Sarkoidoz, part II: clinic, diagnostics, treatment

Sarkoidoz, part II: clinic, diagnostics, treatmentClinic
Frequency of detection саркоидоза sharply increased with introduction of the preventive photoroentgenography which has revealed an asymptomatic course of this disease approximately at 40 % of patients. At 40 % gradual, hardly noticeable development of the illness, being shown is observed by nonspecific symptoms. Weakness, increased fatigue, perspiration, unproductive dry cough are observed. In process of progressing of an illness there can be a short wind at the moderate physical activity, the expressed short wind is noted only in far come cases («a cellular lung»). The feeling of discomfort behind a breast is occasionally noted. In 10-20 % of cases the sharp onset of the illness, характеризуещееся by body temperature increase (to subfebrilny figures at 25 % of patients), the expressed weakness, artralgiya, cough is noted.

Sarkoidoz, part I: classification, etiology, clinic.>>>

Depending on features of a current traditionally distinguish sharp (10-20 %) and primary and chronic (80-90 %) illness forms. For a sharp form two eponimichesky syndromes are classically described: Lefgren’s syndrome (a bilateral limfadenopatiya of a sredosteniye, knotty эритема, temperature increase of a body, an artralgiya, SOE increase), arising mainly at women till 30 years. Heerfordta-Valdenstrem’s syndrome includes along with a limfadenopatiya of a sredosteniye and body temperature increase, parotitis, forward увеит and paresis of a facial nerve. In 70-80 % the sharp form is characterized by return spontaneous development of an illness.

Knotty эритема (UE) at саркоидозе is characterized by the certain features allowing during fizikalny survey to suspect this disease:

  1. UE emergence is preceded often by intensive hypostasis of the bottom extremities.
  2. Primary localization of elements on back and lateral surfaces of shins, over knee joints, in forearms, hips.
  3. Tendency to merge of elements.
  4. Large sizes (> 2 cm).
  5. It is authorized within 3-4 weeks.
  6. Expressiveness of artralgiya and periartikulyarny changes premushchestvenno ankle joints, is more rare than knee, luchezapyastny joints.
  7. Often – increase of antibodies to yersiniya (in absence of clinic).

Spontaneous development of a primary and chronic form саркоидоза is observed in 50-60 % of cases (in the first 1-2 years). A number of authors allocates a secondary and chronic form to which process generalization is peculiar. In the pro-gnostic plan this form is most adverse. Frequency of defeat of separate bodies and systems is presented in table 2.

Table 2 Frequency of defeat of bodies and fabrics sarkoidozy

Body/fabric
Defeat %

Note

L / at a sredosteniye
(75-100)

The unilateral

Lungs
(60-90)

65 % – an auskultativny picture N, 20 of % – are weakened vesicular breath. The cellular lung is formed only at 5-10 % (the krepitatsiya is listened)

Liver
(50-90)

Gepatomegaliya – 20-30 % function as a rule – N, is rare холестаз, cirrhosis. Detection of granulomas of sarkoidny type possibly at many diseases.

Spleen (50-80)

Splenomegaliya – 5-10 % the Biopsy – 50-80 %

Mucous bronchial tubes
(40-50)

Small consolidations with nearby sites of expanded vessels. Granulomas settle down more often subepitelialno. Stenozirovaniye, the kompressionny sdavleniye – is the extremely rare.

Joints
(25-50)

Migrating artralgiya of large joints are more often. Erozirovaniya, deformations – are not characteristic.

Eyes
(20-25)

Meets at women more often. Uveita – 60-70 %; конъюктивиты – 10-15 %; a raduzhka – 5-7 %. Complications: cornea turbidity, development of a cataract, glaucoma, up to sight loss.

Muscles
(15-20)

Are described to. the item without function violation. Seldom – clinic полимиозита.

Pleura
(10-100)

Exudate – Torakoskopy’s 1-3 % – diagnosis confirmation histologically.

Marrow
(0-43)

Frequency of involvement is studied insufficiently. Anemia, leykopeniye, thrombocytopenia.

Heart
(5-52)

4-5 % – conductivity violation (к.п. ekstrasistoliya-25 %). In 15-20 % – an immediate cause of death of patients (in 40-50 % – sudden). At children practically does not meet. Stsintigrafiya with Ga63, Tc20.

Salivary glands
(10-12)

As a rule – bilateral. Parotid (6-8 %). Parotitis – Heerfordta-Valdenstrem’s cm, but can be surprised hypoglossal, submaxillary glands.

Skin
(4-10)

Knotty эритема – sharp process, is observed in 25 % of cases. 4-10 % – true granulematozny саркоидоз skin (саркоидоз Beka, Lyupoid). Swelling, increase in skin changes – an activity sign саркоидоза. Seldom – саркоид to Darya-Russi (J.Darrier, G. Russy), dense, hypodermic, painless knots of 1-3 cm in diameter.

Kidneys
(1-10)

Giperkaltsiyemiya, a giperkaltsiuriya conducting to development нефролитиаза. Normalization of a metabolism of calcium occurs in the first 2 weeks of treatment of GKS. Seldom – sarkoidozny гломерулонефрит. Adrenal glands – casuistry

Bones (5)

Brushes, Feet, the Skull, the Backbone, Dinnye tubular bones – the multiple kistoobrazny centers of depression. Seldom – a pripukhaniye, morbidity in the field of defeat.

ЦНС (2-5)

Cerebral, spinal арахноидиты, периваскулиты., paresis of mimic muscles, narrowing of fields of vision. Brain covers> spinal cord> зрит. nerves

ПНС (5)

Clinically

Throat (5)

Cases of defeat of almonds, okologlotochny ring, vocal chords are described. Clinically – dense small knots with the hyperemic periphery or pale yellow plaques. Histology – an epitelioidno-cellular granuloma.

ЖКТ (0-1)

Generally – as a pathoanatomical find

Now it is considered to be the most informative signs of activity of an illness fever, увеит, skin changes, a poliartralgiya, a splenomegaliya, cough and short wind strengthening, deterioration radiological change and ventilating ability of lungs, positive results of Ga67 of scanning.

Diagnostics
Typical for саркоидоза changes гемограммы are not present. Average values of hemoglobin, erythrocytes, leukocytes do not fall outside the limits normal values. The main changes of laboratory indicators are presented in table 3.

Table 3

Indicator

Note

vЛейкоцитов – 30-35 %

СОЭ

In 55 % does not change; ^> 20 mm/hours at a sharp form (+ ^leu)

^Эозинофилов> 5 % – 20 %

More often at it is long accepting antibiotics

v Lymphocytes

At the expense of abslyutny v T-lymphocytes

^ V-lymphocytes – 40-45 %

The absolute

^IgA – 60 %; ^gM – 25-50 %

Especially at aggravations. In the I-II stages

^ЦИК

Often ^ even in remission

^CD8/v CD4; vTa (active)

+ v fagotsitarny number / фагоцитарного index

Giperkaltsiyuriya – 20-40 %

Can be and without a giperkaltsiyemiya

Giperkaltsiyemiya – 15-20 %

To thicket at the people living in R – x with ^ insolation

^АПФ – 50-70 %

At 10 % healthy

The maintenance of IgA increases mainly at patients in the II stage, in an aggravation phase. In remission level of IgA tends to decrease to normal values. IgM authentically exceeds norm in the I-II stages саркоидоза. Essential IgG loudspeakers – it is noted. Full antipulmonary antibodies are defined in 22 %, incomplete – at 57 %, antinuclear – at 29 % of patients. S-jet protein does not come to light at a half of patients, at other half – is registered in moderate quantities. Level of APF is raised at 50-70 % of the patients who were not exposed to treatment, lozhnopolozhitelny increase of APF is observed approximately at 10 % of healthy people. Increase of level of APF is registered and at other diseases (table 4).

Table 4

^АПФ

vАПФ

Diabetes
Virus hepatitis
Gipertireoz
Silikoz, Asbestosis, Berillioz
Leprosy
Illness to Gosha

Tuberculosis
Bronchial asthma
ХОБЛ
Cancer of a lung

As laboratory markers of activity of a disease the following indicators of peripheral blood are accepted:

  1. Characterizing a makrofagalno-granulematozny stage: кальцитриол (giperkaltsiyemiya), APF, lizotsy, карбоксипептидаза N, termolizinopodobny металлопептидаза, неоптерин.
  2. Connected with lymphocytes: ?2-микроглобулин, soluble Il2-receptors, ?-интерферон, ?-глобулины, Central Election Commission.
  3. Connected with extracellular the matriksy: syvorotochny pro-collagen – 3-peptid, гиалуронан, фибронектин, витронектин.

Kveym’s test
It is offered for diagnostics саркоидоза in 1941. Still finds application in many countries. The standardized sarkoidny anti-gene enter vnutrikozhno into forearm area (0,15-0,2 ml.), in 3-4 weeks an introduction place (including hypodermic fatty cellulose) investigate even in the absence of visible changes. Eritema arising in 3-4 days of diagnostic value has no, as sarkoidny granulomas are formed only in 2-3 weeks. For the period of carrying out the GKS test should be cancelled. The diagnostic informativnost of dough averages 60-70 %. Lozhnopolozhitelnye results – 1-3 % of patients. At patients with tuberculosis – the positive result is observed in 30 % of cases. Application of test of Kveym of expediently contra-indication to carrying out a biopsy (or its results negative), podostry meningitis of not clear etiology, paresis of cranial nerves.

Tuberkulinovy anergiya
There is an inverse relationship between expressiveness of a skin anergiya to туберкулину and activity of pathological process. At accession of a tubercular infection test becomes positive. The skin anergiya and on other anti-genes (кандиды, стрептокиназа, трихофитин) also comes to light. [8]]

Research of liquid of a bronkhoalveolyarny unleavened wheat cake (ZhBAL)
Studying of cellular structure of ZhBAL showed that it is identical to that of a biopsiyny material of a pulmonary fabric of the same patients. Possibility of repeated research of the cages reflecting dynamics of pathological process, and safety of a method favourably distinguish BALL from biopsiyny manipulations. At cytologic research comes to light: authentic increase in total number of cages, the maintenance of lymphocytes (norm 6, 7±1, 43 %), neutrophils (norm 0,60±0,42 %), and both in an aggravation phase, and in remission (though to a lesser extent). At a sharp form лимфоцитоз reaches 35-40 %. In process of progressing of process and fibrozirovaniye increase паренхимы lungs percentage of lymphocytes falls, and neutrophils – grows. Nevertheless, at 30 % of patients лимфоцитоз can be absent. At the same time лимфоцитоз, exceeding 15 % 43 % – tuberculosis of lungs, 20 % – patients with a cancer of a lung, 10 % – пневмокониозами are observed in 60 % of sick HIV, 52 % of patients with DZST. [6]. At active саркоидозе the maintenance of IgA, IgM, CD4 + authentically raises, CD8 + – is lowered; CD4 +/CD8 + can make 6:1 (norm 1,8:1). [9]]

Research of function of external breath
FVD violations at patients sarkoidozy lungs are characterized by moderately expressed restrictive syndrome moderated by decrease in diffusive ability and a moderate gipoksemiya. [10]] Violations of bronchial conductivity at level of peripheral respiratory ways are defined at 10-13 % of patients, and as a rule are combined with a restrictive syndrome that points to far come process.

Histologic verification of the diagnosis
Is essentially important instrument of diagnostics саркоидоза, especially at atypical or asymptomatic options of its current. The material for research gets first of all from the places which are most available to research (the struck sites of the skin, increased peripheral лимфоузлы. Mediastinoskopiya (a diagnostic informativnost – 60-80 %) is shown in case of a neinformativnost of bronkhologichesky methods of inspection, and also at suspicion on existence at a sick limforetikulyarny disease (for example лимфогранулематоза). The open biopsy of a lung (diagnostic value reaches 90-95 %) is used now everything more rare with introduction in clinical practice of a chrezbronkhialny biopsy. [11]] Absence of radiological changes of a pulmonary fabric in the presence of a limfadenopatiya of a sredosteniye is not contra-indication to a chrezbronkhialny biopsy of a lung.

Treatment
Approaches to treatment саркоидоза are very various, they reflect ambiguity of understanding of an etiology and патогенеза this disease. A main objective of treatment саркоидоза – suppression of an uncontrollable granulematozny inflammation.

Glyukokortikosteroida
The basis of treatment of a disease is made by GKS which are used for this purpose more than 50 years. However the question of expediency of appointment them at patients sarkoidozy still finally is not solved. Along with that there are numerous supporters of kortikosteroidny therapy, a number of researchers does not consider purpose of corticosteroids shown, giving reason for the opinion absence of the authentic data testifying to positive influence on a forecast. It is also proved that GKS do not influence formation фиброза. [12]] Besides possibility of spontaneous treatment does not allow to estimate with reliability a role of corticosteroids in positive dynamics of pathological process. Nevertheless, ability of these preparations to brake development альвеолита is proved, formation of granulomas and also to normalize CD4 ratio +/CD8 +.

Now application of system GKS in the I stage of an illness is shown only at the expressed clinical manifestations of an illness, and also a giperkaltsiyemiya. The main indications to purpose of GKS are: progressing of a radiological picture, and also existence of signs of generalization of process (defeat of eyes, bones, skin, etc.) . Opinions on modes of dispensing of corticosteroids vary. Usually the dose does not exceed 0,5 mg/kg per day or every other day before knocking over of the main manifestations, with the subsequent decrease on 5 mg each 6-8 weeks. At generalization of system process with defeat of heart, TsNS the increase in a dose to 1 mg/kg/days, and in the absence of effect – addition цитостатиков is necessary. In recent years the increasing distribution receives application of inhalation corticosteroids, the main indication to which appointment is the I-II stage of a disease – as monotherapy, in case of their combination to system GKS, the dose of the last should be reduced twice. [13]]

Thus, the main indication to purpose of steroid therapy is the II stage of a disease. In case of need purposes of GKS in the III stage of a disease, their dose should be reduced to 10-15 mg/days.

Antimalarial preparations
It was shown that хлорохин and гидроксихлорохин are most effective at skin manifestations, defeat of nervous system and a giperkaltsiyemiya connected with the sarkoidozy. Long application of these preparations can cause the irreversible defeat of sight demanding continuous supervision of the ophthalmologist. Positive influence on braking of a fibrozirovaniye of lungs is not proved. In recent years the relation to these preparations became reserved, them rank as so-called medicines of doubtful efficiency.

Cytostatics
The main to the indication to purpose of cytostatic therapy at the moment is the torpidnost to GKS monotherapy, and also high activity of an illness with extra pulmonary manifestations. Treatment schemes, and also preparations are in process of studying.

There are many clinical descriptions of successful application of a methotrexate at refrakterny to GKS саркоидозе in doses from 5-15 mg/weeks. The main contra-indication to purpose of this preparation is development signif
icant фиброза lungs. Possible alternative is лефлуномид (Crowd), possessing antiproliferativny action. Baughman R.P. in comparative research of 17 patients receiving лефлуномид with 15 patients, accepting метотрексат+лефлуномид, showed that at identical shipping, лефлуномид, at least, does not concede to a methotrexate in efficiency [14], demands carrying out further researches.

Pilot researches of clinical efficiency both as monotherapy, and in a combination with GKS for decrease in a dose of the last, such preparations as азатиоприн, хлорамбуцил, азатиоприн, циклоспорин, микофенолат мофетил proceed.

Biological active preparations
When using инфликсимаба good results at patients chronic resistant sarkoidozy lungs and pulmonary sarkoidozy, by resistant GKS to therapy and cytostatics [15] are received, the effect was comparable to GKS. Individual data on efficiency этанерсепта – are inconsistent [9].

Proceeding from патогенеза diseases, development and application of the immunokorregiruyushchy therapy directed on restriction of development or blocking of action of IL1 is represented perspective. The Retseptorny antagonist of IL1 (Anakinra) is already allowed for use in clinical practice while inhibitor of IL1 converting enzyme (Pralnacasan) – passes I/II of a phase of tests.

Ekstrakorporalnye methods
Main objective of treatment – influence on immunological mechanisms of a granulematozny inflammation [16]. Are applied at patients with bad shipping of GKS, цитостатиков, existence of accompanying diseases (diabetes, stomach ulcer of a stomach, a duodenal gut, etc.). Carrying out courses плазмафереза – on 2-5 procedures (for one session 200-700 ml of plasma are removed and 0,9 % are replaced with isotonic solution) with an interval of 5-8 days is recommended. Except плазмафереза at treatment of patients the sarkoidozy are used лимфоцитаферез and ekstrakorporalny saturation центрифугата GKS lymphocytes.

Thus, now carrying out randomizirovanny controllable clinical researches of efficiency of treatment саркоидоза both traditional, and new methods, and also a real assessment of probability of development of spontaneous remissions and development of undesirable medicinal reactions is necessary.

List of references

  1. Daniele R. Immunology of sarcoidosis//In: Immunology and immunologic disease of the lung/Ed. R. Daniele. – Blackwell Sci. Publ., 1988. – P.335-349.
  2. Neville. E. Sarcoidosis: The clinical problem//Post-grad.med. J. – 1988. – Vol. 64, N753. – P. 531-535
  3. Scharkoff Th. Epidemiologic der Sarcoidoze//Z.Erkr.Atm. – 1988. – Bd 170, N 3. – S. 279-283.
  4. Wurm K., Reindell H., Heimeyer L. Der Lungenboeck im Roengenbild. – Stuttgard: Georg Thieme, 1958. – 219 S.
  5. Venet A., Sandron D., Irael-Biet D. Le Lavage bronchalveolare en pathologie interstitielle pulmonaire//Bull. Europ. Phisiopathol. Res. – 1985. – Vol. 21, N 6. – 456-476.
  6. Baughman RP, Teirstein AS, Judson MA et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001; 164:1885-9.
  7. Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17:60-6
  8. Baughman RP, Lower EE, Lynch JP III. Treatment modalities for sarcoidosis. Clin Pulm Med 1994; 1:223-9.
  9. Wyser CP, van Schalkwyk E, Alheit B et al. Treatment of progressive pulmonary sarcoidosis with cyclosporin A. Am J Respir Crit Care Med 1997; 156:1371-6.
  10. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2004 Mar; 21 (1):43-8.
  11. Majithia V, Sanders S, Harisdangkul V, Wilson JG. Successful treatment of sarcoidosis with leflunomide. Rheumatology (Oxford). 2003 May; 42 (5):700-2.
  12. Agostini C. Tailoring immunosuppressive therapy in interstitial lung diseases. Sarcoidosis Vasc Diffuse Lung Dis. 2004 Mar; 21 (1):3-9. Review.
  13. Roberts SD, Wilkes DS, Burgett RA, Knox KS.Refractory sarcoidosis responding to infliximab. Chest. 2003 Nov; 124 (5):2028-31.
  14. Pettersen, JA, Zochodne, DW, Bell, RB, et al Refractory neurosarcoidosis responding to infliximab. Neurology 2002; 59,1660-1661
  15. Yee, AM, Pochapin, MB Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med 2001; 135,27-31
  16. Mallbris, L, Ljungberg, A, Hedblad, MA, et al Progressive cutaneous sarcoidosis responding to anti-tumor necrosis factor-alpha therapy. J Am Acad Dermatol 2003; 48,290-293
  17. Prior, C, Knight, RA, Herold, M, et al Pulmonary sarcoidosis: patterns of cytokine release in vitro. Eur Respir J 1996; 9,47-53
  18. R. P. Baughman, E. E. Lower, D. A. Bradley, L. A. Raymond, and A. Kaufman Etanercept for Refractory Ocular Sarcoidosis: Results of a Double-Blind Randomized Trial Chest, August 1, 2005; 128 (2): 1062-1047. (Абстракт)
  19. J. D. Doty, J. E. Mazur, and M. A. Judson Treatment of Sarcoidosis With Infliximab Chest, March 1, 2005; 127 (3): 1064-1071 (Абстракт)

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