of the disease appear. Stable asymptomatic stage I does not require treatment, but requires long-term observation (at least once a year). Patients with a persistent course at stages II, III and IV, regardless of whether treatment is prescribed or not, also require long-term monitoring at least once a year. Patients in whom remission was caused by the prescription of glucocorticosteroids (GCS) require more attention, due to the higher frequency of exacerbations and relapses among them. In patients with spontaneous remission, disease progression or relapses are rare. Patients with serious extrapulmonary manifestations require long-term observation, regardless of the radiographic stage of the process.

Opinions about symptoms requiring steroid or cytotoxic therapy remain controversial. In patients with such manifestations of the disease as skin lesions, anterior uveitis or cough, topical corticosteroids (creams, drops, inhalations) are used. Systemic treatment of GCS is carried out in patients with systemic lesions in the presence of increasing complaints. Systemic hormonal therapy is absolutely necessary in cases of cardiac involvement, nervous system involvement, hypercalcemia, and ocular lesions that do not respond to local therapy. The use of systemic treatment of GCS for other extrapulmonary manifestations and for lung damage, according to most doctors, is indicated only when symptoms progress. Patients with persistent changes in the lungs (infiltration) or progressive deterioration of respiratory function (vital capacity and DLCO), even in the absence of other symptoms, require systemic treatment with corticosteroids.

When deciding to initiate hormonal therapy, the physician must weigh the predicted danger of adverse reactions with the expected benefit for the patient. Recently, we have been starting treatment with alternative, gentle regimens, and this gives encouraging results.

How to treat?

Many studies have shown that short courses of treatment with adrenocorticotropic hormone or corticosteroids can have a beneficial effect on infiltrative changes detected on radiographs, and long-term treatment with corticotropic hormones leads to the resolution of granulomas, which has been proven in repeated biopsies. The use of corticosteroids per os usually leads to relief of respiratory symptoms, improvement of the X-ray picture and pulmonary function (RPF).

However, after cessation of treatment, resumption of symptoms and radiological deterioration quite often occur (in some groups, relapses within 2 years after the end of therapy were observed in more than 1/3 of patients).

The main drugs for the treatment of sarcoidosis:

System GCS; inhaled corticosteroids; methotrexate; chloroquine and hydroxychloroquine; pentoxifylline, infliximab; antioxidants.

System GCS

The main drugs used to treat sarcoidosis are prednisolone and other corticosteroids: methylprednisolone, triamcinolone, dexamethasone, betamethasone in dosages equivalent to 20–40 mg of prednisolone. Khomenko A.G. et al. recommend prescribing 20–40 mg of prednisolone for 2–3 months, then gradually reducing the dose over 3–4 months by 1/4 tablet for 4 days (by 5 mg every 2 weeks), maintenance doses (5–10 mg) use from several months to 1–1.5 years. For maintenance therapy, prednisolone is preferred. Patients are recommended diets enriched with protein and potassium, vitamins, diuretics, restriction of fluid intake, table salt, and spicy foods. Schemes for intermittent therapy have been developed.

Kostina Z.I. et al. recommend prednisolone or methylprednisolone 25–30 mg/day with a reduction of 5 mg every 3–4 weeks (general course 2200–2500 mg) in combination with other non-hormonal drugs. Borisov S.E. and Kupavtseva E.A. report a positive experience in treating patients with sarcoidosis with oral GCS at an initial dose of 0.5 mg/kg daily.

Small doses of GCS (up to 7.5 mg/day) in combination with delagil and vitamin E caused adverse reactions 2–3 times less often, but were ineffective in patients with infiltrates, confluent lesions, areas of hypoventilation, massive disseminations, and impaired respiratory function ( especially obstructive), with bronchial sarcoidosis.

There are recommendations to conduct pulse therapy in patients with newly diagnosed sarcoidosis and with a recurrent course of the disease. The technique consists of prescribing prednisolone at a dose of 5 mg/kg intravenously (per 200 ml of isotonic sodium chloride solution at a rate of 40–60 drops per minute) three times with an interval of 3 days and orally at a dose of 0.5 mg/kg per day for 2 day after each intravenous injection. After pulse therapy, the daily dose of prednisolone is gradually reduced from 0.5 to 0.25 mg/kg over a month, then the dose is reduced weekly by 2.5 mg to 0.15 mg/kg.

Maintenance therapy with this dose is continued for up to 6 months.

In Löfgren's syndrome, the use of systemic corticosteroids is advisable only in extreme cases. This type of disease in most cases has a good prognosis, although its clinical presentation greatly worries the patient and frightens the doctor. It is advisable to use non-steroidal anti-inflammatory drugs, pentoxifylline, vitamin E.

Inhaled corticosteroids

Continuous improvement of inhaled corticosteroids (ICS) is carried out for the treatment of bronchial asthma, which in most cases allows the disease to be brought under control. The results of using ICS in sarcoidosis are less optimistic. However, we can agree with the opinion that for pulmonary sarcoidosis without systemic damage, it is advisable to start with ICS.

Ilkovich M.M. et al. showed that inhalation of flunisolide 500 mcg 2 times a day in patients with sarcoidosis stages I and II for 5 months leads to significantly positive X-ray dynamics of the process compared to untreated patients, and a decrease in systolic pressure in the pulmonary artery. According to researchers, the advantage of ICS is associated not only with the absence of side effects characteristic of systemic drugs, but also with a direct effect on the target organ. The feasibility of sequential and combined use of inhaled and systemic corticosteroids for sarcoidosis of stage II and higher was noted. We also have positive experience in long-term control of stage II sarcoidosis using inhaled flunisolide. Staff at St. George's Hospital (London) conducted a meta-analysis of literature data regarding the use of GCS in pulmonary sarcoidosis. The treatment included 66 adult patients with histologically verified pulmonary sarcoidosis who received ICS budesonide at a dose of 0.8–1.2 mg/day. It has been proven that in mild forms of sarcoidosis, especially with severe cough, the use of budesonide for 6 months is promising. At the same time, no significant effect on the x-ray picture was noted.

Methotrexate

This drug was developed and well studied in rheumatology. It belongs to the group of antimetabolites and is structurally similar to folic acid. The therapeutic effectiveness and toxic reactions that occur during treatment with methotrexate are largely determined by the antifolate properties of the drug. There are many studies in the literature describing the successful treatment of sarcoidosis with methotrexate.

In low doses (7.5–15 mg once a week), methotrexate is indicated for the treatment of refractory forms of sarcoidosis, especially those affecting the musculoskeletal system and skin.

We have limited experience in treating patients with stage II–III sarcoidosis with this drug with high efficiency (in 75% of cases). With long-term treatment, even with small doses of methotrexate, monitoring of liver function and liver biopsy are required for treatment durations of more than 12 months.

Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine have long been widely used for sarcoidosis. In domestic studies, chloroquine (Delagil) is often recommended in the early stages of sarcoidosis, before the prescription of hormones. Sharma O.P. showed the effectiveness of chloroquine phosphate in neurosarcoidosis in patients tolerant to GCS or intolerant to GCS. The most informative method of diagnosis and observation turned out to be MRI using gadolinium-based contrast agents.

Hydroxychloroquine (Plaquenil) 200 mg every other day for 9 months may be useful for the treatment of cutaneous sarcoidosis and hypercalcemia. Both drugs can cause irreversible visual damage, which requires constant monitoring by an ophthalmologist.

TNF antagonists

Tumor necrosis factor (TNF) plays a significant role in the formation of granulomas and the progression of sarcoidosis. Therefore, in recent years, drugs that reduce the activity of this cytokine have been intensively studied. These include pentoxifylline, the notoriously teratogenic thalidomide, and infliximab, chimeric monoclonal antibodies that specifically inhibit TNF.

We have positive experience in treating patients with stage II sarcoidosis with pentoxifylline. The figure illustrates the effect of treatment with pentoxifylline (200 mg 3 times a day after meals) in combination with vitamin E for 1 year. Baughman R.P. and Lower E.E. recommend infliximab for chronic refractory sarcoidosis if present lupus pernio.

Antioxidants

In sarcoidosis, a sharp intensification of free radical reactions has been established against the background of depletion of the body's antioxidant supply. This fact is the basis for the use of antioxidants, among which tocopherol (vitamin E) is most often prescribed. In domestic practice, intravenous administration of sodium thiosulfate has been used for many years, but to date no studies have been conducted to reliably prove its effect on the course of sarcoidosis.

N-acetylcysteine ​​(ACC, fluimucil) also has antioxidant properties.

Other drugs and methods

In the treatment of sarcoidosis, drugs of various groups are used, such as azathioprine (cytostatic and immunosuppressant), cyclophosphamide (antineoplastic drug with a strong immunosuppressive effect), cyclosporine A (immunosuppressant that inhibits the reactions of cellular and humoral immunity), colchicine (alkaloid), isotretinoin (dermatoprotector), ketoconazole (fungicidal and antiandrogenic drug) and many others. All of these require further investigation in controlled studies.

The experience of the Central Research Institute of Tuberculosis of the Russian Academy of Medical Sciences deserves special attention, whose employees successfully use extracorporeal methods to treat sarcoidosis. In case of repeated relapses of sarcoidosis and a significant amount of immune complexes in the blood, plasmapheresis is indicated. Extracorporeal modification of lymphocytes (EML) with prednisolone most actively affects the interstitial process in the lung tissue, leading to a significant reduction in the manifestations of alveolitis, and EML with cyclosporine, on the contrary, has a greater effect on the granulomatous process. The mechanism of action of EML is indirect, through a decrease in the functional activity of T-lymphocytes and suppression of the synthesis of pro-inflammatory cytokines.

Fasting-dietary therapy for 10–14 days has a stimulating effect on the adrenal cortex, an antioxidant effect, and modulates the immunological status. It is most effective in patients with stage I and II pulmonary sarcoidosis with a disease duration of no more than 1 year. For those who are sick, fasting for a longer period is indicated as an auxiliary method in combination with GCS.

In recent years, lung transplantation has become a real operation in many countries around the world. Indications for transplantation may include severe forms of pulmonary sarcoidosis stages III–IV. Survival after lung transplantation during the first year is up to 80%, within 4 years – up to 60%. The fight against transplant rejection is important. Clinics in the USA, Great Britain, Norway, and France have positive experience in lung transplantation for sarcoidosis.

Conclusion

The question of the place and methods of treatment of sarcoidosis remains open. The current level of development of medical science provides only control over symptoms, but there is still no convincing evidence that any method of therapy can change the course of sarcoidosis.

Pulmonologists, rheumatologists, phthisiatricians, immunologists and specialists in many other branches of medicine have a lot of work to do to unravel the etiology of sarcoidosis and search for clues to its treatment.

References

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2. Borisov S.E., Kupavtseva E.A. // Sat. scientific tr., dedicated 80th anniversary of the Research Institute of Phthisiopulmonology MMA named after. THEM. Sechenov. M., 1998. P. 62.

3. Ilkovich M.M. and others // Ter. archive. 1996. No. 3. P. 83.

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5. Kostina Z.I. and others // Probl. tube 1995. No. 3. P.34.

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8. Romanov V.V. // Problem tube 2001. No. 3. P. 45.

9. Khomenko A.G. and others. Sarcoidosis as a systemic granulomatosis. M., 1999.

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11. Baughman R.P., Lower E.E. // Sarcoidosis Vasc. Diffuse Lung Dis. 2001. V. 18. No. 1. P. 70.

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Sarcoidosis (D86), Pulmonary Sarcoidosis (D86.0)

Pulmonology

general information

Short description

Ministry of Health of the Russian Federation
Russian Respiratory Society

Diagnosis and treatment of sarcoidosis(Federal Consensus Clinical Guidelines)

DEFINITION

Sarcoidosis is a systemic inflammatory disease of unknown origin, characterized by the formation of non-caseating granulomas, multisystem involvement with a certain frequency of involvement of various organs, and activation of T cells at the site of granulomatous inflammation with the release of various chemokines and cytokines, including tumor necrosis factor (TNF-alpha). The clinical signs of sarcoidosis are varied, and the lack of specific diagnostic tests makes non-invasive diagnosis difficult. Variations in the presentation of this disease suggest that sarcoidosis has more than one cause, which may contribute to different clinical course (phenotypes) of the disease.

Classification

Phenotypes (special variants of the course) of sarcoidosis
1. By localization
a. Classic, with a predominance of intrathoracic (pulmonary) lesions
b. With a predominance of extrapulmonary lesions
c. Generalized
2. According to the characteristics of the flow
a. With an acute onset of the disease (Löfgren's, Heerfordt-Waldenström syndromes, etc.)
b. With an initially chronic course.
c. Relapse.
d. Sarcoidosis in children under 6 years of age.
e. Sarcoidosis refractory to treatment.

Currently, sarcoidosis of the chest is divided into 5 stages (from 0 to IV). This classification is used in most foreign and some domestic works and is included in the international agreement.

D50- DCLASS 89III. Diseases of the blood, hematopoietic organs and certain disorders involving the immune mechanism

D86 Sarcoidosis
D86.0 Pulmonary sarcoidosis
D86.1 Sarcoidosis of the lymph nodes.
D86.2 Sarcoidosis of the lungs with sarcoidosis of the lymph nodes
D86.3 Sarcoidosis of the skin
D86.8 Sarcoidosis of other specified and combined locations
Iridocyclitis in sarcoidosis +(H22.1*)
Multiple cranial nerve palsies in sarcoidosis +(G53.2*)

Sarcoidosis:
athropathy +(M14.8*)
myocarditis +(I41.8*)
myositis +(M63.3*)

D86.9 Sarcoidosis, unspecified.

Etiology and pathogenesis

MORPHOLOGY OF SARCOIDOSIS

The morphological substrate of sarcoidosis is epithelioid cell granuloma - a compact accumulation of mononuclear phagocytes - macrophages and epithelioid cells, with or without the presence of giant multinucleated cells, lymphocytes and granulocytes. The processes of cell transformation and differentiation are regulated by cytokines - low molecular weight proteins produced by cells of the immune system.

More often than other organs, sarcoidosis affects the lungs and intrathoracic lymph nodes (up to 90% of cases). Each granuloma in sarcoidosis goes through several stages of development: 1) early - an accumulation of macrophages, sometimes with an admixture of histiocytes, lymphocytes, neutrophils, 2) a granuloma with an accumulation of epithelioid cells in the center and macrophages along the periphery, 3) epithelioid-lymphocytic granuloma 4) the appearance of giant multinucleated cells (first “foreign body” cells, and subsequently Pirogov-Lanhhans cells), 5) early cellular necrosis in the center of the granuloma due to pyknosis of nuclei, the appearance of apoptotic bodies, necrosis of epithelial cells, 6) central fibrinoid, granular, coagulation necrosis, 7) granuloma with partial fibrosis, sometimes reminiscent of amyloid; when stained with silver, reticulin fibers are revealed, 8) hyalinizing granuloma. However, biopsy specimens almost always reveal granulomas at various stages of development, and there is no correspondence between the clinical, radiological and morphological stages of the process in sarcoidosis.

The process of organizing granulomas begins from the periphery, which gives them a clearly defined, “stamped” appearance. Domestic authors distinguish three stages of granuloma formation - proliferative, granulomatous and fibrous-hyalinous. Granulomas in sarcoidosis are usually smaller in size than in tuberculosis and are not characterized by fusion. With sarcoidosis, central necrosis may develop in 35% of cases, however, it is usually point-like and poorly visualized. In this case, in the center of the granuloma there may be an accumulation of cellular detritus and necrotic giant cells. Small necrobiotic foci or single apoptotic cells should not be regarded as fibrosis. In the initial stage of necrosis formation, neutrophils can be detected. Sarcoid granulomas heal either by characteristic concentric fibrosis or as homogeneous hyaline bodies. Unlike sarcoidosis, tuberculous granulomas heal in the form of linear or stellate scars, or lymphohistiocytic accumulations remain in their place.

Monocytes, tissue macrophages and epithelioid cells have a common origin and belong to the mononuclear phagocytic system. Epithelioid cells are larger than macrophages, their size is 25-40 µm, they have a centrally or eccentrically located nucleus with nucleoli and heterochromatin. A significant number of lymphocytes in lung tissue in sarcoidosis are represented predominantly by T cells. Lymphocytes are usually numerous and clearly visible in histological sections along the periphery of granulomas.

Giant cells are formed by the fusion of mononuclear phagocytes, however, their phagocytic activity is low. At first, giant cells contain randomly located nuclei - cells of the “foreign body” type; subsequently, the nuclei shift to the periphery, which is characteristic of Pirogov-Lanhhans cells. Sometimes giant cells may contain inclusions in the cytoplasm, such as asteroid bodies, Schaumann bodies, or crystalloid structures.

Asteroid inclusions are also found in the cytoplasm of giant cells in various granulomatoses. In sarcoid granulomas they are detected in 2-9% of patients. Hamazaki-Wesenberg bodies are also found in sarcoidosis. These bodies are found in granulomas, in the areas of peripheral sinuses of lymph nodes inside giant cells and extracellularly. They are also called yellow or spiral bodies. These are oval, round or elongated structures measuring 0.5-0.8 microns, containing lipofuscin. Slit-like (needle-like) crystalloid structures, which are cholesterol crystals, occur in more than 17% of patients with sarcoidosis. Also in sarcoidosis, the presence of centrospheres is described - defined clusters of vacuoles in the cytoplasm of giant cells. When stained with hematoxylin and eosin, these structures may resemble mushrooms.

When examining biopsy specimens of the bronchi and lungs in granulomatous diseases, as a rule, a disseminated lesion with vasculitis, perivasculitis, and peribronchitis is detected; granulomas are most often localized in the interalveolar septa; sometimes diagnosis is complicated by developing fibrosis. Granulomatous lesions of the bronchi and bronchioles in sarcoidosis are common and are described in 15-55% of patients. In this case, the mucous membrane of the bronchi may not be changed; in a number of observations, it thickens, edema, and hyperemia occurs. A study of bronchobiopsies confirms the presence of granulomas in the bronchial wall in 44% with unchanged mucous membrane and in 82% with endoscopically visible changes. Granulomatous lesions of the bronchi can lead to bronchoconstriction with subsequent development of atelectasis. Bronchoconstriction may also be associated with the development of fibrosis and, extremely rarely, with compression of the bronchi by enlarged lymph nodes.

Vascular involvement in the pulmonary circulation is a common finding; the incidence of granulomatous angiitis can reach 69%. In some observations, the appearance of granulomas in the vessel wall is due to the growth of granulomas from perivascular pulmonary tissue, but in most cases, granulomas initially form in the vessel wall. In rare cases, sarcoid granulomas are found in the intima of the vessel.
It is believed that the development of alveolitis precedes the formation of granulomas. Alveolitis in sarcoidosis is characterized by the presence of inflammatory infiltration in the interstitium of the lung, with 90% of the cellular composition represented by lymphocytes.

ETIOLOGY OF SARCOIDOSIS
No guidelines currently provide precise information about the etiology of this disease, limiting them to a number of hypotheses.

Hypotheses related to infectious factors. The infection factor in sarcoidosis is considered a trigger: constant antigenic stimulation can lead to dysregulation of cytokine production in a genetically predisposed individual. Based on the results of studies published around the world, triggers of sarcoidosis may include:
- myocobacteria (classical and filterable forms)
- Chlamydophila pneumoniae ;
- Borrelia burgdorferi- causative agent of Lyme disease;
- Propionibacterium acnes commensal bacteria of the skin and intestines of a healthy person;
- certain types of viruses: hepatitis C virus, herpes virus, JC virus (John Cunningham).
The significance of the trigger theory is confirmed by the possibility of transmission of sarcoidosis from animal to animal in experiments, during organ transplantation in humans

Environmental hypotheses. Inhalation of metal dust or smoke can cause granulomatous changes in the lungs, similar to sarcoidosis. Dusts of aluminum, barium, beryllium, cobalt, copper, gold, rare earth metals (lanthanides), titanium and zirconium have the ability to stimulate the formation of granulomas. The international ACCESS study found an increased risk of sarcoidosis among people employed in industries exposed to organic dust, especially those with white skin. An increased risk of sarcoidosis was noted among workers who worked with construction and gardening materials, as well as among teachers. The risk of sarcoidosis was also higher among people who worked in contact with children. There have been isolated studies linking sarcoidosis to inhalation of toner powder. American researchers noted that there are quite convincing studies indicating that agricultural dust, mold, work in fires and military service associated with contact with mixed dust and smoke are risk factors for the development of sarcoidosis.

Smoking in sarcoidosis has two different effects. In general, sarcoidosis was significantly less common among smokers, however, smokers suffering from sarcoidosis had lower values ​​of pulmonary function, interstitial changes were more common, and the level of neutrophils in the BAL fluid was higher. In heavy smokers, the diagnosis is made late because sarcoidosis is hidden by other symptoms.

Hypotheses related to heredity. Prerequisites for possible inherited susceptibility to sarcoidosis include familial cases of this disease, the first of which was described in Germany in two sisters in 1923. Family members of people with sarcoidosis are several times more likely to develop sarcoidosis than other people in the same population. The multicenter study ACCESS (A Case-Control Etiology Study of Sarcoidosis) showed that among first- and second-level relatives of a patient with sarcoidosis, the risk of the disease is significantly higher than in the general population. In the United States, familial sarcoidosis occurs in 17% of cases among African-Americans and 6% among whites. The phenomenon of familial sarcoidosis admits the presence of specific genetic causes.

The most likely hereditary factors are:
- chromosome loci responsible for leukocyte antigens of the human major histocompatibility complex (HLA);
- polymorphism of tumor necrosis factor genes - TNF-alpha;
- polymorphism of the antiotensin-converting enzyme (ACE) gene;
- polymorphism of the vitamin D receptor gene (VDR);
- other genes (there are still separate publications).

The role of macrophages and lymphocytes, key cytokines. The basis of the immunopathogenesis of pulmonary sarcoidosis is a delayed-type hypersensitivity reaction (DTH). This type of immune inflammation represents the effector phase of a specific cellular response. The classic HRT reaction includes the following immunoreactivity processes: activation of the vascular endothelium by cytokines, recruitment of monocytes and lymphocytes from the bloodstream and tissues to the HRT site, activation of the functions of alveolar macrophages by lymphokines, elimination of the causative antigen and tissue damage by secretion products of activated macrophages and lymphocytes. The most common effector organ of inflammation in sarcoidosis is the lungs; lesions of the skin, heart, liver, eyes and other internal organs can also be observed.

In the acute phase of development of HRT, an antigen that persists in the body and is difficult to destroy stimulates the secretion of IL-12 by macrophages. Activation of T lymphocytes by this cytokine leads to suppression of the cytokine-secreting function of Th2 lymphocytes and to increased secretion of IFN-γ, TNF-α, IL-3, GM-CSF by Th1 lymphocytes, which activate macrophages/monocytes, contributing not only to the stimulation of their production, but also their migration from the bloodstream to the site of inflammation. Failure to eliminate the antigenic stimulus causes macrophages to differentiate into epithelioid cells that secrete TNF-α. Subsequently, some epithelioid cells fuse to form multinucleated giant cells.
The granulomatous type of inflammation, which is based on the HRT reaction, is characterized by the activation of type 1 T helper cells. One of the key cytokines for inducing a cellular immune response in the lungs is IL-12. The interaction of IL-12 with specific receptors on the surface membrane of lymphocytes leads to the activation of g-INF synthesis and the development of a Th1 cell clone.

The progressive course of sarcoidosis is characterized by the following indicators:

1. High levels of chemokines in BALF and in the supernatants of BALF cells - CXC chemokines (MIP-1, MCP-1, RANTES), as well as CC chemokine - IL-8. It is these chemokines that are responsible for the recruitment of inflammatory effector cells into the lung tissue.
2. Increased levels of expression of IL-2 and INF-g, as well as CXCR3, CCR5, IL-12R, IL-18R by CD4+ lymphocytes of BALF.
3. The level of TNF-a synthesis by alveolar macrophages has the greatest prognostic value. Using this criterion, it is possible to identify a group of patients in whom the disease will progress in the near future and may enter the stage of formation of pneumofibrosis.

Epidemiology

EPIDEMIOLOGY OF SARCOIDOSIS

The detection of sarcoidosis is closely related to the level of knowledge of doctors about the signs of this disease, since sarcoidosis is considered to be the “great imitator”. Intrathoracic forms of the disease are most often detected during fluorographic and radiographic examination, after which the patient is immediately sent to a phthisiatrician (to rule out tuberculosis) and/or to a pulmonologist for further examination and observation. When presenting with complaints, articular, skin, ocular, neurological (other localizations - less often) manifestations of sarcoidosis are most often detected. The process of diagnosing sarcoidosis is far from perfect, and until 2003, when all patients with sarcoidosis were under the supervision of phthisiatricians, every third patient underwent trial anti-tuberculosis therapy and almost everyone received preventive therapy with isoniazid. Currently, this practice is recognized as irrational.

Morbidity sarcoidosis in Russia has not been sufficiently studied; according to available publications, it ranges from 2 to 7 per 100 thousand of the adult population.

Prevalence sarcoidosis in Russia varies from 22 to 47 per 100 thousand adult population and depends on the availability of centers and specialists. In Kazan in 2002, the first active screening of these patients was carried out, the prevalence was 64.4 per 100 thousand. The prevalence of sarcoidosis among African-Americans reaches 100 per 100 thousand, in Scandinavian countries - 40-70 per 100 thousand population, and in Korea, China, African countries, Australia - sarcoidosis is rare. There are ethnic features in the manifestation of the disease - frequent skin lesions among black patients, a high prevalence of cardiac sarcoidosis and neurosarcoidosis - in Japan. The prevalence of familial sarcoidosis was 1.7% in the UK, 9.6% in Ireland and up to 14% in other countries, 3.6% in Finland and 4.3% in Japan. The greatest risk of developing sarcoidosis was found in siblings, followed by uncles, then grandparents, then parents. In Tatarstan, cases of familial sarcoidosis were 3%.

Fatal outcomes from sarcoidosis in Russia are relatively rare - from 0.3% of all observed and up to 7.4% of chronically ill patients. Their cause is mainly pulmonary heart failure, neurosarcoidosis, cardiac sarcoidosis, and during immunosuppressive therapy - as a consequence of the addition of a nonspecific infection and tuberculosis. Mortality from sarcoidosis is no more than 5-8%. In the USA, the mortality rate from sarcoidosis is 0.16-0.25 per 100 thousand adults. Mortality from sarcoidosis in reference samples reaches 4.8%, which is more than 10 times than in the population sample (0.5%). In the reference sample, corticosteroids were prescribed 7 times more often than in the population, and this factor was highly correlated with mortality. This led to the conclusion that excessive use of steroids in sarcoidosis may adversely affect the prognosis of this disease.

Diagnostics

CLINICAL DIAGNOSIS

History (exposure to environmental and occupational factors, symptoms)
Physical examination
Plain X-ray of the chest organs in frontal and lateral projections
RCT of the chest organs
Respiratory function testing: spirometry and DLco
Clinical blood test: white blood, red blood, platelets
Blood serum content: calcium, liver enzymes (ALAT, AST, ALP), creatinine, blood urea nitrogen
General urine analysis
ECG (Holter monitoring if indicated)
Examination by an ophthalmologist
Tuberculin skin tests

Anamnesis collection, complaints. Patients with acute sarcoidosis describe their condition most vividly: Löfgren's syndrome, which is easily recognized on the basis of acute fever, erythema nodosum, acute arthritis of the ankles and bilateral hilar lymphadenopathy, clearly visible on a direct and lateral plain chest radiograph.

Weakness. The frequency of fatigue and fatigue varies from 30% to 80% depending on age, gender, race and may not have a direct correlation with damage to certain organs involved in the granulomatous process.

Pain and discomfort in the chest are common and unexplained symptoms. Chest pain in sarcoidosis does not have a direct connection with the nature and extent of changes detected even on RCT. Patients often note discomfort in the back, burning in the interscapular area, and heaviness in the chest throughout the entire active period of the disease. The pain can be localized in the bones, muscles, joints and does not have any characteristic signs.

Dyspnea may have various causes - pulmonary, central, metabolic and cardiac origin. Most often, it is a sign of increasing restrictive disorders and a decrease in the diffusion capacity of the lungs. When detailing the complaint, the patient usually characterizes shortness of breath as a feeling of lack of air, and the doctor specifies whether it is inspiratory, expiratory, or mixed.

Cough with sarcoidosis it is usually dry. When the intrathoracic lymph nodes are enlarged, it may be caused by compartment syndrome. At the same time, in the later stages, cough is a consequence of extensive interstitial changes in the lungs, and relatively rarely - a consequence of damage to the pleura.

Fever- characteristic of the acute course of Löfgren's syndrome or Heerfordt-Waldenström syndrome - “uveoparotid fever”, when the patient, along with fever, has enlarged parotid lymph nodes, anterior uveitis and paralysis of the facial nerve (Bell's palsy). The incidence of fever in sarcoidosis varies from 21% to 56%.

Joint syndrome most pronounced in Löfgren's syndrome, but can occur as an independent symptom. Pain and swelling may occur in the ankles, fingers and toes, and less commonly in other joints, including the spine. Joint syndrome is divided into acute, which can pass without consequences, and chronic, which leads to deformation of the joints.

Decreased visual acuity and/or blurred vision- may be important signs of sarcoidous uveitis, which requires mandatory ophthalmological examination and active treatment.

Unpleasant sensations from the heart, palpitations or bradycardia, a feeling of irregularities - may be a sign of heart damage from sarcoidosis, which is one of the most serious manifestations of this disease, leading to sudden cardiac death. According to the clinical manifestations of sarcoidosis of the cardiovascular system, three main syndromes are distinguished: pain (cardialgic), arrhythmic (manifestations of rhythm and conduction disturbances) and circulatory failure syndrome. Infarct-like and myocardial variants of the course of cardiac sarcoidosis have also been described. The diagnosis of cardiac sarcoidosis is based on the results of instrumental examinations and, if possible, a biopsy.

Neurological complaints varied. Bell's palsy, a unilateral paralysis of the facial nerve, is considered pathognomonic for sarcoidosis, which is considered to be a sign of a favorable prognosis. Cerebral disorders manifest themselves in advanced stages of sarcoidosis, since neurosarcoidosis can be asymptomatic for quite a long time. The complaints are nonspecific: a feeling of heaviness in the occipital region, decreased memory for current events, headaches that increase over time, meningeal symptoms without fever, moderate paresis of the limbs. In sarcoidosis with “volumetric” brain damage, epileptiform seizures and mental changes develop. There have been cases of stroke-like onset followed by severe neurological deficits. The volume of neurological damage is determined by the death of nerve cells and the destruction of interneuron connections between surviving neurons.

Inspection is a critical aspect of the diagnosis of sarcoidosis, since the skin is affected quite often and can be biopsied. Erythema nodosum is an important but nonspecific sign, its biopsy has no diagnostic value. Nodules, plaques, maculopapular changes, lupus pernio, cicatricial sarcoidosis are specific for sarcoidosis. Manifestations of cutaneous sarcoidosis are likely to occur in areas of the skin where foreign bodies may have entered (scars, scars, tattoos, etc.). Detection of skin changes and their histological examination can sometimes avoid endoscopic or open diagnostic operations. Detection of enlarged salivary glands (mumps) is of great clinical importance in sarcoidosis of younger children.

Physical examination may not detect pulmonary pathology even with pronounced changes on chest x-rays. Palpation can reveal painless, mobile, enlarged peripheral lymph nodes (usually cervical and inguinal), as well as subcutaneous lumps - Darier-Roussy sarcoids. Steto-acoustic changes occur in approximately 20% of patients with sarcoidosis. It is important to assess the size of the liver and spleen. Obvious clinical signs of respiratory failure are detected in sarcoidosis of the respiratory organs relatively rarely, as a rule, in the case of the development of pronounced pneumosclerotic changes and stage IV.

Damage to organs and systems in sarcoidosis

Lung damage in sarcoidosis is the most common, its manifestations form the basis of these recommendations.

Skin changes in sarcoidosis occur with a frequency of 25% to 56%. Skin changes in sarcoidosis can be divided into reactive ones - erythema nodosum, which occurs during the acute and subacute course of the disease, and skin sarcoidosis itself - specific polymorphic disorders that are difficult to visually recognize and require a biopsy.
Erythema nodosum ( Erythema nodosum ) is a vasculitis with primary destructive-proliferative damage to arterioles, capillaries, and venules. Perivascular histiocytic infiltration is observed in the dermis. Signs of septal panniculitis are observed. The subcutaneous fat septa are thickened and infiltrated by inflammatory cells, which extend to the periseptal areas of the fat lobules. Thickening of the septa is caused by edema, hemorrhage and neutrophil infiltration. The histopathological marker of erythema nodosum is the presence of so-called Miescher radial granulomas - a type of necrobiosis lipoidica - which consist of well-defined nodular clusters of small histiocytes arranged radially around a central cleft. Erythema nodosum does not contain sarcoid granulomas, a biopsy of its elements has no diagnostic significance. In sarcoidosis, erythema nodosum often manifests itself as part of Löfgren's syndrome, which makes it advisable conducting direct plain radiography in frontal and lateral projections to identify or exclude hilar lymphadenopathy.
Typically, erythema nodosum nodes regress spontaneously within a few weeks, and often simply rest and bed rest are sufficient treatment. Aspirin, NSAIDs, and potassium iodide help relieve pain and resolve the syndrome. Systemic corticosteroids can quickly eliminate the manifestations of erythema nodosum. We should not forget about the high probability of spontaneous remission of sarcoidosis, and erythema nodosum itself is not an indication for prescribing SCS for sarcoidosis.

Sarcoidosis of the skin occurs with a frequency of 10-30% or almost every 3rd patient with systemic sarcoidosis, which makes a thorough examination of the skin of a patient with sarcoidosis highly important. Skin lesions may be the first noticeable manifestation of the disease. Nodules, plaques, maculopapular changes, lupus pernio, cicatricial sarcoidosis are specific for sarcoidosis. Rare manifestations include lichenoid, psoriasiform, ulcers, angiolupoid, ichthyosis, alopecia, hypopigmented macules, nail lesions, and subcutaneous sarcoidosis. Sarcoidosis can also manifest as annular, indurative plaques - granuloma annulare. The following forms of cutaneous sarcoidosis are distinguished: clinically typical - Beck's cutaneous sarcoid - large-nodular, small-nodular and diffuse-infiltrative; lupus pernio of Besnier-Thenesson, Broca-Pautrier angiolupoid; subcutaneous Darrieus-Roussy sarcoids and atypical forms - spotted, lichenoid, psoriasis-like sarcoids, as well as mixed forms - small nodular and large nodular, small nodular and subcutaneous, small nodular and angiolupoid, diffuse-infiltrating and subcutaneous.
Sarcoidosis plaques usually localized symmetrically on the skin of the torso, buttocks, limbs and face, they are painless, clearly defined, raised areas of skin compaction of a purplish-bluish color along the periphery and atrophic, paler ones in the center. Plaques are one of the systemic manifestations of chronic sarcoidosis, combined with splenomegaly, damage to the lungs and peripheral lymph nodes, persist for a long time and require treatment. Histological examination of the plaque has a high diagnostic value.
The histological picture of skin sarcoidosis is most often characterized by the presence of a “naked” epithelioid cell granuloma, that is, without an inflammatory reaction around and inside the granuloma, without caseation (fibrinoid necrosis may occur); the presence of a different number of giant cells of the Pirogov-Langhans type and the type of foreign bodies; unchanged or atrophic epidermis. All these signs are used in the differential diagnosis of cutaneous sarcoidosis and tuberculous lupus.
Lupus pernio (Lupus pernio) - chronic lesions of the skin of the nose, cheeks, ears and fingers. The most common changes are in the skin of the nose, cheeks and ears, and less commonly in the forehead, limbs and buttocks; they cause serious cosmetic defects and thereby cause significant psychological suffering to patients. The affected areas of the skin are thickened and colored red, purple or violet due to the large number of blood vessels in the area of ​​change. The disease is chronic, usually with relapses in winter. Lupus pernio, as a rule, is one of the components of chronic systemic sarcoidosis with damage to the lungs, bones, and eyes; it does not go away spontaneously, is often resistant to therapeutic and surgical interventions, and can be used as a marker of the effectiveness of treatment of systemic sarcoidosis.
Acute cutaneous sarcoidosis usually resolves spontaneously, whereas chronic cutaneous sarcoidosis causes aesthetic damage and requires treatment. Local application of GCS in the form of ointments, creams and intradermal injections of triamsinolone acetonide (3-10 mg/ml) is effective for limited skin lesions without pronounced systemic manifestations, when systemic GCS are not used or their dose must be reduced. Severe skin lesions and generalized sarcoidosis involving the skin are indications for systemic therapy, including systemic steroids, methotrexate, and antimalarials.

Damage to the organ of vision in sarcoidosis are considered the most dangerous, requiring the attention of doctors and treatment, since inadequate assessment of the condition and untimely prescribed therapy can lead to a significant decrease and even loss of vision. The eyes are affected in sarcoidosis in approximately 25-36% of cases. 75% of them have anterior uveitis, 25-35% have posterior uveitis. There are lesions of the conjunctiva, sclera and iris. Eye damage requires active therapy, local and systemic. Untreated eye lesions can lead to blindness. Sarcoidosis is a possible cause of long-term inflammatory processes in the vascular tract of the eyes. 1.3-7.6% of patients with chronic uveitis and uveoretinitis have a sarcoid etiology. 13.8% of chronic granulomatous uveitis are sarcoid. With ocular sarcoidosis, 80% have systemic disorders (parotid and submandibular glands, lymph nodes of the roots of the lungs, pathology of the skeletal system, liver, spleen, skin and mucous membranes). Uveitis is a component of Heerfordt-Waldenström syndrome or “uveoparotid fever”, characteristic of sarcoidosis, when the patient, along with fever, has enlarged parotid lymph nodes, anterior uveitis and facial paralysis (Bell's palsy).
When uveitis of any nature is detected, long-term monitoring of the patient is necessary, since systemic sarcoidosis can be detected over the next 11 years. In addition, if uveitis preceded the diagnosis of sarcoidosis by 1 year or more, sarcoidosis should be regarded as chronic. Patients with sarcoidosis are advised to undergo an annual examination by an ophthalmologist with determination of visual acuity and examination with a slit lamp. Children under 5 years of age are characterized by a clinical triad of uveitis, skin lesions and arthritis. Involvement of the optic nerve by sarcoidosis is uncommon but is an indication for long-term treatment with corticosteroids.

Sarcoidosis of peripheral lymph nodes (LN), accessible palpation occurs in every fourth patient. More often, the process involves the posterior and anterior cervical lymph nodes, supraclavicular, ulnar, axillary and inguinal. The lymph nodes are densely elastic, do not soften and do not form fistulas. The appearance of sarcoidosis in peripheral lymph nodes or their involvement in the process is a poor prognostic sign. The course of the disease in this case can be recurrent. Histological examination of the removed lymph node and the detection of epithelial cell granulomas in it requires comparison with the clinic and damage to other organs for the differential diagnosis of sarcoidosis and sarcoid reaction.

Damage to the spleen in sarcoidosis. In sarcoidosis, splenomegaly occurs - an enlargement of the spleen, and hypersplenism - an enlargement of the spleen with an increase in the number of cellular elements in the bone marrow and a decrease in formed elements in the peripheral blood (red blood cells, leukocytes or platelets). The incidence of splenic involvement varies from 10% to 40%. Changes are detected by ultrasound, MRI and CT studies and are the basis for differential diagnosis with neoplastic and infectious diseases. Changes in the spleen have the character of foci or foci, the size of the organ increases (homogeneous splenomegaly).
Splenomegaly may present clinically with abdominal discomfort and pain. Systemic effects may include thrombocytopenia with purpura and agranulocytosis. Sarcoidosis may affect the spleen and skull bones without intrathoracic pathology; cases of splenomegaly and hypersplenism have been described in patients with multiple organ sarcoidosis.
Needle biopsy of the spleen (informativeness reaches 83%) under the control of computed tomography or ultrasound imaging is difficult if the size of the changed areas is small. It can be dangerous if the lesion is located close to the hilum or is localized on the periphery. In case of massive splenomegaly with pronounced systemic manifestations, splenectomy is performed. Sometimes splenectomy has a beneficial effect on the course of sarcoidosis. Splenic lesions in sarcoidosis are most often sensitive to SCS treatment.

Sarcoidosis of the hematopoietic system. Granulomas are an uncommon finding on bone marrow biopsy and can be associated with a wide range of infectious and non-infectious disorders. In this context, sarcoidosis is the most likely cause of granulomas in the bone marrow. Granulomas can also occur secondary, caused by taking medications (toxic myelopathy), as well as in myelopathy caused by HIV infection. In these cases, granulomas are small, associated with the underlying disease and difficult to recognize. To identify microorganisms, special staining is necessary. Fibrin annular granulomas (ring-like granulomas) are typical of Q fever, but can occur in reactive conditions, after drug therapy, and during other infectious diseases such as Lyme disease. One of the manifestations of non-caseating bone marrow granulomas may be fever of unknown origin in combination with lymphopenia. Most often, damage to the hematopoietic system is detected in multiple organ sarcoidosis.

Kidney damage with sarcoidosis it occurs in 15-30% of patients. The spectrum of clinical signs associated with renal involvement in sarcoidosis is quite wide, from subclinical proteinuria to severe nephrotic syndrome, tubulointerstitial disorders and renal failure. Kidney damage in sarcoidosis is caused by changes due to the formation of granulomas and nonspecific sarcoid-like reactions, including electrolyte imbalances and, above all, calcium metabolism disorders. Granulomas in the kidneys are most often localized in the cortex.
An important contribution to the development of nephropathy in sarcoidosis is made by calcium metabolism disorders, hypercalcemia and hypercalciuria. Calcium nephrolithiasis is detected in 10-15% of patients with sarcoidosis; in some patients, calcifications disappear when calcium metabolism is normalized.
It should be borne in mind that the detection of epithelioid cell granulomas in the kidneys in itself does not definitively confirm the diagnosis of sarcoidosis, since it can also occur in other diseases, for example, infections, drug-induced nephropathy, and rheumatic diseases.

Damage to the musculoskeletal system in sarcoidosis it often occurs, primarily in the form of articular syndrome, while lesions of bones and muscles are diagnosed much less frequently.
Joint damage in sarcoidosis it is included in the symptom complex of Löfgren's syndrome. The incidence of articular syndrome in acute sarcoidosis reaches 88%. Most often, arthritis is localized in the ankles, knees and elbows, and arthritis is often accompanied by erythema nodosum. Clinical manifestations disappear within a few weeks, chronic or erosive changes have been extremely rare and are always accompanied by systemic manifestations of sarcoidosis. Rheumatic manifestations of sarcoidosis, along with arthritis, may be accompanied by swelling of the soft tissues adjacent to the joint, tenosynovitis, dactylitis, bone damage and myopathy. There are 2 types of arthritis, differing in clinical course and prognosis. Acute arthritis in sarcoidosis often resolves spontaneously and without sequelae. Chronic arthritis, although less common, can progress and cause joint deformities. In this case, proliferative and inflammatory changes occur in the synovium, and noncaseating granulomas occur in half of the patients. Differential diagnosis is most often carried out with rheumatoid arthritis.
Sarcoidosis of bones occurs with varying frequency in different countries - from 1% to 39%. The most common is asymptomatic cystoid osteitis of the small bones of the hands and feet. Lytic lesions were rare, localized to the vertebral bodies, long bones, pelvis, and scapula, and were usually accompanied by visceral lesions. In the diagnosis, radiography, X-ray CT, MRI, PET, radioisotope scanning are informative, but only a bone biopsy allows us to confidently speak about the presence of granulomatosis. Damage to the bones of the fingers is manifested by bone cysts of the terminal phalanges and nail dystrophy; most often, this combination is a sign of chronic sarcoidosis. The scintigraphic picture is similar to multiple bone metastases.
Damage to the skull bones It is rare and manifests itself as cyst-like formations of the lower jaw, extremely rarely - in the form of destruction of the bones of the skull.
Spinal lesions manifested by back pain, lytic and destructive changes in the vertebrae, and may be similar to ankylosing spondylitis.
Muscle sarcoidosis manifested by the formation of nodes, granulomatous myositis and myopathy. The diagnosis is confirmed by electromyography. Muscle biopsy reveals the presence of mononuclear cell infiltration with the formation of noncaseating granulomas.

Sarcoidosis of ENT organs and oral cavity accounts for 10-15% of sarcoidosis cases.
Sinonasal sarcoidosis occurs more often than other localizations of sarcoidosis in the ENT organs. Damage to the nose and paranasal sinuses in sarcoidosis occurs in 1-4% of cases. Sarcoidosis of the nose is manifested by nonspecific symptoms: nasal congestion, rhinorrhea, crusting on the mucous membrane, nosebleeds, nasal pain, and impaired sense of smell. Endoscopic examination of the nasal mucosa most often reveals a picture of chronic rhinosinusitis with nodes on the septum and/or in the nasal turbinates, with the formation of crusts; small sarcoid nodules can be detected. The most typical localization of changes in the mucous membrane is the nasal septum and superior turbinate. In rare cases, with sarcoidosis, destruction of the nasal septum, sinuses, and palate is observed, which creates serious differential diagnostic problems and requires mandatory histological verification of the diagnosis.
Sarcoidosis of the tonsils occurs as a manifestation of generalized sarcoidosis, much less often as an independent pathology. It can manifest as asymptomatic unilateral or bilateral enlargement of the palatine tonsils, in the tissue of which, after tonsillectomy, non-caseating granulomas characteristic of sarcoidosis were detected.
Sarcoidosis of the larynx(0.56-8.3%) is often a manifestation of multi-organ, systemic sarcoidosis and can lead to symptoms such as dysphonia, dysphagia, cough, and sometimes increased breathing due to obstruction of the upper respiratory tract. Sarcoidosis of the larynx can be detected by direct or indirect laryngoscopy: the tissues of the upper part of the larynx are symmetrically changed, the tissue is pale, swollen and similar to the tissue of the epiglottis. You can detect swelling and erythema of the mucous membrane, granulomas and nodes. The final diagnosis is confirmed by biopsy. Sarcoidosis of the larynx can lead to life-threatening airway obstruction. Inhaled and/or systemic steroids may be prescribed initially, but if symptoms persist and/or upper airway problems occur, corticosteroids may be injected into the affected area. In severe cases, tracheotomy, low-dose radiation therapy, and surgical excision are used.
Sarcoidosis of the ear refers to rare localizations of the disease and is usually combined with other localizations of the disease. Sarcoidosis of the ear is manifested by hearing loss, ringing in the ears, deafness, and vestibular disorders. Damage to the ear can be combined with damage to the salivary glands, often accompanied by paresis and paralysis of the facial nerve. Sarcoidosis can cause sensorineural hearing loss of varying severity. Cases with damage to the middle ear and conductive hearing loss have been reported. Granulomas are identified in the middle ear during diagnostic tympanotomy. The granulomatous process causes necrosis of the incus of the inner ear and surrounds the chorda tympani nerve. Ear involvement in sarcoidosis can be similar to many other ear diseases. Sarcoidosis is not suspected, and intrathoracic manifestations of the disease may be absent or go unnoticed. A combination of damage to several organs helps to suspect ear sarcoidosis.
Sarcoidosis of the mouth and tongue It is not common and can manifest as swelling and ulceration of the mucous membrane of the mouth, tongue, lips, and gums. Oropharyngeal sarcoidosis can cause obstructive sleep apnea as the only manifestation of the disease. Just as with sarcoidosis of other localizations, damage to the oral cavity and tongue can be either isolated or a manifestation of a systemic disease. Sarcoidosis of the oral cavity and tongue creates differential diagnostic problems. In case of histological confirmation of sarcoidosis of the oral cavity and tongue, further examination of the patient is necessary, aimed at searching for other localizations of sarcoidosis or the source of a sarcoid-like reaction. In cases of severe multiple organ damage, as a rule, the administration of systemic corticosteroids is required; in case of isolated damage, local use of anti-inflammatory drugs may be sufficient.

Sarcoidosis of the heart is one of the life-threatening manifestations of the disease, occurring in 2-18% of patients with sarcoidosis. The course of cardiac sarcoidosis is characterized by a certain autonomy, not coinciding with the phases of the process in the lungs and intrathoracic lymph nodes. There are fulminant (sudden cardiac death, infarction-like variant, cardiogenic shock), rapidly progressive (with an increase in the severity of manifestations to a critical level within a maximum of 1-2 years) and slowly progressive (chronic, with relapses and improvements) variants of cardiac sarcoidosis. Independent predictors of mortality are the functional class of circulatory failure (NC, according to the New York classification), end-diastolic size of the left ventricle (LV), and the presence of sustained ventricular tachycardia. Laboratory markers There are currently no drugs specific for cardiac sarcoidosis. The role of increased natriuretic peptides type A and B in patients with normal ejection fraction is discussed. The level of cardiac-specific enzymes and troponins increases extremely rarely. In patients with cardiac sarcoidosis, an increase in the titer of antibodies to the myocardium has been described without specifying the quantitative range. Frequency of detection of ECG pathology significantly depends on the nature of granulomatosis in the heart: 42% for the microscopic type and 77% for extensive granulomatous infiltration. To clarify the diagnosis, carry out myocardial scintigraphy with perfusion radiopharmaceuticals, cardiac MRI with delayed contrast enhancement with gadolinium diethyl pentaacetate, PET.

Neurosarcoidosis
Lesions of the nervous system occur in 5-10% of cases. The following clinical manifestations of neurosarcoidosis are distinguished:
1. Damage to the cranial nerves.
2. Damage to the membranes of the brain.
3. Hypothalamic dysfunction.
4. Lesions of the brain.
5. Lesions of spinal cord tissue.
6. Convulsive syndrome.
7. Peripheral neuropathy.
8. Myopathy.
The granulomatous process in sarcoidosis involves any parts of the central and peripheral nervous system, individually or in various combinations. Patients complain of chronic headaches of a dull, much less acute, and sometimes migraine nature; moderate, rarely intense, dizziness, usually in an upright position; swaying when walking, sometimes for several years; constant daytime sleepiness. The dominant place in objective neurological symptoms is occupied by dysfunction of the analyzers: vestibular, gustatory, auditory, visual, olfactory. In examining patients, CT and MRI studies are of leading importance. Sarcoidosis of the pituitary gland can manifest as dysfunction and impotence. Many nonspecific symptoms in sarcoidosis may indicate damage to small nerve fibers (small fiber neuropathy), the manifestation of which in 33% of cases is impotence. Clinical data, quantitative sensitivity testing, and skin biopsies suggest that small fiber neuropathy is a common finding in sarcoidosis. As a rule, patients with neurosarcoidosis require active treatment with SCS and immunosuppressants.

Sarcoidosis in gynecology

Sarcoidosis of the urinary tract. Sarcoidosis of the urethra in women occurred in isolated cases and was manifested by a decrease in the strength of the urine stream.

Sarcoidosis of the external genitalia is a very rare condition that manifests as nodular changes in the vulva and skin of the perianal area

Sarcoidosis of the ovaries and uterus. The most dangerous manifestation of sarcoidosis of the uterus is bleeding in postmenopause. The diagnosis is usually made accidentally after histological examination of material obtained during curettage or removal of the uterus.

Fallopian tube damage in sarcoidosis it was extremely rare in women with multiple organ damage.

Sarcoidosis of the breast often detected during examination for suspected breast cancer. It is diagnosed by biopsy of a dense, painless formation in the mammary gland based on the identification of multiple non-caseating granulomas.
Thus, sarcoidosis should not be considered as a condition that frequently and seriously impairs a woman’s reproductive function. In most cases, pregnancy can be saved, but in each case the issue must be resolved individually, and patronage of the pregnant woman should be carried out by both antenatal clinic doctors and sarcoidosis specialists.

Sarcoidosis in urology.
Sarcoidosis of the testis and appendages can occur both with intrathoracic lesions, with other extrathoracic manifestations, and without them. Sarcoidosis of the testis and appendages can be combined with oncopathology of the same location, or a granulomatous reaction can accompany the tumor process without being a sign of sarcoidosis.
Sarcoidosis of the prostate creates difficulties in differential diagnosis with prostate cancer, since it may be accompanied by elevated PSA levels.
Opinion about the active treatment of urogenital sarcoidosis in men is ambiguous: from the early use of glucocorticosteroids to prevent the development of male infertility to many years of observation without treatment and serious consequences; impotence in patients with sarcoidosis is very likely a consequence of damage to the pituitary gland and small fiber neuropathy.

Damage to the digestive system in sarcoidosis

Sarcoidosis of the salivary glands(6%) should be differentiated from changes in chronic sialadenitis, tuberculosis, cat scratch disease, actinomycosis and Sjogren's syndrome. It manifests itself as bilateral swelling of the parotid salivary glands, which is usually accompanied by damage to other organs. Occurs as part of a characteristic syndrome - Heerfordt-Waldenström) , when the patient has fever, enlarged parotid glands, anterior uveitis and facial paralysis (Bell's palsy).

Sarcoidosis of the esophagus extremely rare and difficult to diagnose localization. Traction diverticula are more common with granulomatous inflammation of the mediastinal lymph nodes; secondary achalasia due to sarcoidosis of the esophagus is described.
Sarcoidosisstomach occurs more often as granulomatous gastritis, can cause the formation of ulcers and gastric bleeding, formations similar to polyps during gastroscopy. In all patients, histological examination of biopsy specimens reveals noncaseating epithelioid cell granulomas.
Sarcoidosis of the intestine both thin and thick are presented in the literature by descriptions of individual cases confirmed by histological studies of biopsy specimens. May be combined with limited and massive abdominal lymphadenopathy.
Sarcoidosis of the liver referred to as a frequent (66-80% of cases) localization of the disease, often occurring latently. Multiple focal changes of reduced density have been described in the liver and spleen on RCT of the abdominal organs, even with a normal chest x-ray. Hepatopulmonary syndrome (HPS), characterized by a triad of severe liver pathology, arterial hypoxemia and intrapulmonary vascular dilatation, was rare in sarcoidosis. Liver sarcoidosis leads to cirrhosis and portal hypertension in only 1% of cases.
Pancreas It is rarely affected and changes may resemble cancer. Abdominal pain occurs in 2/3 of patients with pancreatic sarcoidosis, and hilar lymphadenopathy occurs in 3/4 of cases. Chronically elevated lipase levels may be one of the primary signs to rule out sarcoidosis. In some cases, diabetes mellitus may develop as a result of sarcoidosis infiltration of the pancreas.

FUNCTIONAL STUDIES
A mandatory and quite informative method is spirometry. From the entire complex of spirometric examinations, forced expiratory spirometry should be used with determination of volumes (FVC, FEV 1 and their ratio FEV 1 / FVC%) and volumetric velocities - peak (POV), and instantaneous at the level of 25%, 50% and 75% from the beginning forced expiration (MOE 25, MOE 50 and MOE 75). In addition, it is advisable to determine the average volumetric velocity in the area from 25% to 75% FVC (SOS 25-75). Spirometry should be performed at least once every 3 months during the active phase of the process and annually during follow-up.

The second important method is to measure diffusion capacity of the lungs single breath method to assess the degree of carbon monoxide absorption ( DLco). This technique is usually available in pulmonary or diagnostic centers.
Assessment of lung compliance, based on measurement of intraesophageal and transdiaphragmatic pressure, is not recommended for widespread use, but can be used in centers involved in the diagnosis of sarcoidosis to assess the dynamics of the condition of patients with a pronounced interstitial process in the lungs.

Results of pulmonary respiratory function (RPF) studies in sarcoidosis very heterogeneous. In stage I, the state of the respiratory apparatus remains intact for a long time. As sarcoidosis progresses, changes occur that are characteristic of both interstitial lung lesions and hilar lymphadenopathy. Most patients with progressive sarcoidosis develop restrictive disorders, but endobronchially located granulomas can lead to the development of irreversible bronchial obstruction. The type of impairment does not strictly correlate with the stage of sarcoidosis (with the exception of stage IV). Thus, in patients with stage III sarcoidosis, both types of dysfunction of external respiration are described - with a predominance of obstruction and with a predominance of restriction.

Restrictive changes with progressive intrathoracic sarcoidosis, they are primarily due to increasing fibrosis of the lung tissue and the formation of a “honeycomb lung”. A decrease in VC (FVC) during a dynamic study indicates the need for active therapy or correction of treatment. To accurately diagnose restrictive syndrome, it is necessary to conduct body plethysmography with assessment of total lung capacity (TLC) and residual volume (RR).

Obstructive syndrome in the early stages it is manifested by a decrease only in MOS 75 . Approximately half of the patients have reduced MOC 50 and MOC 75 in combination with a decrease in DLco. The classic test with a short-acting bronchodilator in patients with sarcoidosis is negative; the use of SCS does not improve the response to the bronchodilator. Some patients may experience improvement in obstruction after treatment with SCS or methotrexate. Bronchial hyperreactivity, proven by a methacholine test, often accompanies endobronchial sarcoidosis.
To assess the safety and reversibility of the functional state of the lungs during observation and treatment, FVC (VC) and DLco are the most informative

Diffusion capacity of the lungs (DLco) - an indicator that is included in the standard of mandatory examination for interstitial (diffuse, disseminated) lung diseases. In sarcoidosis, DLco is a highly informative and dynamic parameter. Cellular infiltration can deform the capillary bed and lead to reversible disturbances in gas exchange. More often, disorders of diffusion capacity in patients occur in stages II, III and IV of the disease, with dissemination of sarcoid foci and the development of pneumofibrosis.

Gas exchange disorders in sarcoidosis can be detected by measuring blood oxygen saturation (saturation, Sa0 2) during the 6-minute walk test (6MWT). In patients with stage II or higher sarcoidosis, 6MWD may be reduced. Factors limiting this distance were FVC, saturation during exercise, and self-assessed respiratory health status.

Violations of central respiratory function and muscle disorders. The lungs are affected in most cases of sarcoidosis, but respiratory failure is not necessarily a consequence of damage to the lungs themselves. Impaired respiratory regulation with hypoxemia requiring ventilatory support may be due to neurosarcoidosis (this should be taken into account when saturation is reduced in patients with sarcoidosis). A decrease in spirometry parameters may also be a consequence of muscle damage by sarcoidosis. Maximum oral pressure during inspiration (PImax) and during expiration (PEmax) are reduced in every third patient with sarcoidosis.

Cardiopulmonary stress tests are more sensitive indicators of early detection of lung disease than pulmonary function tests in patients with sarcoidosis. Changes in gas exchange during exercise may be the most sensitive method to reflect the prevalence of sarcoidosis in its early stages. In sarcoidosis, there is a decrease in maximum aerobic capacity (VO2max) by 20-30%. This was noted in patients with both normal and impaired respiratory function, which makes the mechanism of this phenomenon unclear. Explanations for hypoventilation could include muscle weakness or decreased stimulus from the central nervous system.

VISUALIZATION METHODS

Due to the difficulties of clinical and laboratory recognition of sarcoidosis in various organs, a decisive role in its diagnosis belongs to medical imaging methods, which include traditional X-ray techniques, computed tomography (CT), magnetic resonance imaging (MRI), radionuclide methods, ultrasound ( Ultrasound), including endoscopic ultrasound with fine-needle biopsy of lymph nodes.

Traditional X-ray techniques important in the primary diagnosis of intrathoracic sarcoidosis are verification fluorography and plain radiography in two projections. Radiography retains its importance in dynamic monitoring and evaluation of treatment effectiveness. Special X-ray techniques, such as linear tomography, contrast techniques, and x-ray functional techniques have now lost their practical significance and are replaced by computed tomography (CT). An X-ray of a patient with intrathoracic sarcoidosis reveals a symmetrical enlargement of the lymph nodes of the roots of the lungs and/or bilateral focal interstitial changes in the lungs. There is a characteristic discrepancy between the relatively satisfactory condition of the patient and the prevalence of the pathological process in the photographs. It should be remembered that an atypical radiological picture of sarcoidosis is possible - unilateral enlargement of the upper mediastinal lymph nodes or lymph nodes, unilateral dissemination, foci, infiltrates, cavities, bullae. In 5-10% of cases of sarcoidosis, there are no changes in the lungs on radiographs at all.
The X-ray method, while maintaining a leading place in the primary detection of pulmonary pathology, is gradually losing its importance in characterizing pulmonary disease. Moreover, the so-called radiological stages that form the basis for the classification of sarcoidosis do not reflect the chronology of the process; they are more accurately called types or variants of the course of the process. This became especially obvious when X-ray computed tomography became widely used in the diagnosis and monitoring of patients with sarcoidosis.

CT scan is currently the most accurate and specific method for diagnosing intrathoracic and extrapulmonary sarcoidosis.
Currently, two CT technologies are used in the diagnosis of sarcoidosis. The first of these is a traditional step-by-step study, in which individual thin tomographic slices (1-2 mm) are separated from each other by a distance of 10-15 mm. Such a study can be carried out on any tomograph. It allows you to obtain a detailed image of the smallest anatomical structures of the lung tissue and identify minimal pathological changes in it. The disadvantage of step-by-step technology is the selective image of the pulmonary parenchyma, the impossibility of constructing two and three-dimensional reformations, the difficulty of assessing soft tissue structures and blood vessels of the mediastinum, for which it is necessary to first perform a series of standard tomograms with a thickness of 8-10 mm.

The advent of multi-slice CT (MSCT) has significantly changed the approach to diagnosing pulmonary pathology. Tomographs with a multi-row detector allow one X-ray beam to be divided into several tomographic layers, from 4 to 300 or more. The advantage of MSCT is the ability to obtain a series of adjacent tomographic slices with a thickness of 0.5 - 1 mm. The result of spiral scanning with MSCT is the ability to construct two and three-dimensional reformations, as well as simultaneous HRCT and CT angiography.

Sarcoidosis is characterized by enlargement of the lymph nodes of all groups of the central mediastinum and the roots of the lungs, which is radiographically manifested by a bilateral expansion of the shadow of the mediastinum and the roots of the lungs, and the polycyclic nature of their contours. Lymph nodes have a spherical or ovoid shape, a homogeneous structure, smooth clear contours, without perifocal infiltration and sclerosis. With a significant increase in lymph nodes, causing external compression of the bronchi, changes characteristic of hypoventilation and atelectatic disorders may appear in the lungs. However, such changes are observed much less frequently than with tuberculosis or tumor damage to the lymph nodes. With a long-term chronic course, calcifications appear in the structure of the lymph nodes in a third of patients. The latter in the CT image appear as multiple, bilateral, monolithic, irregularly shaped calcareous inclusions located away from the bronchi in the center of the lymph nodes.

The most characteristic sign of sarcoidosis is dissemination of a mixed, focal and interstitial nature. Most large ones show polymorphism of focal changes. Multiple small foci are located along the bronchovascular bundles, interlobar fissures, costal pleura, and in the interlobular septa, causing uneven (“bead-shaped”) thickening of the interstitial structures of the lungs. This type of distribution of foci along the pulmonary interstitium is defined in CT as perilymphatic, i.e. lesions arise and are visualized along the course of the lymphatic vessels. Unlike other diseases with a similar distribution of foci, such as lymphogenous carcinomatosis, in sarcoidosis it is focal changes in combination with peribronchial and pervascular couplings that predominate, while thickening of the interlobular and intralobular septa is observed to a much lesser extent. One of the manifestations of active sarcoidosis on HRCT may be a “ground glass” symptom of varying extent and localization. The morphological substrate of the ground glass symptom is a multitude of tiny foci that are indistinguishable on HRCT as independent formations or, in more rare cases, true “ground glass” is observed as a manifestation of diffuse thickening of the interalveolar septa due to alveolitis. Such changes must be differentiated from lymphogenous disseminated tuberculosis, allergic alveolitis and desquamative interstitial pneumonia.

The chronic relapsing course of sarcoidosis is characterized by the appearance of polymorphism of focal changes, in the form of an increase in the size of the lesions, deformation of their contours and merging into small zones of consolidation. Along with this, varying degrees of severity of infiltration and sclerosis of the interstitial structures of the lungs are determined. More or less large soft tissue conglomerates are formed around the upper lobe bronchi, inseparable from the anatomical structures of the root. In the structure of the soft tissue masses, deformed lumens of the bronchi are visible. Peribronchial conglomerates spread deep into the lung tissue along the bronchovascular bundles. In such infiltrates, cavities may form.

The fourth stage of intrathoracic sarcoidosis is characterized by fibrous transformation of the lung tissue of varying degrees with the formation of pleuropneumocirrhosis, dystrophic changes, the development of honeycomb lung or emphysema. In most cases, extensive areas of pneumosclerosis form in the lung tissue in the form of zones of compaction of the lung tissue with dilated and deformed air gaps of the bronchi visible in them. Such changes are usually observed in the upper lobes, in the basal region. The volume of the upper lobes decreases. Which leads to swelling of the cortical and supradiaphragmatic parts of the lungs, and in the most severe cases - to the formation of bullous emphysema and honeycomb lung.

Magnetic resonance imaging(MRI) in patients with sarcoidosis has diagnostic capabilities similar to CT in detecting hilar lymphadenopathy. But in assessing the condition of the pulmonary parenchyma, MRI is significantly inferior to CT and therefore has no independent diagnostic value. MRI is informative in neuro- and cardiac sarcoidosis.

From radionuclide methods Studies for respiratory sarcoidosis use perfusion pulmonary scintigraphy with MMA-Tc-99m and positive pulmonary scintigraphy with Ga-67 citrate. Scintigraphic methods have an important diagnostic value for characterizing disturbances in pulmonary microcirculation and the function of lymph nodes, both in the area of ​​localization of the process and in intact parts of the lung, and make it possible to clarify the prevalence and degree of activity of the inflammatory process in patients with various courses of respiratory sarcoidosis.
However, radionuclide testing is not a method of nosological diagnosis and a positive result of pneumoscintigraphy with Ga-67 citrate is not diagnostic for sarcoidosis, since increased accumulation of radiopharmaceuticals in the lungs and VLN is found in tumors, metastatic lesions, various inflammatory and granulomatous diseases, and tuberculosis.

Positron emission tomography(PET) is one of the relatively new methods of radiological diagnostics. The most common indicator is 18-fluoro-2-dioxyglucose (18FDG). In addition, the clinic uses radiopharmaceuticals labeled with 13N and 15O. In sarcoidosis, PET allows one to obtain reliable information about the activity of the process, and in combination with anatomical imaging methods (CT, MRI) to identify the localization of increased metabolic activity, that is, the topography of active sarcoidosis. Treatment with prednisolone suppressed inflammatory activity to such an extent that it was undetectable by PET.

Endoscopic ultrasound examination with transesophageal fine-needle aspiration biopsy of the mediastinal lymph nodes, it is currently becoming the most promising method for the differential diagnosis of lymphadenopathy. The endoscopic echographic picture of the lymph nodes in sarcoidosis has some distinctive features: the lymph nodes are well delimited from each other; the structure of the nodes is isoechoic or hypoechoic with atypical blood flow. However, these features do not allow differentiating lymph node damage in sarcoidosis from tuberculosis or tumor.

Radiation diagnosis of extrapulmonary sarcoidosis. Ultrasound usually reveals multiple hypoechoic nodes, which are localized in both the liver and spleen. In some patients, CT examinations will not only confirm hepatolienal changes, but also detect small focal changes and infiltrates in both lungs, with or without hilar lymphadenopathy. Computed tomograms, as a rule, show hepatomegaly with smooth or wavy contours and diffuse heterogeneity of the parenchyma. When contrasting, small foci of low density can be detected in the liver structure. In most cases, splenomegaly and enlarged lymph nodes in the hepatoduodenal ligament, at the hilum of the liver and spleen, and in peripancreatic tissue are also detected. CT changes in granulomatous diseases are nonspecific and require morphological verification.

In cardiac sarcoidosis, ultrasound reveals single lesions in the myocardium, including in the interventricular septum, measuring 3-5 mm. Lesions in the heart can become calcified over time. An ECG may record extrasystoles and conduction disturbances. With MRI, in the affected area of ​​the heart there may be an increase in signal intensity on T-2 weighted images and after contrast on T-1 weighted images. In rare cases, on CT, cardiac sarcoidosis may manifest itself as areas of myocardial thickening that weakly accumulate the contrast agent, but this sign is nonspecific and can only be considered in conjunction with clinical and laboratory data.
In neurosarcoidosis, MRI reveals hydrocephalus, dilatation of the basal cisterns, single or multiple granulomas, isointense on T-1 weighted tomograms and hyperintense on T-2 weighted images with good signal enhancement after contrast. Typical localization of sarcoids is the hypothalamus and the optic chiasm area. Vascular thrombosis with micro-strokes is possible. MRI is especially sensitive for meningeal lesions.

Sarcoidosis of bones and joints appears on radiographs and X-rays as cystic or lytic changes. MRI for musculoskeletal symptoms reveals infiltration of small and large bones, signs of osteonecrosis, arthritis, infiltration of soft tissues, mass formations of various locations, myopathy and nodular formations in the muscles. It is important that of those patients in whom bone lesions were detected on MRI, X-ray examination showed similar changes in only 40% of cases.

INVASIVE DIAGNOSTIC METHODS
Pulmonary sarcoidosis requires differential diagnosis with a number of pulmonary diseases, which is based on morphological verification of the diagnosis. This makes it possible to protect such patients from the most often unreasonably prescribed anti-tuberculosis chemotherapy or chemotherapy with antitumor drugs. Systemic steroid therapy used as indicated for sarcoidosis should also be used only in the presence of a morphologically confirmed diagnosis, so as not to cause a sharp progression of the disease in people with an erroneous diagnosis of sarcoidosis.
Sarcoidosis refers to diseases in which only the study of tissue material allows one to obtain diagnostically significant data, in contrast to tuberculosis and some lung cancers, when it is possible to examine natural secretions (sputum) for the content of the pathogen or tumor cells.

Ideally, the diagnosis of sarcoidosis is established when clinical and radiological data are supported by the identification of non-caseating (without necrosis) epithelioid cell granulomas in a biopsy of lung tissue and/or lymph node and/or bronchial mucosa.
In patients with pulmonary sarcoidosis, morphological verification of the diagnosis should be carried out in all cases immediately after identifying radiological changes in the lymph nodes of the mediastinum and/or pulmonary tissue, regardless of the presence or absence of clinical manifestations. The more acute the process and the shorter its duration, the greater the likelihood of obtaining a biopsy containing structures typical for this disease (non-caseating epithelioid cell granulomas and foreign body cells).
In world practice (including in the Russian Federation), it is considered advisable to use the following biopsy methods for diagnosing pulmonary sarcoidosis:

Bronchoscopic:
· Transbronchial lung biopsy (TBL). It is performed during bronchoscopy with special micronippers, which move into the subpleural space under X-ray control or without it and biopsy the lung tissue there. As a rule, it is carried out in the presence of dissemination in the lung tissue, but in patients with sarcoidosis it is quite effective even with radiologically intact lung tissue.
· Classical transbronchial needle biopsy of intrathoracic lymph nodes - KCHIB VGLU (synonym transbronchial needle aspiration (VHLN), international abbreviation TBNA). It is carried out during bronchoscopy with special needles; the puncture site through the bronchial wall and the depth of penetration are selected in advance according to computed tomography data. It is carried out only with a significant increase in the VGLU of certain groups.
· Endoscopic fine-needle puncture of mediastinal lymph nodes under endosonography control. It is carried out during endoscopy with an ultrasound bronchoscope or ultrasound gastroscope with special needles, “targeting” and the puncture itself are controlled by ultrasound scanning [EUSbook 2013]. Use only for enlarged VGLUs. There are the following types of these biopsies used for pulmonary sarcoidosis:

♦ Transbronchial fine-needle aspiration biopsy guided by endobronchial sonography EBUS-TTAB (international abbreviation - EBUS-TBNA) . Performed during bronchoscopy using an ultrasound bronchoscope.
♦ Fine-needle aspiration biopsy under endosonography control EUS-FNA (international abbreviation - EUS-FNA) (transesophageal using an ultrasound gastroscope). It is carried out during esophagoscopy with an ultrasound gastroscope.
♦ Fine-needle aspiration biopsy under endosonography control EUS-b-FNA (international abbreviation - EUS-b-FNA) (transesophageal using an ultrasound bronchoscope). It is carried out during esophagoscopy with an ultrasound bronchoscope.
· Direct biopsy of the bronchial mucosa (direct biopsy). Biting of the mucous membrane is performed during bronchoscopy. It is used only in the presence of changes in the mucosa characteristic of sarcoidosis.
· Brush biopsy of the bronchial mucosa (brush biopsy). Scarification is carried out and the layer of bronchial mucosa is removed with a special brush. It is used only in the presence of mucosal changes characteristic of sarcoidosis.
· Bronchoalveolar lavage (BAL), to obtain bronchoalveolar lavage (synonym - bronchoalveolar lavage fluid), is performed during bronchoscopy by injecting and aspirating saline into the bronchoalveolar space. The ratio of lymphocyte subpopulations has diagnostic value, but the cytogram is mainly used to determine the activity of sarcoidosis.

Surgical methodsbiopsy

Thoracotomy With biopsy lung And intrathoracic lymphatic nodes .
The so-called “open biopsy” is currently used extremely rarely due to its traumatic nature; its more gentle version is more often used - minithoracotomy, which also makes it possible to remove fragments of the lung and lymph nodes of any group.
During the operation, endotracheal anesthesia is used and an anterolateral thoracotomy is used through the 4th or 5th intercostal space, which provides an optimal approach to the elements of the lung root.
Indications For this type of surgical intervention, it is impossible at the preoperative stage to classify the process in the lung tissue and mediastinal lymph nodes as benign. Suspicious cases are isolated asymmetrical round shadows in combination with mediastinal lymphadenopathy, which are often manifestations of a blastomatous process in people over 50 years of age. In such cases, the diagnosis of respiratory sarcoidosis is a histological finding within the walls of oncological institutions.
Relative contraindications As with any abdominal surgery, there are unstable conditions of the cardiovascular and respiratory systems, severe liver and kidney diseases, coagulopathy, decompensated diabetes mellitus, etc.
Thoracotomy is accompanied by a long postoperative recovery period. Patients in most cases complain of pain in the area of ​​the postoperative scar, a feeling of numbness in the dermatome along the damaged intercostal nerve, which persists for up to six months and, in some cases, for life.
Thoracotomy provides the best access to the organs of the chest cavity, but the risks of general anesthesia, surgical trauma, and prolonged hospitalization must always be assessed. Typical complications of thoracotomy are hemothorax, pneumothorax, the formation of bronchopleural fistulas, and pleurothoracic fistulas. The mortality rate from this type of surgical intervention ranges from 0.5 to 1.8%, according to various sources.

Videothoracoscopy/ video- assisted thoracoscopy (VATS).
There are the following types of minimally invasive intrathoracic interventions:
· Videothoracoscopic operations, in which a thoracoscope and instruments combined with a video camera are inserted into the pleural cavity through thoracoports,
· Operations with video-assisted support, when they combine mini-thoracotomy (4-6 cm) and thoracoscopy, which allows for a double view of the operated area and the use of traditional instruments.
These methods of minimally invasive interventions significantly reduced the length of hospitalization of patients and the number of postoperative complications.
Absolute contraindications for videothoracoscopy are obliteration of the pleural cavity - fibrothorax, unstable hemodynamics and the patient's shock state.
Relative contraindications are: the impossibility of separate ventilation of the lungs, previous thoracotomies, a large volume of pleural damage, coagulopathy, previous radiation therapy for lung tumors and plans for lung resection in the future.

Mediastinoscopy

The procedure is low-traumatic, highly informative in the presence of enlarged groups of lymph nodes available for inspection, and is significantly lower in cost than thoracotomy and videothoracoscopy.

Absolute contraindications: contraindications for anesthesia, extreme kyphosis of the thoracic spine, the presence of a tracheostomy (after laryngectomy); superior vena cava syndrome, previous sternotomy, mediastinoscopy, aortic aneurysm, tracheal deformities, severe lesions of the cervical spinal cord, radiation therapy of the mediastinum and neck organs.

Algorithm for using biopsies:
· first, endoscopic (bronchoscopic or transesophageal) biopsies are performed, if there are changes in the bronchial mucosa - direct biopsy and brush biopsy of areas of the mucosa. If enlarged VLNs are identified that are available for aspiration biopsy, CCIP VLNs or EBUS-TBNA and/or transesophageal EUS-b-FNA are also performed
· surgical biopsies are performed only in those patients in whom endoscopic methods failed to obtain diagnostically significant material, which is about 10% of patients with sarcoidosis. More often this is VATS resection, as the least traumatic of the operations, less often classic open biopsy, and even less often mediastinoscopy (due to the small number of available VGLU groups).
Positive points use of endoscopic techniques: the ability to perform on an outpatient basis, under local anesthesia or sedation; conducting several types of biopsies from different groups of lymph nodes and different areas of the lung and bronchi in one study; low rate of complications. Significantly lower cost than surgical biopsies.
Negative points: small size of the biopsy, which is sufficient for cytological, but not always for histological studies.
Contraindication for all types of endoscopic biopsies there are all contraindications for bronchoscopy and additionally - a violation of the blood coagulation system, the presence of an infectious process in the bronchi, accompanied by purulent discharge
Indicators of the effectiveness of endoscopic biopsies, including comparative ones.

Transbronchial lung biopsy(NBL) is the recommended biopsy for sarcoidosis. Diagnostic yield largely depends on the experience of the procedure performed and the number of biopsies, and also carries the risk of pneumothorax and bleeding.
The overall diagnostic level for sarcoidosis was significantly better by EBUS-TBNA than by PBL (p<0,001). Но анализ с учетом стадии процесса показал, что эта разница за счет пациентов с 1 стадией процесса - у них диагностирован саркоидоз по EBUS-TBNA в 90,3% (обнаружены неказеозные гранулёмы и/или эпителиоидные клетки), при ЧБЛ у 32,3% пациентов (p<0.001). У пациентов со II стадии каждый метод имеет 100% диагностическую эффективность при отсутствии осложнений. Частота ятрогенного пневмоторакса составляет 0,97% (из них 0,55% требующего дренирования плевральной полости) и частота кровотечений 0,58%.

Classic transbronchial needle biopsy intrathoracic lymph nodes - KIB VGLU has a diagnostic value of up to 72% in patients with stage 1 pulmonary sarcoidosis, sensitivity - 63.6%, specificity - 100%, positive predictive value - 100%, negative predictive value - 9.1%.

Transesophageal fine-needle aspiration biopsy under endosonography-guided EUS-FNA (EUS- FNA) AndEUS- b- FNA have a very high diagnostic value and have sharply reduced the number of mediastenoscopies and open biopsies in the diagnosis of pulmonary sarcoidosis. These types of biopsies are used only when the mediastinal lymph nodes adjacent to the esophagus are affected.

Transbronchial fine needle aspiration biopsy guided by endobronchial sonography EBUS-TBNA is a reasonable method for assessing the condition of intrathoracic lymphatics in the absence of severe complications. With its help, it is possible to diagnose sarcoidosis, especially in stage I, when there is adenopathy, but there are no radiological manifestations in the lung tissue. Comparison of the results of modern sonography-guided biopsy - EBUS-TBNA and mediastinoscopy for mediastinal pathology proved a high agreement of methods (91%; Kappa - 0.8, 95% confidence interval 0.7-0.9). The specificity and positive predictive value for both methods were 100%. Sensitivity, negative predictive value, and diagnostic accuracy were 81%, 91%, 93% and 79%, 90%, 93%, respectively. At the same time, there are no complications with EBUS - TBNA, and with mediastinoscopy - 2.6%.

Direct biopsy of the bronchial mucosa (direct biopsy) and brush biopsy of the bronchial mucosa (brush biopsy). During bronchoscopy, in 22 - 34% of patients in the active phase of pulmonary sarcoidosis, changes in the bronchial mucosa characteristic of this disease are revealed: tortuous vessels (vascular ectasia), single or multiple whitish formations in the form of nodules and plaques, ischemic areas of the mucosa (ischemic spots). With such changes in 50.4% of patients, and with unchanged mucosa - in 20%, it is possible to identify non-caseating granulomas and/or epithelioid cells in the biopsy specimen.

Bronchoalveolar lavage, Liquid biopsy is performed in patients with sarcoidosis during diagnosis and during treatment. Thus, the CD4/CD8 ratio > 3.5 is characteristic of sarcoidosis, and occurs in 65.7% of patients with stage 1-2 sarcoidosis. An endopulmonary cytogram of bronchoalveolar lavage obtained as a result of BAL is used to characterize the activity of pulmonary sarcoidosis and the effectiveness of treatment: with an active process, the proportion of lymphocytes reaches 80%, with stabilization it decreases to 20%.

Laboratory diagnostics

Laboratory diagnostics

Interpretation of laboratory results and additional tests
Clinical blood test

may be within normal limits. Nonspecific and at the same time important is the increase in ESR, which is most pronounced in acute variants of sarcoidosis. Wave-like changes in ESR or a moderate increase are possible for a long time with a chronic and asymptomatic course of the disease. An increase in the number of leukocytes in peripheral blood is possible in acute and subacute sarcoidosis. Signs of activity also include lymphopenia. Interpretation of a clinical blood test should be carried out taking into account the therapy being performed. When using systemic steroids, the ESR decreases and the number of peripheral blood leukocytes increases, and lymphopenia disappears. During methotrexate therapy, monitoring the number of leukocytes and lymphocytes is a criterion for the safety of treatment (simultaneously with assessing the values ​​of aminotransferases - ALT and AST). Leuko- and lymphopenia in combination with an increase in ALT and AST are indications for discontinuation of methotrexate.

Thrombocytopenia in sarcoidosis it occurs with damage to the liver, spleen and bone marrow, which requires appropriate additional examinations and differential diagnosis with autoimmune thrombocytopenic purpura.

Renal function assessment includes a general urine test, determination of creatinine, blood urea nitrogen.

Angiotensin converting enzyme (ACE). In granulomatous diseases, local stimulation of macrophages leads to abnormal ACE secretion. Determining ACE activity in the blood takes 5-10 minutes. When taking blood from a vein for this study, you should not apply a tourniquet for too long a time (more than 1 minute), as this will distort the results. 12 hours before taking blood, the patient should not drink or eat. The basis for determining ACE is the radioimmune method. For persons over 20 years of age, values ​​from 18 to 67 units per liter (u/l) are considered normal. In younger people, ACE levels fluctuate significantly and this test is not usually used. With a sufficient degree of certainty, a pulmonary process can be defined as sarcoidosis only when serum ACE activity reaches more than 150% of normal. An increase in ACE activity in the blood serum should be interpreted as a marker of the activity of sarcoidosis, and not a significant diagnostic criterion.

C-reactive protein- a protein of the acute phase of inflammation, a sensitive indicator of tissue damage during inflammation, necrosis, and injury. Normally less than 5 mg/l. Its increase is characteristic of Löfgren's syndrome and other variants of the acute course of sarcoidosis of any localization.

Calcium levels in blood and urine. Normal serum calcium levels are as follows: general 2.0—2.5 mmol/l, ionized 1.05-1.30 mmol/l; in urine - 2.5 -- 7.5 mmol/day; in the cerebrospinal fluid - 1.05 - 1.35 mmol/l; in saliva - 1.15 - 2.75 mmol/l. Hypercalcemia in sarcoidosis is considered to be a manifestation of active sarcoidosis, caused by overproduction of the active form of vitamin D (1,25-dihydroxyvitamin D3 or 1,25(OH)2D3) by macrophages at the site of the granulomatous reaction. Hypercalciuria is much more common. Hypercalcemia and hypercalciuria with established sarcoidosis are a reason to start treatment. In this regard, you should be careful with nutritional supplements and vitamin complexes containing high doses of vitamin D.

Kveim-Silzbach test. Kveim Breakdown called intradermal injection of tissue from a lymph node affected by sarcoidosis, in response to which in patients with sarcoidosis a papule is formed, upon biopsy of which characteristic granulomas are found. Louis Silzbach improved this test using a spleen suspension. Currently, the test is not recommended for widespread use and can be used in well-equipped centers specifically involved in the diagnosis of sarcoidosis. This procedure may introduce an infectious agent if the antigen is poorly prepared or poorly controlled.

Tuberculin test is included in the list of mandatory primary research in both international and domestic recommendations. The Mantoux test with 2 TE PPD-L in active sarcoidosis gives a negative result. When treating SCS in patients with sarcoidosis who were previously infected with tuberculosis, the test may become positive. A negative Mantoux test has high sensitivity for diagnosing sarcoidosis. BCG vaccination carried out in childhood has no correlation with tuberculin reaction in adults. Tuberculin anergy in sarcoidosis is not associated with tuberculin sensitivity in the general population. A positive Mantoux test (papule 5 mm or more) in a suspected case of sarcoidosis requires a very careful differential diagnosis and exclusion of concomitant tuberculosis. The significance of Diaskintest (intradermal injection of recombinant tuberculosis allergen - CPF10-ESAT6 protein) in sarcoidosis has not been definitively established, but in most cases its result is negative.

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It is an epithelioid cell granulomatosis. The nature of its occurrence has not yet been established. Sarcoidosis affects more than just the lungs. The disease is multiorgan. That is, it can damage many organs.

Epidemiology

Most often, sarcoidosis develops in adults aged 20 to 40 years, but this does not mean that people of other age groups cannot get sick. For sarcoidosis, there are no boundaries in its distribution such as gender or race.

The most severe cases of pathology are found in residents of African countries and representatives of the Negroid race. Uveitis is considered common in these people. Residents of Europe experience such sarcoidosis symptoms, as skin lesions that are very painful, the eyes and heart are affected in Asians.

In Russia, sarcoidosis manifests itself as intrathoracic diseases, which include lung diseases.

Possibilities of modern medicine in relation to sarcoidosis

At the moment, sarcoidosis can be easily diagnosed using modern examination methods. Everything would be fine, but in the treatment of the disease there are many pitfalls associated with the unknown origin of the disease. If we don't know what caused the pathology, we don't know how to treat it effectively.

Lung damage in sarcoidosis

In the lungs, granulomatous inflammation can occur due to many reasons. Of these, one can distinguish the presence of a specific antigen, which causes the development of the inflammatory process.

This reaction is very similar to the reaction in pulmonary tuberculosis, but in tuberculosis the microbe itself is the antigen that provokes a granulomatous response of the immune system. It is clear that it is necessary to treat tuberculosis with antibiotics, because there is a known microorganism.

Who should treat a patient with sarcoidosis?

Sarcoidosis should always be managed with the participation of a pulmonologist. However, if there are symptoms from the eyes, heart, nervous system, kidneys, consultations with specialized specialists are necessary, which, in principle, is carried out when the patient sees a doctor and an appropriate diagnosis is made. Many doctors believe that there are patients with sarcoidosis who do not need treatment.

Criteria for assessing sarcoidosis

Using these criteria, doctors can determine the activity of the disease and its negative dynamics. Of these, the most important are:

• deterioration of respiratory function;
• deterioration of the X-ray picture of the lungs;
• increased shortness of breath with light physical activity and at rest;
• increased need for treatment.

If immunosuppressive therapy (therapy that suppresses the activity of the patient's immune system) is stopped, the disease relapses in 15-75% of cases, although some experts caution not to treat all such relapses as relapses themselves, since they may be a normal exacerbation of the disease. Relapse differs from exacerbation in that it occurs after complete cure of the pathology. An exacerbation develops against the background of a chronic process.

In order to correctly assess the activity of the process and the effectiveness of treatment, determination of the level of soluble interleukin is used.

What medications are used for sarcoidosis?

Glucocorticosteroids

The first drugs for treatment of sarcoidosis glucocorticosteroids (GCS) are considered to be used. When using oral corticosteroids, systemic inflammation subsides in many patients, which helps save the organ from irreversible damage. These medications can be prescribed either alone or in combination with other drugs. GCS is prescribed per day in a dosage of 3 to 40 mg/kg, and the dosage decreases over the course of a year.

GCS drugs are quite dangerous and the consequences of their use can be:

• diabetes;
• significant increase in body weight;
• development .

If there is bronchial hyperreactivity, which has been clinically proven, GCS can be used in the form of inhalations.

Antimalarials

Hydroxychloroquine has been used successfully to treat sarcoidosis. However, for pulmonary lesions it is almost never used. This drug is effective mainly for skin lesions, hypocalcemia and joint damage. Of the side effects of hydrochloroquine, the most striking are diseases of the eyes, skin and liver. To prevent the occurrence of eye diseases, an ophthalmologist is examined every six months.

For pulmonary sarcoidosis, another drug from this group is used - chloroquine. This form of antimalarial drug is more toxic and is therefore rarely used.

Methotrexate

This drug replaces GCS in sarcoidosis and is cytotoxic. Its effectiveness is high, toxicity is low, and the drug is also affordable. The use of methotrexate is recommended only in case of ineffectiveness of GCS, in the presence of adverse reactions caused by them, as a means of helping to reduce the dose of GCS.

Methotrexate can also be used as a base drug, but only in combination with GCS.

To reduce toxicity to a minimum, folic acid is prescribed along with methotrexate.

Azathioprine

Research on the drug shows. That it is as effective as methotrexate described above. Azathioprine is used in cases of intolerance to methotrexate. Contraindications to the use of methotrexate include renal and liver failure.

Side effects of azathioprine:

• dyspepsia;
• mouth ulcers;
• muscle pain;
• jaundice;
• weakness;
• blurred vision.

However, azathioprine is more likely to cause opportunistic infections and cancer.

Mycophenolate mofetil

The drug was first synthesized to relieve rejection after organ transplantation. At the moment, its use is wider: autoimmune diseases, inflammatory processes of a systemic nature, such as lupus nephritis, rheumatoid arthritis.

Side effects of the drug include diarrhea, vomiting, and sepsis. When prescribing it, it is necessary to conduct a laboratory blood test every 3 months.

Peculiarities treatment of sarcoidosis lungs

The doctor will approach the treatment of pulmonary sarcoidosis individually, depending on the presence of symptoms and functional disorders. If there are no symptoms and the radiation stage of the disease is in the range 0-1, there is no need to treat such a disease. It is necessary to carry out dynamic observation so as not to miss the activation of the pathological process.

If there is no shortness of breath in patients with stage 2-4 sarcoidosis, GCS should not be prescribed. This type of patient management tactics is used by European doctors. If the respiratory function is preserved or if it is slightly reduced, the patient can only be observed without the use of medications. Practice shows that the condition of 70% of these patients remains stable, and some even improve.

Patients with stage 0-1 sarcoidosis and shortness of breath are recommended to undergo cardiac ultrasound every six months to identify the causes of shortness of breath. X-ray computed tomography is also used, which makes it possible to detect changes in the lungs that are indiscernible with conventional radiography.

We know that this is caseless granulomatosis, we can recognize it with a high degree of probability during an X-ray examination, we have studied Löfgren's syndrome well... However, we do not know what causes this disease, so all therapeutic interventions are aimed at the effect, and not at the cause. In such a situation, any medicinal or other medical intervention should first of all be guided by the principle of “do no harm.” Therefore, it is necessary to determine where and when patients with sarcoidosis should be treated.

Where to treat?

If the leading role of the TB service in the early detection of intrathoracic sarcoidosis is to retain its importance, then the stay of these patients in TB hospitals should be reconsidered. At the very least, it is inhumane to treat a patient without tuberculosis with hormones and cytostatics in the same clinic with patients from whose sputum in 30–50% of cases mycobacteria resistant to anti-tuberculosis drugs are cultured. In anti-tuberculosis institutions, patients with sarcoidosis are often prescribed tuberculostatic drugs for preventive or differential diagnostic purposes, which creates new problems.

If a TB doctor wants to protect himself from a lawsuit from a patient, then he should obtain the informed consent of the patient, which clearly states the risk of contracting tuberculosis.

Quite a long time ago, phthisiopediatricians proposed keeping records of children with sarcoidosis in anti-tuberculosis dispensaries during the period of differential diagnosis (registration group 0), and then observing them with a local pediatrician, conducting repeated courses of treatment in children's hospitals. It is also proposed to cancel the 8th group of dispensary registration in anti-tuberculosis institutions, and transfer information about patients with sarcoidosis to the clinic at the place of residence.

This question remains open, in reality, some patients are still under the patronage of phthisiatricians and receive isoniazid along with prednisolone, while the other part is observed in pulmonology centers or institutes. Our experience shows the advisability of monitoring patients in multidisciplinary diagnostic centers, where all necessary non-invasive studies can be carried out within 2–3 days in day hospitals. Cytological and histological verification of the diagnosis is best carried out in the thoracic departments of oncology dispensaries.

Pulmonology departments in modern conditions are often filled with patients with severe destructive pneumonia, and the stay of non-infectious patients there is no less dangerous than in anti-tuberculosis institutions.

Treatment of patients with sarcoidosis, in our opinion, is best carried out on an outpatient basis, concentrating these patients in regional (regional, regional, republican) centers under the supervision of 1–2 specialists per region. In exceptional cases (less than 10%), patients should be hospitalized in specialized departments: for neurosarcoidosis - in the neurological department, for cardiac sarcoidosis - in the cardiological department, for nephrosarcoidosis - in the nephrological department, etc. These patients require highly qualified care and expensive monitoring methods, which are available only to such “organ” specialists. Thus, we observed 3 patients with cardiac sarcoidosis who underwent Holter monitoring, and a teenager with neurosarcoidosis who was treated in the neurosurgical department under the control of magnetic resonance imaging (MRI) of the brain. In this case, a phthisiopulmonologist, who constantly deals with sarcoidosis, served as a leading consultant. It should be recalled once again that, according to ICD_10, sarcoidosis is classified in the class “Diseases of the blood, hematopoietic organs and certain disorders involving the immune mechanism.”

When to start treatment?

Worldwide and domestic experience in monitoring patients with sarcoidosis indicates that up to 70% of newly identified cases can be accompanied by spontaneous remission. Therefore, it is advisable to adhere to the 1999 international agreement, according to which monitoring of patients with sarcoidosis should be most intensive during the first two years after diagnosis in order to determine the prognosis and the need for treatment. For stage I, observation once every 6 months is sufficient. For stages II, III, IV, this should be done more often (every 3 months). Therapeutic intervention is indicated for patients with severe, active or progressive disease. After cessation of treatment, all patients, regardless of radiological stage, should be observed for at least 3 years. Late monitoring will not be required until new symptoms arise (old ones worsen) or extrapulmonary manifestations of the disease appear. Stable asymptomatic stage I does not require treatment, but requires long-term observation (at least once a year). Patients with a persistent course at stages II, III and IV, regardless of whether treatment is prescribed or not, also require long-term monitoring at least once a year. Patients in whom remission was caused by the prescription of glucocorticosteroids (GCS) require more attention, due to the higher frequency of exacerbations and relapses among them. In patients with spontaneous remission, disease progression or relapses are rare. Patients with serious extrapulmonary manifestations require long-term observation, regardless of the radiographic stage of the process.

Opinions about symptoms requiring steroid or cytotoxic therapy remain controversial. In patients with such manifestations of the disease as skin lesions, anterior uveitis or cough, topical corticosteroids (creams, drops, inhalations) are used. Systemic treatment of GCS is carried out in patients with systemic lesions in the presence of increasing complaints. Systemic hormonal therapy is absolutely necessary in cases of cardiac involvement, nervous system involvement, hypercalcemia, and ocular lesions that do not respond to local therapy. The use of systemic treatment of GCS for other extrapulmonary manifestations and for lung damage, according to most doctors, is indicated only when symptoms progress. Patients with persistent changes in the lungs (infiltration) or progressive deterioration of respiratory function (vital capacity and DLCO), even in the absence of other symptoms, require systemic treatment with corticosteroids.

When deciding to initiate hormonal therapy, the physician must weigh the predicted danger of adverse reactions with the expected benefit for the patient. Recently, we have been starting treatment with alternative, gentle regimens, and this gives encouraging results.

How to treat?

Many studies have shown that short courses of treatment with adrenocorticotropic hormone or corticosteroids can have a beneficial effect on infiltrative changes detected on radiographs, and long-term treatment with corticotropic hormones leads to the resolution of granulomas, which has been proven in repeated biopsies. The use of corticosteroids per os usually leads to relief of respiratory symptoms, improvement of the X-ray picture and pulmonary function (RPF). However, after cessation of treatment, resumption of symptoms and radiological deterioration quite often occur (in some groups, relapses within 2 years after the end of therapy were observed in more than 1/3 of patients).

The main drugs for the treatment of sarcoidosis: systemic corticosteroids; inhaled corticosteroids; methotrexate; chloroquine and hydroxychloroquine; pentoxifylline, infliximab; antioxidants.

System GCS

The main drugs used to treat sarcoidosis are prednisolone and other corticosteroids: methylprednisolone, triamcinolone, dexamethasone, betamethasone in dosages equivalent to 20–40 mg of prednisolone. Khomenko A.G. et al. recommend prescribing 20–40 mg of prednisolone for 2–3 months, then gradually reducing the dose over 3–4 months by 1/4 tablet for 4 days (by 5 mg every 2 weeks), maintenance doses (5–10 mg) use from several months to 1–1.5 years. For maintenance therapy, prednisolone is preferred. Patients are recommended diets enriched with protein and potassium, vitamins, diuretics, restriction of fluid intake, table salt, and spicy foods. Schemes for intermittent therapy have been developed.

Kostina Z.I. et al. recommend prednisolone or methylprednisolone 25–30 mg/day with a reduction of 5 mg every 3–4 weeks (general course 2200–2500 mg) in combination with other non-hormonal drugs. Borisov S.E. and Kupavtseva E.A. report a positive experience in treating patients with sarcoidosis with oral GCS at an initial dose of 0.5 mg/kg daily.

Small doses of GCS (up to 7.5 mg/day) in combination with delagil and vitamin E caused adverse reactions 2–3 times less often, but were ineffective in patients with infiltrates, confluent lesions, areas of hypoventilation, massive disseminations, and impaired respiratory function ( especially obstructive), with bronchial sarcoidosis.

There are recommendations to conduct pulse therapy in patients with newly diagnosed sarcoidosis and with a recurrent course of the disease. The technique consists of prescribing prednisolone at a dose of 5 mg/kg intravenously (per 200 ml of isotonic sodium chloride solution at a rate of 40–60 drops per minute) three times with an interval of 3 days and orally at a dose of 0.5 mg/kg per day for 2 day after each intravenous injection. After pulse therapy, the daily dose of prednisolone is gradually reduced from 0.5 to 0.25 mg/kg over a month, then the dose is reduced weekly by 2.5 mg to 0.15 mg/kg. Maintenance therapy with this dose is continued for up to 6 months.

In Löfgren's syndrome, the use of systemic corticosteroids is advisable only in extreme cases. This type of disease in most cases has a good prognosis, although its clinical presentation greatly worries the patient and frightens the doctor. It is advisable to use non-steroidal anti-inflammatory drugs, pentoxifylline, vitamin E.

Inhaled corticosteroids

Continuous improvement of inhaled corticosteroids (ICS) is carried out for the treatment of bronchial asthma, which in most cases allows the disease to be brought under control. The results of using ICS in sarcoidosis are less optimistic. However, we can agree with the opinion that for pulmonary sarcoidosis without systemic damage, it is advisable to start with ICS.

Ilkovich M.M. et al. showed that inhalation of flunisolide 500 mcg 2 times a day in patients with sarcoidosis stages I and II for 5 months leads to significantly positive X-ray dynamics of the process compared to untreated patients, and a decrease in systolic pressure in the pulmonary artery. According to researchers, the advantage of ICS is associated not only with the absence of side effects characteristic of systemic drugs, but also with a direct effect on the target organ. The feasibility of sequential and combined use of inhaled and systemic corticosteroids for sarcoidosis of stage II and higher was noted. We also have positive experience in long-term control of stage II sarcoidosis using inhaled flunisolide. Staff at St. George's Hospital (London) conducted a meta-analysis of literature data regarding the use of GCS in pulmonary sarcoidosis. The treatment included 66 adult patients with histologically verified pulmonary sarcoidosis who received ICS budesonide at a dose of 0.8–1.2 mg/day. It has been proven that in mild forms of sarcoidosis, especially with severe cough, the use of budesonide for 6 months is promising. At the same time, no significant effect on the x-ray picture was noted.

Methotrexate

This drug was developed and well studied in rheumatology. It belongs to the group of antimetabolites and is structurally similar to folic acid. The therapeutic effectiveness and toxic reactions that occur during treatment with methotrexate are largely determined by the antifolate properties of the drug. There are many studies in the literature describing the successful treatment of sarcoidosis with methotrexate. In low doses (7.5–15 mg once a week), methotrexate is indicated for the treatment of refractory forms of sarcoidosis, especially those affecting the musculoskeletal system and skin.

We have limited experience in treating patients with stage II–III sarcoidosis with this drug with high efficiency (in 75% of cases). With long-term treatment, even with small doses of methotrexate, monitoring of liver function and liver biopsy are required for treatment durations of more than 12 months.

Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine have long been widely used for sarcoidosis. In domestic studies, chloroquine (Delagil) is often recommended in the early stages of sarcoidosis, before the prescription of hormones. Sharma O.P. showed the effectiveness of chloroquine phosphate in neurosarcoidosis in patients tolerant to GCS or intolerant to GCS. The most informative method of diagnosis and observation turned out to be MRI using gadolinium-based contrast agents.

Hydroxychloroquine (Plaquenil) 200 mg every other day for 9 months may be useful for the treatment of cutaneous sarcoidosis and hypercalcemia. Both drugs can cause irreversible visual damage, which requires constant monitoring by an ophthalmologist.

TNF antagonists

Tumor necrosis factor (TNF) plays a significant role in the formation of granulomas and the progression of sarcoidosis. Therefore, in recent years, drugs that reduce the activity of this cytokine have been intensively studied. These include pentoxifylline, the notoriously teratogenic thalidomide, and infliximab, chimeric monoclonal antibodies that specifically inhibit TNF.

We have positive experience in treating patients with stage II sarcoidosis with pentoxifylline. The figure illustrates the effect of treatment with pentoxifylline (200 mg 3 times a day after meals) in combination with vitamin E for 1 year. Baughman R.P. and Lower E.E. Infliximab is recommended for chronic resistant sarcoidosis in the presence of lupus pernio.

Antioxidants

In sarcoidosis, a sharp intensification of free radical reactions has been established against the background of depletion of the body's antioxidant supply. This fact is the basis for the use of antioxidants, among which tocopherol (vitamin E) is most often prescribed. In domestic practice, intravenous administration of sodium thiosulfate has been used for many years, but to date no studies have been conducted to reliably prove its effect on the course of sarcoidosis. N-acetylcysteine ​​(ACC, fluimucil) also has antioxidant properties.

Other drugs and methods

In the treatment of sarcoidosis, drugs of various groups are used, such as azathioprine (cytostatic and immunosuppressant), cyclophosphamide (antineoplastic drug with a strong immunosuppressive effect), cyclosporine A (immunosuppressant that inhibits the reactions of cellular and humoral immunity), colchicine (alkaloid), isotretinoin (dermatoprotector), ketoconazole (fungicidal and antiandrogenic drug) and many others. All of these require further investigation in controlled studies.

The experience of the Central Research Institute of Tuberculosis of the Russian Academy of Medical Sciences deserves special attention, whose employees successfully use extracorporeal methods to treat sarcoidosis. In case of repeated relapses of sarcoidosis and a significant amount of immune complexes in the blood, plasmapheresis is indicated. Extracorporeal modification of lymphocytes (EML) with prednisolone most actively affects the interstitial process in the lung tissue, leading to a significant reduction in the manifestations of alveolitis, and EML with cyclosporine, on the contrary, has a greater effect on the granulomatous process. The mechanism of action of EML is indirect, through a decrease in the functional activity of T-lymphocytes and suppression of the synthesis of pro-inflammatory cytokines.

Fasting-dietary therapy for 10–14 days has a stimulating effect on the adrenal cortex, an antioxidant effect, and modulates the immunological status. It is most effective in patients with stage I and II pulmonary sarcoidosis with a disease duration of no more than 1 year. For those who are sick, fasting for a longer period is indicated as an auxiliary method in combination with GCS.

In recent years, lung transplantation has become a real operation in many countries around the world. Indications for transplantation may include severe forms of pulmonary sarcoidosis stages III–IV. Survival after lung transplantation during the first year is up to 80%, within 4 years – up to 60%. The fight against transplant rejection is important. Clinics in the USA, Great Britain, Norway, and France have positive experience in lung transplantation for sarcoidosis.

Conclusion

The question of the place and methods of treatment of sarcoidosis remains open. The current level of development of medical science provides only control over symptoms, but there is still no convincing evidence that any method of therapy can change the course of sarcoidosis.

Pulmonologists, rheumatologists, phthisiatricians, immunologists and specialists in many other branches of medicine have a lot of work to do to unravel the etiology of sarcoidosis and search for clues to its treatment.

References

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2. Borisov S.E., Kupavtseva E.A. // Sat. scientific tr., dedicated 80th anniversary of the Research Institute of Phthisiopulmonology MMA named after. THEM. Sechenov. M., 1998. P. 62.

3. Ilkovich M.M. and others // Ter. archive. 1996. No. 3. P. 83.

4. Ilkovich M.M. and others // Pulmonology. 1999. No. 3. P. 71.

5. Kostina Z.I. and others // Probl. tube 1995. No. 3. P.34.

6. Lebedeva L.V., Olyanishin V.N. // Problem tube 1982. No. 7. P. 37.

7. Ozerova L.V. and others // Probl. tube 1999. No. 1. P. 44.

8. Romanov V.V. // Problem tube 2001. No. 3. P. 45.

9. Khomenko A.G. and others. Sarcoidosis as a systemic granulomatosis. M., 1999.

10. Shilova M.V. and others // Probl. tube 2001. No. 6. P. 6.

11. Baughman R.P., Lower E.E. // Sarcoidosis Vasc. Diffuse Lung Dis. 2001. V. 18. No. 1. P. 70.

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Sarcoidosis, also called sarcoid, is a disease involving abnormal collections of inflammatory cells (granulomas) that can form nodules in various organs. Granulomas are most often found in the lungs or associated lymph nodes, but any organ can be affected. Sarcoidosis appears to be caused by an immune response to an infection or some other trigger (called an antigen, which may come from the environment) that continues even after the primary infection or other antigen has cleared from the body. In most cases it can be cured without medical intervention, but in some cases it causes long-term effects or becomes life-threatening and requires medical intervention, most often with medication. 1 alpha, 25(OH)2 vitamin D3 is the main cause of high blood calcium levels in sarcoidosis and is produced in excess by sarcoid granulomas. Interferon gamma, produced by activated macrophages and lymphocytes, plays a significant role in the synthesis of 1 alpha, 25(OH)2 vitamin D3.

Treatment is usually intended to relieve symptoms and thus does not directly change the course of the disease. Such treatment usually consists of anti-inflammatory drugs such as ibuprofen or aspirin. When the condition develops to the point that it is progressive and/or life-threatening, treatment most often involves steroids such as prednisone or prednisolone. In addition, drugs that are most commonly used to treat cancer and suppress the immune system, such as methotrexate, azathioprine and leflunomide, may be used. The average mortality rate is less than 5% in untreated cases.

In the United States, the disease most often affects people of Northern European (especially Scandinavian or Icelandic) or African/African American descent aged 20–29 years, although people of any race or age group can be affected. Japan has a lower prevalence of sarcoidosis than the United States, although in these people the disease tends to be more aggressive and the heart is often affected. In the Japanese, the peak incidence occurs at a different age - 25-40 years. The disease develops approximately 2 times more often in women, in whom it often takes a more aggressive course. Sarcoid in developing countries is often misdiagnosed as tuberculosis because its symptoms often resemble tuberculosis.

Signs and symptoms

Sarcoidosis is a systemic inflammatory disease that can affect any organ, although it may be asymptomatic and is discovered incidentally in approximately 5% of cases. Characteristic symptoms are usually vague and include fatigue (not relieved by sleep; present in 66% of cases), weight loss, lack of energy, joint pain and pain (which occurs in approximately 70% of cases), arthritis (14-38% of individuals) ), dry eyes, swollen knees, blurred vision, shortness of breath, dry hacking cough, or broken skin. In more rare cases, people may cough up blood. Skin symptoms range from rashes and nodules (small bumps) to erythema, granuloma annulare, or lupus pernio. Sarcoidosis and cancer can mimic each other, making it difficult to differentiate.

The combination of erythema nodosum, bilateral hilar lymphadenopathy and joint pain is called Löfgren's syndrome, which has a relatively favorable prognosis. This form of the disease is much more common in Scandinavian patients.

Airways

Today, localization in the lungs is considered the most common manifestation of sarcoidosis. At least 90% of victims experience pulmonary involvement. In general, almost 50% of cases develop permanent pulmonary disorders and 5-15% develop progressive fibrosis of the pulmonary parenchyma. Pulmonary sarcoidosis is primarily an interstitial lung disease in which inflammation involves the alveoli, bronchi, and small blood vessels. Physical examination in acute and subacute cases usually reveals dry rales. At least 5% of people will suffer from pulmonary arterial hypertension. Less commonly, there may be disturbances in the upper respiratory tract (including the larynx, pharynx, paranasal sinuses), which occurs in 5-10% of cases.

Pulmonary sarcoidosis can be divided into four stages. Stage 0 – without intrathoracic involvement. Stage I – bilateral hilar lymph nodes. Stage II – pulmonary parenchyma. Stage III – pulmonary infiltrates with fibrosis. Stage IV is end-stage lung disease with pulmonary fibrosis and void formation.

Leather

The disease affects the skin in 9-37% of individuals. After the lungs, the skin is the second most commonly affected organ. The most common skin lesions include erythema nodosum, plaques, maculopapular eruptions, lupus pernio, and subcutaneous nodules. No treatment is required as the lesions usually resolve spontaneously within 2-4 weeks. Although it can be unsightly, cutaneous sarcoidosis rarely causes serious problems. Sarcoidosis of the scalp manifests as diffuse or focal hair loss.

Eyes

Eye damage occurs in approximately 10-90% of cases. Ophthalmic manifestations include uveitis, uveoparotitis, and inflammation of the retina, which can lead to loss of visual acuity or blindness. The most common manifestation of ophthalmic sarcoidosis is uveitis. The combination of anterior uveitis, mumps, VII cranial nerve palsy and fever is called uveoparotid fever or Heerford syndrome. The development of a scleral nodule associated with sarcoidosis has been observed.

Heart

The prevalence of cardiac involvement in this disease varies and is largely dependent on race. Thus, in Japan, more than 25% of people with sarcoidosis experience symptomatic cardiac involvement, while in the United States and Europe only about 5% of cases have cardiac involvement. In autopsies in the United States, the incidence of cardiac involvement is about 20-30%, while in Japan it is 60%. Manifestations of cardiac sarcoidosis can range from asymptomatic conduction disturbances to fatal ventricular arrhythmias. Conduction abnormalities most commonly occur as cardiac manifestations of sarcoidosis and may include complete heart block. In addition to conduction disturbances, ventricular arrhythmias often develop, occurring in approximately 23% of individuals with cardiac disease. Sudden cardiac death due to ventricular arrhythmia or complete heart block is a rare complication of cardiac sarcoidosis. Cardiosarcoidosis can cause fibrosis, granuloma formation or fluid accumulation in the cardiac interstitium, or a combination of the first two.

Nervous system

The disease can affect any part of the nervous system. Sarcoidosis that affects the nervous system is known as neurosarcoidosis. The cranial nerves are most commonly affected, accounting for about 5–30% of cases of neurosarcoidosis, and peripheral facial nerve palsy, often bilateral, is the most common nervous system manifestation of sarcoid. It occurs suddenly and is usually temporary. CNS involvement is present in 10-25% of cases. Other common manifestations of neurosarcoidosis include optic nerve dysfunction, palatal dysfunction, papilledema, neuroendocrine changes, hearing impairment, hypothalamic and pituitary disorders, chronic meningitis, and peripheral neuropathy. Myelopathy, a lesion of the spinal cord, occurs in approximately 16-43% of cases of neurosarcoidosis and is often associated with a poor prognosis of subtypes of neurosarcoidosis. In turn, facial paralysis and acute meningitis caused by sarcoidosis tend to have the most favorable prognosis. Another common finding in sarcoidosis with neurological involvement is small autonomic or sensory fiber neuropathy. Neuroendocrine sarcoidosis accounts for about 5-10% of cases of neurosarcoidosis and can cause diabetes insipidus, menstrual cycle changes and hypothalamic dysfunction. The latter can lead to changes in body temperature, mood and prolactin levels.

Endocrine and exocrine systems

In sarcoid, prolactin levels often increase, and in 3-32% of cases hyperprolactinemia is noted. This often results in amenorrhea, galactorrhea, or non-puerperal mastitis in women. It also often results in an increase in 1,25-dihydroxy vitamin D, an active metabolite of vitamin D that is normally hydrolyzed in the kidneys, but in patients with sarcoidosis, hydroxylation of vitamin D may occur outside the kidneys, specifically within immune cells found in granulomas formed by the kidney. with illness. 1 alpha, 25(OH)2D3 is the main cause of hypercalcemia in sarcoidosis and is produced in excess by sarcoid granulomas. Interferon gamma, produced by activated macrophages and lymphocytes, plays a significant role in the synthesis of 1 alpha, 25(OH)2D3. Hypercalciuria (excessive calcium excretion in the urine) and hypercalcemia (increased calcium in the blood) are observed in<10% людей и, вероятно, происходят от повышенного производства 1,25-дигидрокси витамина D. Дисфункция щитовидной железы наблюдается у 4,2-4,6% больных.

Enlargement of the parotid gland occurs in approximately 5-10% of individuals. As a rule, involvement is two-way. The gland is most often not painful, but elastic and smooth. Possible dry mouth; the disease rarely affects other exocrine glands. The eyes, their glands or parotid glands are affected in 20-50% of cases.

Gastrointestinal and genitourinary systems

Symptomatic GI involvement occurs in less than 1% of individuals (excluding the liver), and the condition most commonly affects the stomach, although the small or large intestine may also be affected in a small percentage of cases. Autopsy studies have found gastrointestinal involvement in less than 10% of people. These cases likely mimic Crohn's disease, a more common granulomatous disease affecting the intestines. At autopsy, almost 1-3% of people have evidence of pancreatic involvement. Symptomatic renal involvement occurs in only 0.7% of cases, although autopsy evidence of renal involvement is found in 22% of people, and this occurs exclusively in cases of chronic disease. Symptomatic involvement of the kidneys usually manifests itself in the form of nephrocalcinosis, followed by granulomatous interstitial nephritis, which manifests itself in the form of decreased creatinine clearance and decreased proteinuria. Less commonly, the epididymis, prostate, ovaries, fallopian tubes, uterus or vulva may be affected, in the latter case vulvar itching may occur. In 5% of cases, autopsy reveals testicular involvement. In men, sarcoidosis can lead to infertility.

About 70% of people have granulomas in the liver, although only 20-30% of cases show abnormal liver function tests to reflect this fact. In 5-15% of people, hepatomegaly is detected, that is, an enlarged liver. Only 5-30% of cases of liver damage are symptomatic. Typically, these changes reflect a cholestatic pattern and include elevated levels of alkaline phosphatase (the most common abnormal liver function test in sarcoidosis), whereas bilirubin and aminotransferase are only slightly elevated. Jaundice is rare.

Hematological and immunological changes

Abnormal CBCs are common, accounting for more than 50% of cases, but are not diagnostic. Lymphopenia is the most common hematologic abnormality in sarcoidosis. Anemia occurs in about 20% of people with sarcoid. Leukopenia is less common and occurs in even fewer people, but is rarely serious. Thrombocytopenia and hemolytic anemia are quite rare. In the absence of splenomegaly, leukopenia may reflect bone marrow involvement, but the most common mechanism is redistribution of blood T cells to sites of disease. Other nonspecific findings include monocytosis, which occurs in most cases of sarcoid, and increased liver enzymes or alkaline phosphatase. People with sarcoidosis often have immunological abnormalities, such as allergies to test antigens such as Candida or purified protein product (PPD). Polyclonal hypergammaglobulinemia is also a fairly common immunological abnormality in this disease.

Enlarged lymph nodes are common in sarcoidosis and occur in 15% of patients. The size of intrathoracic nodes increases in 75-90% of people. This usually includes the hilar nodes, but the paratracheal nodes are most often involved. Peripheral lymphadenopathy is very common, especially involving the cervical (usually the head and neck), axillary, epitrochlear and inguinal nodes. About 75% of cases occur with microscopic involvement of the spleen, and only in 5-10% of cases does splenomegaly appear.

Bones, joints and muscles

Bone involvement in sarcoidosis is noted in 1-13% of cases. In 5-15% of cases, the disease affects bone, joint or muscle tissue.

Video about sarcoidosis

Causes of sarcoidosis

The exact cause of the disease remains unclear. The current working hypothesis is that in individuals with genetic susceptibility, sarcoidosis is caused by changes in the immune response after exposure to an environmental, occupational, or infectious agent. In some cases, treatment with TNF inhibitors such as etanercept may be started.

Genetic

The heritability of sarcoidosis varies by race; for example, about 20% of African Americans with the disease have a family member with it, while the rate for white Americans is about 5%. Genetic susceptibility studies have identified many candidate genes, but only a few have been confirmed in further studies, and reliable genetic markers remain unknown. Currently, the most interesting candidate is the BTNL2 gene. A number of HLA-DR risk alleles are also being studied. In persistent sarcoidosis, the HLA haplotype HLA-B7-DR15 is associated with the disease, or another gene between these two loci is associated. In unstable disease, a strong genetic association with HLA-DR3-DQ2 was noted.

Infectious

Several infectious agents appear to be significantly associated with sarcoidosis, but none of the known associations can be considered specific enough to suggest a direct causative role. The main infectious agents involved include mycobacteria, fungi, Borrelia, and rickettsia. A recent meta-analysis examining the role of mycobacteria in sarcoidosis found that they were present in 26.4% of cases, but the meta-analysis also identified possible publication bias, so the results need further confirmation. Mycobacterium tuberculosis catalase peroxidase has been identified as a possible sarcoidosis antigen catalyst. Transmission of the disease through organ transplantation has also been reported.

Autoimmune

The association of autoimmune disorders has been observed repeatedly. The exact mechanism of this relationship is not known, but some evidence supports the hypothesis that it is a consequence of the abundance of Th1 lymphokines. Delayed cutaneous hypersensitivity tests were used to measure progression.

Pathophysiology

Granulomatous inflammation is characterized primarily by the accumulation of monocytes, macrophages and activated T lymphocytes, with increased production of the main inflammatory mediators, TNF, IFN-γ, IL-2, IL-8, IL-10, IL-12, IL-18, IL-23 and TGF-β, indicating a Th1-mediated immune response. Sarcoidosis has a paradoxical effect on inflammatory processes. It is characterized by increased activation of macrophages and CD4 helper T cells, leading to accelerated inflammation, but the immune response to antigenic stimulation such as tuberculin is suppressed. This paradoxical state of simultaneous hyper- and hypofunction suggests a state of anergy. Anergy may also be responsible for an increased risk of infections and cancer.

Regulatory T cells at the periphery of sarcoid granulomas appear to suppress IL-2 secretion, which presumably induces a state of anergy, preventing antigen-specific memory responses. Schaumann bodies found in sarcoidosis are calcium and protein inclusions within Langhans giant cells, as part of a granuloma.

Although TNF appears to play an important role in granuloma formation (supported by the finding that in animal models of mycobacterial granuloma formation, inhibition of TNF or IFN-γ production inhibits granuloma formation), sarcoidosis can and still occurs in humans treated with TNF antagonists. such as etanercept. It is likely that B cells also play a role in the pathophysiology of this disease. Serum levels of soluble HLA class I antigens and ACE are higher in individuals with sarcoidosis. Similarly, the CD4/CD8 T cell ratio in bronchoalveolar lavage tends to be higher in individuals with pulmonary sarcoid (usually >3.5), although it may be normal or even abnormally low in some cases. ACE levels have been found to generally correlate with overall granuloma load.

Sarcoidosis has also been reported as part of HIV immune reconstitution syndrome, that is, when people receive treatment for HIV, their immune system is restored and as a result, it begins to attack opportunistic infection antigens captured before said restoration, and the resulting immune reaction causes damage to healthy tissue.

Diagnostics

The diagnosis of sarcoidosis is made by exclusion because there are no specific tests for this condition. To rule out sarcoidosis when presenting with pulmonary symptoms, chest x-ray, chest CT, CT biopsy, PET scan, mediastinoscopy, open lung biopsy, bronchoscopy with biopsy, endobronchial ultrasound, and endoscopic ultrasound with mediastinal lymph node FNC can be used. Tissue from lymph node biopsies is subjected to both flow cytometry to rule out cancer and special staining (AFB stain and Gomori methenamine silver stain) to rule out microorganisms and fungi.

Serum markers of sarcoidosis include serum amyloid A, soluble interleukin 2 receptor, lysozyme, angiotensin-converting enzyme, and KL-6 glycoprotein. Angiotensin converting enzyme in the blood is used in monitoring sarcoidosis. BAL fluid may show an elevated (at least 3.5-fold) CD4/CD8 T cell ratio, which is suggestive (but not proof) of pulmonary sarcoid. In at least one study, the ratio of induced sputum CD4/CD8 and TNF levels correlated with the ratio in the lavage fluid.

Differential diagnoses include metastatic disease, lymphoma, septic embolism, rheumatoid nodules, granulomatosis with polyangiitis, varicella, tuberculosis, and atypical infections such as mycobacterial complex, cytomegalovirus, and cryptococcus. Sarcoidosis is most often confused with neoplastic diseases, such as lymphoma, or with disorders also characterized by granulomatous inflammation of mononuclear cells, such as mycobacterial and fungal diseases.

Changes on a chest x-ray are divided into four stages:

• Stage 1: hilar lymphadenopathy
• Stage 2: hilar lymphadenopathy and reticulonodular infiltrates
• Stage 3: bilateral pulmonary infiltrates
• Stage 4: fibrocystic sarcoidosis, usually with breast retraction, cystic and bullous changes

Although people with stage 1 x-ray findings typically have acute or subacute reversible forms of the disease, people with stages 2 and 3 often have chronic, progressive disease; these models do not represent sequential “stages” of sarcoidosis. In this regard, other than for epidemiological purposes, this X-ray classification is mainly of historical interest.

In sarcoidosis in whites, thoracic lymphadenopathy and erythema nodosum are the most commonly reported initial symptoms. In this population, a gastrocnemius muscle biopsy is a useful tool in correct diagnosis. The presence of noncaseating epithelioid granulomas in gastrocnemius muscle specimens is definitive evidence of sarcoidosis, as are other tuberculoid and fungal diseases that are extremely rarely present in this muscle histologically.

Classification

Experts have identified the following types of sarcoidosis:

• annular
• erythrodermic
• ichthyosoform
• hypopigmented
• Löfgren's syndrome
• lupus pernio
• morpheaform
• slimy
• neurosarcoidosis
• papular
• scar sarcoidosis
• subcutaneous
• systemic
• ulcerative

Treatment of sarcoidosis

Most people (>75%) require only symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or aspirin. In persons with pulmonary symptoms, unless respiratory compromise is devastating, pulmonary sarcoidosis is actively monitored, usually without therapy for 2 to 3 months; if the inflammation does not subside spontaneously, therapy is started. Corticosteroids, usually prednisolone or prednisolone, have been the standard treatment for many years. In some patients, such treatment may slow or reverse the progression of the disease, but other people do not respond to steroid therapy. The use of corticosteroids for mild disease is controversial because in many cases the disease resolves spontaneously. Despite their widespread use, the evidence supporting the use of corticosteroids is weak at best.

Severe symptoms are usually treated with corticosteroids, although steroid-sparing agents such as azathioprine, methotrexate, mycophenolic acid and leflunomy are often used as an alternative. Of these, methotrexate is the most widely used and studied. Methotrexate is considered the first-line treatment for neurosarcoidosis, often in combination with corticosteroids. Long-term treatment with this drug is associated with liver damage in 10% of people, and therefore can be a significant problem in people with liver damage, requiring regular monitoring through liver function tests. In addition, methotrexate may cause pulmonary toxicity (lung damage), although this is quite rare and may more often confound leukopenia due to sarcoidosis. Because of these safety concerns, methotrexate is often recommended to be combined with folic acid to prevent toxicity. Treatment with azathioprine may also cause liver damage. Leflunomide is used as a replacement for methotrexate, possibly due to its supposed reduced pulmonary toxicity. Mycophenolic acid has been successfully used in the vascular form of the disease, neurosarcoidosis (especially with central nervous system involvement; minimally effective in myopathy) and pulmonary sarcoidosis.

Because granulomas are caused by accumulations of immune system cells, particularly T cells, there has been some success with immunosuppressants (cyclophosphamide, cladribine, chlorambucil, cyclosporine), immunomodulatory agents (pentoxifylline and thalidomide), and anti-tumor necrosis factor (eg, infliximab, etanercept). , golimumab and adalimumab).

In a clinical trial, cyclosporine in combination with prednisone did not show significant benefit over prednisone alone in people with pulmonary sarcoidosis, although there is evidence of increased toxicity due to the addition of cyclosporine to steroids, including infections, malignancies (cancer), hypertension, and kidney dysfunction. Similarly, chlorambucil and cyclophosphamide are rarely used in the treatment of sarcoidosis due to their high degree of toxicity, particularly their potential to cause malignancy. In clinical trials, infliximab has been successfully used to treat pulmonary sarcoidosis in several people. Etanercept, on the other hand, failed to demonstrate significant efficacy in people with vascular sarcoidosis in a pair of clinical trials. Similarly, golimumab showed no benefit in individuals with pulmonary sarcoidosis. One clinical trial of adalimumab showed a response to treatment in about half of the subjects, which can also be seen with infliximab, but since adalimumab is better tolerated, it may be preferable to infliximab.

Ursodeoxycholic acid has been used successfully to treat cases involving the liver. Thalidomide has also been successfully tested as a treatment for refractory lupus pernio in a clinical trial, which may be related to its anti-TNF activity, although its effectiveness against pulmonary sarcoidosis was not observed in a clinical trial. The skin disease can be successfully treated with antimalarials (such as chloroquine and hydroxychloroquine) and the tetracycline antibiotic, minocycline. Antimalarial drugs have also demonstrated effectiveness in treating sarcoidosis-related hypercalcemia and neurosarcoidosis. However, long-term use of antimalarial drugs is limited by their potential to cause irreversible blindness and, therefore, by the need for regular ophthalmological examination. This toxicity is generally less with hydroxychloroquine than with chloroquine, although hydroxychloroquine may interfere with glucose homeostasis.

Recently, selective phosphodiesterase 4 (PDE4) inhibitors, such as apremilast (a thalidomide derivative), roflumilast, and a less subtype-selective PDE4 inhibitor, pentoxifylline, have been tested for the treatment of sarcoidosis. Successful results were achieved in the treatment of cutaneous sarcoidosis with apremilast in a small open-label study. Pentoxifylline has been used successfully to treat acute illness, although its use is largely limited by its gastrointestinal toxicity (mainly nausea, vomiting, diarrhea). Case reports have supported the effectiveness of rituximab, an anti-CD20 monoclonal antibody, and a clinical trial of atorvastatin is currently underway as a treatment for sarcoidosis. ACE inhibitors have been reported to induce remission of cutaneous sarcoidosis and improvements in the pulmonary form, including improved lung function, pulmonary parenchymal remodeling, and prevention of pulmonary fibrosis in one case series. Nicotine patches have been found to have anti-inflammatory effects in patients with sarcoidosis, although disease-modifying effects require further study. Antimycobacterial treatments (drugs that kill mycobacteria, the causative agents of tuberculosis and leprosy) have also been shown to be effective in treating chronic cutaneous sarcoidosis in one clinical trial. One small study also tried quercetin for the treatment of pulmonary sarcoid with some early success.

Due to its unusual nature, the treatment of sarcoidosis of the male reproductive tract is controversial. Thus, the differential diagnosis includes testicular cancer, so some experts recommend orchiectomy even if there is evidence of sarcoidosis in other organs. The new approach suggested biopsy of the testis, adnexa, and resection of the largest lesion.

Forecast

The disease can resolve spontaneously or become chronic, with exacerbations and remissions. In some individuals it may progress to pulmonary fibrosis and death. About half of cases go away without treatment or can be resolved within 12-36 months, and most within 5 years. In some cases, however, the disease can persist for several decades. Two thirds of people with the condition achieve remission within 10 years of diagnosis. When the heart is involved, the prognosis is generally less favorable, although corticosteroids appear to be effective in improving atrioventricular conduction. The prognosis is generally less favorable for African Americans compared to white Americans. For people with this disease, the risk of developing cancer is significantly increased, in particular lung cancer, lymphoma and other organs that are affected by sarcoidosis. In the sarcoidosis-lymphoma syndrome, sarcoid is accompanied by the development of lymphoproliferative disorders such as non-Hodgkin's lymphoma. This can be attributed to the main immunological abnormalities that occur in sarcoidosis. It may also follow cancer or occur simultaneously with cancer. Hairy cell leukemia, acute myeloid leukemia, and acute myeloid leukemia have been reported to be associated with sarcoidosis.

Epidemiology

Sarcoidosis most often affects young adults of both sexes, although studies have reported more cases in women. The incidence is highest in persons under 40 and peaks in the 20-29 age group; the second peak is observed in women over 50.

Sarcoid occurs worldwide in all races with an average incidence of 16.5 per 100,000 men and 19 per 100,000 women. The disease is most common in the Nordic countries, and the highest annual incidence (60 per 100,000) is found in Sweden and Iceland. In the United Kingdom, the prevalence is 16 per 100,000. In the US, the disease is more common in people of African descent than whites, with annual incidence rates of 35.5 and 10.9 per 100,000, respectively. Sarcoidosis is less common in South America, India, Spain, Canada and the Philippines. There may be a higher sensitivity to sarcoidosis in patients with celiac disease. A connection between the two disorders has been suggested.

In addition, seasonal clustering is observed in individuals affected by sarcoidosis. In Greece, about 70% of cases are diagnosed in March and May each year, in Spain about 50% are diagnosed between April and June, and in Japan the disease is mainly diagnosed in June and July.

Differences in prevalence worldwide may be at least partly due to the lack of screening programs in some regions of the world, and are obscured by the presence of other granulomatous diseases such as tuberculosis, which may interfere with the diagnosis of sarcoidosis where they are common. In addition, there may be differences in the severity of the disease between people of different nationalities. Some studies suggest that symptoms of the disease may be more severe and diffuse in people of African descent than in whites, who are more likely to have asymptomatic disease. Manifestations appear to vary slightly depending on race and gender. Erythema is much more common in men than women and in whites than in other races. The Japanese are more likely to have eye and heart lesions.

Sarcoidosis is more common among certain occupations, including firefighters, educators, military personnel, people who work in industries that use pesticides, law enforcement, and medical personnel. In the year following the September 11 attacks, the prevalence of sarcoidosis quadrupled (to 86 cases per 100,000).

Story

The disease was first described in 1877 by dermatologist Jonathan Hutchinson as a condition causing a red, raised rash on the face, arms and hands. In 1888, another dermatologist, Ernest Besnier, coined the term “lupus aggravated.” Later in 1892, the histology of lupus pernio was determined. In 1902, bone lesions were first described by a group of three doctors. Between 1909 and 1910 Uveitis was first described in sarcoidosis, and then in 1915, Dr. Schaumann noted that it was a systemic condition. In the same year, pulmonary involvement was also described. In 1937, uveoparotid fever was first described, and in 1941, Löfgren's syndrome. In 1958, the First International Conference on Sarcoidosis was held in London, and in 1961 a similar event was held in the United States in Washington, DC. It is also called Besnier-Beck disease or Besnier-Beck-Schaumann disease.

Sarcoidosis in society and culture

The World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) is an organization of physicians involved in the diagnosis and treatment of this disease and related conditions. WASOG publishes the journal Sarcoidosis, Vasculitis and Diffuse Pulmonary Diseases. In addition, the Foundation for Sarcoidosis Research (FSR) is dedicated to supporting scientific research into the disease and possible treatments for it.

There were concerns that rescuers working in the World Trade Center rubble were at increased risk of sarcoidosis.

In 2014, a letter to the British medical journal Lancet noted that French Revolutionary leader Maximilien Robespierre suffered from sarcoidosis, and suggested that the condition caused him to noticeably deteriorate during his time as head of the Reign of Terror.

Etymology

The word sarcoidosis comes from the Greek word sarcο, “flesh,” the suffix -eidos, meaning “type,” “resembles,” or “similar,” and -sis, a common suffix in Greek meaning “condition.” Thus the whole word means "a state resembling raw flesh." The first cases of sarcoidosis recognized in Scandinavia at the end of the 19th century. as a new pathological entity, manifested as cutaneous nodules resembling cutaneous sarcomas, hence the origin of the original name.

Pregnancy

Sarcoidosis generally does not interfere with successful pregnancy and childbirth; the increase in estrogen levels during this period may even have a mild positive immunomodulatory effect. In most cases, the course of the disease is independent of pregnancy, with improvement in some cases and worsening of symptoms in very rare cases, although it should be noted that a number of immunosuppressive drugs (such as methotrexate, cyclophosphamide, azathioprine) used in corticosteroid-resistant sarcoidosis are teratogenic.