sarcrev98

Sarcoidosis is an enigmatic multisystem disease whose etiology has baffled investigators for more than a hundred years. The author discusses the history, pathogenesis and organ involvement but focuses on the theories about the etiology and presents a rational approach to therapy based on recent investigation of mechanisms leading to granuloma formation. A discussion of future directions follows. The bibliography is intended mainly for the practicing physician but also includes information of a historical and didactic nature.

Key Words: sarcoidosis, noncaseating granuloma, etiology, therapy, interstitial lung disease.

I. Introduction

Call me Ishmael" - yes, studying sarcoidosis and its cause is a little like looking for the great white whale. Sarcoidosis is at once a fascinating and enigmatic disease. From its initial description more than a hundred years ago it has baffled physicians and patients alike. It has been confused with syphilis, tuberculosis, sarcoma, lymphoma, viral diseases, atypical mycobacterial disease, autoimmune diseases, and at one time was even believed to be caused by pine pollen exposure. Since a definite cause has been elusive none of these can be absolutely ruled out with any degree of certainty. Furthermore, because of the variety of presentations, progressions, manifestations and seemingly selective susceptibilities, it cannot be stated even at this time that sarcoidosis represents a single disease entity. Perhaps this is why this disease has enamored the author for the past 25 years. It is the hope of the author in this brief review to impart some of his enthusiasm and awe for this disease by presenting some historical and current data describing it. In this way the author will also touch upon speculation of its cause and future endeavors.

A proper review of sarcoidosis would be too long for the current format and on this basis the author will focus on the etiology and therapy. Several excellent reviews and texts cover the multisystem involvement more extensively than presented here (1-16). There is also an incredible annotated bibliography covering the years 1878 to 1963 published by the U.S. Department of HEW (17).

The author organized this review a little differently from conventional texts. Keeping in mind the major focus described above and grouping together topics that relate closely to each other the history is discussed along with the definition. A presentation of other diseases that mimic or are confused with sarcoidosis follows. In this way the reader gets a clear idea of the nature of the disease we are discussing. Next the review covers the distribution of most organs that have been reported to be involved with the disease. Finally the author approaches the cause by discussing epidemiologic, genetic and immunologic factors. The discussion of the cause precedes the therapy section, a presentation of a logical rationale for the treatment of this disease. Wild speculation about the future then follows.

II. Historical Aspects/Definition

Jonathan Hutchinson (Figure 1) is often credited with one of the first descriptions of the disease, described in 1877 as papillary psoriasis in a patient, John W. (18, Figure 2) who had initially been seen in 1969, a disease which Hutchinson believed was related to the patient's gout. However, Besnier (Figure 3) in 1889 reported a patient with synovitis of the hand, Lupus Pernio of the nose and epitrochlear nodes (19). No histology was obtained. He coined the term Lupus Pernio, a violacious swelling of the nose, ears, and fingers.

Tenneson in 1889 described the clinical findings (20) and then in 1892 the first histology of Lupus Pernio including epithelioid cells and a few giant cells and called it "Lupus of myxomatous and adenomatous type (21)." Later, in 1898, Hutchinson reported another case believed to be similar to Besnier's Lupus Pernio (22). No histology was reported. This was the famous case Mortimer's Malady (Figure 4) named after the patient. To Boeck (Figure 5, and Figure 6) we owe the name sarcoid from the Greek meaning flesh. He likened it to a tumor with sarcomatoid tissue. (23).

Next a series of reports describe various aspects of the disease and speculation about its etiology. Kienbock in 1902 thought it was syphilis (24). Darier and Roussy believed it to be Tuberculosis in 1906 (25). Kreibich in 1904 described cystic changes in the bones and connected these with Lupus Pernio (26). 1920 Jungling described Osteitis Tuberculosa Multiplex Cystica and usually is given credit for the bony descriptions even though Kreibich actually was first (27).

Jorgen Schaumann (Figure 7) in 1917 paved the way for our understanding that this is a multisystem disorder connecting Hutchinson's Papillary Psoriasis, Besnier's Lupus Pernio, Boeck's multiple benign sarcoid and included lung lesions for the first time (28). He wrote a prize winning essay in 1914, published in 1936, calling the disease lymphogranulomatosa benigna to distinguish it from lymphogranulomatosa maligna which was the name formerly used for Hodgkins disease (29).

Heerfordt in 1909 described uveoparotid fever (30). Kuznitsky and Bittorf in 1915 described the relationship between the cutaneous and pulmonary lesions (31). In 1935 Salvesen described plasma protein elevation (32). Burman and Mayer in 1936 described an 8 year old in whom they did arthroscopy to determine that this was a case of sarcoid joint disease (33). Lofgren (Figure 8) in 1946 described bilateral hilar lymphadenopathy with or without erythema nodosum (34). Ustvedt in 1949 described bilateral hilar adenopathy associated with erythema nodosum and noted that it occurred with tuberculosis and with sarcoidosis (35). But Lofgren studied a larger number of patients and described the Bilateral Hilar Lymphoma Syndrome in 1952, a description which he coined and which has remained to honor his name (36). He believed this to be an early form of sarcoidosis, a theory which he solidified in 1953 in a two part article (37,38). He determined that this presentation confers a benign course and usually complete resolution. According to this chronology, our understanding of the disease has transformed from that of a cutaneous to bone to respiratory to multisystem disorder.

Over the past 40 years, there have been 16 world conferences on sarcoidosis. James summarizes them as follows (39). At the twelfth conference, the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) (Figure 9) was initiated and a meeting held. A WASOG meeting was convened at each international conference on sarcoidosis.

Organizers of World Conferences Related to Sarcoidosis

I 1958 D. Geraint James, London (Figure 10)

II 1960 Martin Cummings, Washington (Figure 10)

III 1963 Sven Lofgren, Stockholm (Figure 10)

IV 1966 Jacques Turiaf, Paris (Figure 10)

V 1969 Ladislav Levinsky, Prague (Figure 10)

VI 1972 Ytaka Hosoda, Tokyo (Figure 11)

VII 1975 Louis Siltzbach, New York (Figure 10)

VIII 1978 W. Jones Williams, Cardiff (Figure 11)

IX 1981 Jacques Chretien, Paris (Figure 11)

X 1984 Carol Johns, Baltimore

XI 1987 Gianfranco Rizzato, Milan

XII 1989 Manuel Freitas & E. Costa, Lisbon, First WASOG Meeting

XIII 1991 Takateru Izumi, Kyoto, WASOG 2

XIV 1993 Om P. Sharma, Los Angeles, WASOG 3 (Figure 12)

XV 1995 Ron M. du Bois, London, WASOG 4

XVI 1997 Ulrich Costabel, Essen, WASOG 5 (Figure 13)

XVII 1999 Masayuki. Ando, Kumamoto, WASOG 6 (Figure 14)

XVIII 2002 Olof Selroos (Figure 11), Anders Eklund (Figure 15), Stockholm, WASOG 7

At each successive conference a definition of sarcoidosis has been put forth, each a little more involved and each with a little more basic science added. The consensus has been to use a descriptive paragraph or more to define the disease until a specific etiologic agent can be found. James has provided the most recent descriptive definition, which is repeated here in its entirety (39).

Sarcoidosis is a multisystem disorder of unknown cause(s) most commonly affecting young adults, and frequently presenting with hilar lymphadenopathy, pulmonary infiltration, and ocular and sin lesions. The diagnosis is established most securely when well recognized clinicoradiographic findings are supported by histologic evidence of widespread epithelioid granulomas in more than one system. There is depression of delayed-type hypersensitivity, imbalance of CDT4:T8 subsets, an influx of T-helper 1 (Th1) cells to sites of activity, hyperactivity of B cells, and circulation of immune complexes. Markers of activity include elevated levels of serum angiotensin-converting enzyme (SACE), abnormal calcium metabolism, a positive Kveim-Siltzbach skin test, intrathoracic uptake of radioactive gallium, and abnormal fluorescein angiography.A

The course and prognosis correlate with the mode of onset. An acute onset usually heralds a self-limited course of spontaneous resolution, whereas an insidious onset may be followed by relentless, progressive fibrosis. Corticosteroids relieve symptoms, suppress the formation of granulomas (including Kveim-Siltzbach granulomas), and normalize both levels of SACE and the uptake of gallium. A synthesis of clinical features, radiology, histology, biochemical changes, and immunologic abnormalities helps distinguish sarcoidosis from nonspecific local sarcoid-tissue reactions.

Genetic and other molecular probes may help define a sarcoidosis terrain or diathesis, and determine whether bacteria or viruses play a causative role in susceptible soil.

Sarcoidosis is one member of a large family of granulomatous disorders, which includes infections, reactions to chemicals, an enzyme defect, and several disorders with immunologic aberrations. All members of the family share a common denominator - i.e., granuloma formation. Their differentiation often demands skillful interpretation of the clinical findings and pathologic evidence - in fact, a combined clinicopathologic synthesis of the available information. The numerous mimics of sarcoidosis are a challenge to the chest physician, ophthalmologist, dermatologist, and broad-based general physician alike. The differential diagnosis involves all systems and organs. The common denominator is granuloma formation, which is mediated by Th1 clones. They synthesize and secrete interleukins 1 and 2, tumor necrosis factor, and interferon - gamma. The Th1 response profile is coupled with major histocompatibility class II macrophages and their cytokines, progressing to granuloma formation.

III. Pathology/Diagnosis

The pathology of sarcoidosis has been reviewed extensively elsewhere, (40). The hallmark of the pathology of sarcoidosis is the non-caseating granuloma. Caseation is a process of liquifaction of the tissue, which on a gross level reminded earlier pathologists of cheese, hence the term caseation. It is a form of necrosis that contains a mixture of protein and fat that is absorbed very slowly (41). Necrosis is used to describe cell death (42). Some texts refer to the lesions as non-necrotizing granulomas. Granuloma refers to a nodular inflammatory lesion composed of compactly grouped mononuclear phagocytes (43). The granulomas of sarcoidosis are well formed in contrast to those of hypersensitivity pneumonitis (HSP) which is a disease often confused with sarcoidosis. Bilateral hilar adenopathy is not present in HSP nor is systemic involvement, which is part of the sarcoidosis picture. In order for the diagnosis of sarcoidosis to be made there must be clear-cut evidence histologically of well-formed non-caseating granulomas and the absence of staining (and ultimately cultures) for mycobacteria and fungi. It is important to obtain cultures of the biopsy material to be sure these organisms do not grow. Usually the cultures are held for two months before a final report is rendered. Therapy can begin before final cultures are out if needed for acute cases with clear-cut clinical and histologic features. However, one must not forget that on occasion the cultures may prove the initial diagnosis incorrect.

Granulomas in sarcoidosis are described as monotonous in that they all appear to be in the same stage of development (Figure 16). There are monocyte/macrophages that have been transformed into epithelioid cells and larger multinucleated giant cells in which these transformed macrophages apparently have fused, the so-called Langerhans giant cells (Figure 17). Often there are star-shaped inclusions called asteroid bodies (Figure 17). Surrounding these giant cells are small lymphocytes and a few fibroblasts. These types of lesions imply an early stage of the disease in which granulomas are developing and are being perpetuated by the chemicals produced in response to constant antigenic stimulation. The products of the granuloma lead to increased fibroblastic activity and deposition of collagen. Type III (early, soluble) collagen ultimately is replaced by Type I (late, insoluble) collagen that is more permanent and produces irreversible fibrosis (scarring). Hence the granuloma is self-perpetuating and leads to structural damage that may become permanent and result in functional impairment. Granuloma formation is a complex subject about which much is known and reviewed in several excellent articles and texts (44-50).

Scadding (1985) states that many cases remain undetected because there are no symptoms and that the diagnosis often is a matter of judgement. Further he states that several areas in which data from may studies agree include 1. mass surveys detect more disease than physicians offices and 2. autopsy studies detect even more than mass surveys. 3. an abnormal chest radiograph is the most common presenting feature followed closely by respiratory symptoms except in women in the UK where erythema nodosum is the most common presenting feature. The most important lesson in making the diagnosis is to put together the clinical manifestations and usually pathologic findings and to rule out the other potential causes for similar diseases.

In order to fulfill the definition, tissue is usually required. The Kveim test (51, Figure 18) is an excellent test if it is available and if you are willing to wait 4-6 weeks. Basically Kveim reagent (an extract of sarcoid tissue that has been standardized rigorously) (52) is injected intradermally. 4-6 weeks later the area is biopsied and if non-caseating granulomas are found, the diagnosis is certain in over 95% of cases (53,54).

Transbronchial lung biopsy is a relatively non-invasive technique that can yield positive results in all radiographic presentations, including stage 0 disease (55). If at least four biopsies are taken then the diagnosis can be made in 82% of cases. Among various stages, the diagnosis was made using transbronchial biopsy in 50%, 72%, 90% and 100% of stage 0, I, II, and III, respectively. Others also (56-58) have seen similar results. It is important to culture the biopsy and lavage fluid to eliminate fungal and mycobacterial diseases from the diagnosis but usually if the stains are negative for these organisms and non-caseating granulomas are found the diagnosis can be made especially if the clinical presentation is compatible with sarcoidosis. The diagnosis of sarcoidosis is always a diagnosis of exclusion.

Although we know some of the complex mechanisms of the disease, the etiology is still unclear and often the diagnosis is still sometimes hard to obtain. In reminiscing back to the beginning, Sharma has unearthed a truism coming from the literature of Sir Arthur Conan Doyle, the author of Sherlock Holmes, which may be applicable to sarcoidosis. It is not common knowledge is that Jonathan Hutchinson may have known Sir Arthur Conon Doyle. Several of his stories may have included cases of sarcoidosis. Sir Arthur Conon Doyle was an ophthalmologist who practiced near the famous Harley Street where Hutchinson practiced. In fact they both may have attended the same clinic from time to time. Sharma has made a careful study of the history of medicine and has included a number of interesting tidbits such as this in his publications. In the context of making the diagnosis of sarcoidosis he quotes Holmes, when you have eliminated all which is impossible then whatever remains, however improbable, must be the truth" (59).

IV. Other Diseases Confounded with Sarcoidosis

Hypersensitivity pneumonitis (HSP) is caused by exposure to antigens, usually proteins often from thermophilic fungi found in moldy hay or other similar locations. Many different antigens have been identified which are capable of producing the same syndrome. Symptoms in the early stages of the disease are temporally related to exposure but may be delayed in onset and later in the disease may not appear to be related to exposure. Lung tissue contains poorly formed granulomas which do not contain acid fast organisms and do not stain for fungi. HSP can be confused with sarcoidosis but is not a systemic disease. It usually responds well to avoidance of antigen and systemic corticosteroids.

Beryllium disease is caused by exposure to beryllium. It is identical to sarcoidosis in the lungs but is not a systemic disease. Lymphocytes from beryllium disease patients can be stimulated in vitro to blast transformation upon exposure to beryllium (16). The lymphocyte test is very specific for beryllium disease but is not universally available.

Fungal diseases form granulomas in the lungs but usually manifest some degree of necrosis. Often organisms can be demonstrated in tissue specimens by special stains. However, the absence of fungi on stains is not sufficient to eliminate fungi as a cause for granulomas. Culture confirmation is required. Unfortunately cultures need to be kept for about 2 months before they can be declared negative with certainty.

Tuberculosis causes the classic caseating granuloma. Acid fast organisms usually can be detected in specimens though it may take a very careful review of each slide to be sure of their absence. As in the case of fungal diseases in order to be absolutely sure mycobacterial organisms are not present about two months is required for cultures to be kept.

Other less common granulomatous diseases include Wegener's granulomatosis, lymphogranulomatosis, foreign body reactions, granulomas adjacent to tumors, the GLUE syndrome (Granulomatous Lesions of Unknown Significance), leprosy, and cat scratch fever. Dr. James to whom the reader is referred (39) presents an extremely complete comparison with other granulomatous disorders.

V. Organ Involvement - general distribution

Almost every organ in the body can be affected as shown in Table 1 and Figure 19. Siltzbach and James have described the worldwide occurrence and tallied the various manifestations in several comprehensive references (60,61). Sharma states that organ involvement (anatomic location) is related to symptoms, and notes that the disease is very different in each person so that one person's symptoms can not necessarily be compared with another's (62). Patients need to be educated along these lines because they tend to compare symptoms with each other. Since the lung is often the presenting organ we will focus on pulmonary and then discuss non-pulmonary involvement.

a. Respiratory System/Pulmonary Function

Intrathoracic disease occurs in about 87% and the lungs are involved in over 90% of cases (12). The description of pulmonary sarcoidosis usually centers on the radiographic appearance at presentation and during the course of the disease. On this basis there are four stages that have been utilized over the years (Table 2, Figures 20-23). Keep in mind that these are not true stages in terms of disease progression but are more accurately types of the disease from a radiographic point of view. Furthermore, only 20% of patients have an abnormal chest roentgenogram on presentation (12) despite the fact that 49% have respiratory symptoms. Several years ago there was an effort to rename the stages as types, because of the lack of progression from one to the other. The literature never really changed and we are stuck with the labels (stages) presented here. Nevertheless there is some validity in describing the disease in terms of these stages/types since they allow us to predict outcomes.

There is some danger in treating on the basis of stages of presentation alone. The author reported one case (63) in which the patient presented with stage II disease and was to return for therapy. She missed the next appointment and came in several months later with a normal chest radiograph and no symptoms. Had she done what we requested she would have been treated with steroids and we would have thought we had done a good job in treating her. She would also have been committed to a long course of therapy lasting up to two years. A more recent case presented with stage 0 (64). Her symptoms included extreme lethargy and postural hypotension. She was previously a very active individual but on presentation couldn't walk 25 feet without complete exhaustion. After multiple tests including an extensive cardiac work up she developed iritis which subsided then hilar adenopathy. This lead to transbronchial biopsy and a diagnosis of sarcoidosis. This is an unusual case presenting with symptomatic stage 0 progressing to stage I. Initial therapy converted her chest radiograph to stage 0 and her symptoms abated.

Despite the lack of predictable progression from one stage to the next, the stages can be used to predict outcome to some extent (5). Table 3 depicts remission rate and response to steroids as well as overall mortality and stratifies them according to radiographic stage. As can be seen, stage 0 has little data but there is decreasing remission rate and increasing mortality going from lower to higher numbered stages (65.66). According to Dr. Sharma (12): 60-80% with stage I have clearing in 2 years. Rarely if ever does bilateral hilar lymphadenopathy (BHL) recur. 10% of all stage I cases have a persistent course. 10-15% remain stationary or advances slowly to stage II. Two thirds of stage II resolves. One third remain stationary or progress to stage III. 20% develop fibrosis.

Other presentations include nodular, necrotizing, miliary, or cavitary. A small percentage develops calcification and some (1-3% radiographically, 35% by autopsy) have pleural involvement either pleural effusions or pleural thickening (67). One case of pleural calcification was reported (67). Pulmonary vasculitis may occur (68) and even may lead to pulmonary hypertension (69). Cavitary disease may harbor aspergillomas and may lead to hemoptysis (70, 71). Nodular disease and necrotizing sarcoidosis can mimic Wegener's granulomatosis but has a good prognosis with excellent response to steroids (72-77).

Apart from the usual plain radiographs, additional radiographic techniques have become useful for evaluating the extent of pulmonary disease in sarcoidosis. Conventional computerized tomographic scans (CAT scans) are useful for evaluating lymph node enlargement such as hilar, mediastinal and paratracheal nodes and even intraparenchymal nodes. However, newer high-resolution scans (Figure 24) provide even more information and can detect ground glass shadows presumably representing alveolitis. There are nodular densities along septal regions and other patterns highly suggestive of sarcoidosis that may aid in the early diagnosis of the disease as well as assisting with evaluation of therapy. Details have been reviewed elsewhere (78).

The use of other imaging techniques such as gallium scanning will be address in the section on activity. Bronchoalveolar lavage is discussed below in the section on immunology.

The upper airway can also be involved in sarcoidosis, (SURT, sarcoidosis of the upper respiratory tract), as can larger airways, including the trachea and major bronchi (79). Endobronchial sarcoidosis may occur in 40 to 70% of patients (12). Sinuses can also be involved as well as the larynx (79). When Lupus Pernio involves the face, the nasal bone can occasionally be affected (79).

Utilization of pulmonary function tests remains one of the few means to assess degree of dysfunction and response to therapy. Having said this we must keep in mind that results of pulmonary function tests do not always correlate with a radiographic stage nor of other organ system involvement (80).

Certain tests appear to be better than others for assessing response to therapy. The classic findings of any interstitial lung disease as with sarcoidosis include decreased lung volumes and decreased diffusing capacity for carbon monoxide (DLCO) (81,82). These are very useful tests for following the course of sarcoidosis. Some physicians prefer to use just the vital capacity as a measure of lung volume and very often this is helpful. The author of this report believes that additional information obtained from the dilutional lung volumes and DLCO may be more helpful in estimating the physiologic function as well as directing therapeutic maneuvers, although others have found that the vital capacity may improve without changes in DLCO upon recovery (83).

Recent spirometric studies have determined that a large percentage of patients have airways disease. Inhalation challenge studies have detected others with hyperreactive lung disease not attributable to additional diagnoses such as asthma (84). Chronic airway obstruction is often difficult to treat and may occur in the wake of significant fibrosis (85). In addition, cardiopulmonary exercise testing has been useful in predicting non-pulmonary or cardiac disease, leading toward additional cardiac work up (86).

b. Skin

The skin is involved in about 10-35% of all cases of sarcoidosis (12, Table 4). Schaumann described a man with multiple cutaneous manifestations (Figure 25) For the most part cutaneous disease can be subdivided into acute and chronic forms. Acute skin disease with erythema nodosum predicts a favorable outcome in contrast to other forms of skin disease, which usually accompany a more chronic indolent course. Frequently arthralgias occur with acute skin changes. Usually acute skin changes do not lead to chronic cutaneous disease and arthralgias rarely lead to destructive arthritis. Erythema nodosum an acute febrile illness characterized by a painful nodular, erythematous rash on the shins and forearms and by joint pains and malaise" (87,88). He noted the seasonal variation of its occurrence, the epidemic occurrences, and the fact that it occurs more frequently in young children and young adults than in older individuals. Furthermore he stressed the increased incidence among Nordic races. Other diseases in which erythema nodosum occurs includes streptococcal pharyngitis, pulmonary tuberculosis, histoplasmosis, blastomycosis, coccidioidomycosis, lepromatous leprosy, lymphogranuloma venerum, systemic lupus erythematous, ulcerative colitis, Behcet's disease (89).

Kerley, 1942 also noticed the enlarged pulmonary hilar lymph nodes and pulmonary infiltration, which often accompanied erythema nodosum and that this was identical to the findings in Boeck's cases of sarcoidosis (87). In a separate publication he describes 37 cases and concludes that young people with erythema nodosum and visceral manifestations have sarcoidosis (88).

Chronic skin changes include plaques, nodules, papules, sometimes viteligo, and a curious skin manifestation called Lupus Pernio, a term coined by Besnier (19). The latter consists of purplish (violaceous) discoloration and swelling frequently about the nose and skin around the nose (Figure 26). It can also occur on the ears and fingers. (19). Lupus pernio may be associated with destructive bony changes and arthritis. Often it produces embarrassing disfigurement of the face that may be difficult to treat (90). Tennesen in 1892 presented the histologic manifestations of lupus pernio and as James quotes him predominance of epithelioid cells and a variety of giant cells were present in these lesions (21,91).

James classifies the lesions as erythema nodosum, lupus pernio, persistent plaques, maculo-papular eruption and scars. Many patients with lupus pernio have swollen digits with bone cysts if radiographed. There are also local sarcoid-tissue reactions in which there are no systemic manifestations, thus distinguishing these from true sarcoidosis (by definition, a systemic disease) (91).

c. Eyes

Ocular involvement occurs in up to 20% of cases (12, Table 5) but varies among geographic locations in different countries. Anterior uveitis and posterior uveitis are the most common findings. Untreated these may lead to blindness therefore necessitating early evaluation by slit lamp examination in newly diagnosed cases regardless of presenting organ system manifestations.

Some other areas involved include iris (iritis, Figure 27-29), ciliary body, choroid, retina (inflammation perivascular), conjunctiva (granulomas.25% have conjunctivitis), lacrimal gland (as extension of upper respiratory tract disease) (11).

Acute changes such as iritis, especially when associated with cutaneous lesions of erythema nodosum and pulmonary lesions of bilateral hilar adenopathy predict a good outcome. Posterior uveitis and other eye involvement are usually associated with more severe and more chronic indolent forms of the disease, which are often hard to treat. In this author's opinion, any new sarcoidosis patient should have an ophthalmologic evaluation to be sure there is no treatable form of ocular sarcoidosis. This is important because many eye lesions can lead to blindness but are treatable if detected early in the course.

Heerfordt's Syndrome, Heerfordt's triad or uveoparotid fever all refer to a special syndrome originally described in 1909 (30). As stated by Scadding it was "characterized by a protracted course, low fever, localization in the parotid gland and in the uveal tract, and the frequent appearance of complicating pareses of the cerebro-spinal nerves, especially the facial" (11). Originally it was believed to be a variant of mumps but Bering linked it to sarcoidosis (92).

d. Liver/Spleen/Lymph Nodes

Most cases have liver involvement (58%) (12) but usually it is clinically silent (93). Often it is difficult to determine whether the disease or the therapy causes elevated liver enzymes, especially when non-steroid medications are utilized. Lymph nodes are almost always affected (77%) (12) and involvement was 100% in some autopsy studies even if not obvious before death. Bilateral or symmetrical distribution of affected nodes occurs often. Splenic calcifications can also occur. (94).

e. Nervous System (95-98)

The nervous system is involved in about 5% of cases (97) and can take many forms (Tables 6, 7). The most common form of involvement is cranial nerve palsy, especially VII (see also Heerfordt's triad described above). This may be due to a compression neuropathy but granulomatous angiitis and periangiitis may also be responsible for nerve damage. The nerve involvement is often asymmetric in the peripheral nerves. The most common peripheral neuropathy is mononeuritis multiplex. Other than cranial nerves the central nervous system may manifest leptomeningeal disease or localized tumor-like masses of granulomas. Pituitary involvement in the hypothalamic area occurs in < 1%. Hypopituitarism is not confined to anterior lobe. The hypothalamus is affected relatively frequently, just above the infundibulum and spreads along the neural stalk into the posterior lobe. It may also spread along the meninges. Involvement of optic chiasm and optic tracts is unusual. In general 46% of all cases of neurosarcoid completely recover with therapy and 46% improve. 4% remain stable and 4% worsen (95).

f. Heart (99,100, Table 8)

Porter cautioned that cardiac sarcoid can not be considered a benign disease (101). 20-30% of all cases have asymptomatic cardiac involvement (102). Smaller proportions are symptomatic. 20% of the symptomatic cases die of congestive cardiac failure. Arrhythmias and sudden death are common, in fact, the most common presentation of cardiac sarcoid is sudden death. More cases are reported by autopsy studies than by large population surveys. Both the conducing system and myocardium may be involved. Focal lesions are not always detected in endomyocardial biopsies. (102, 103) but when found, indicate the need for therapy which could be lifesaving. Various imaging techniques may be useful in detecting myocardial involvement antemortem (104).

Therapy for myocardial sarcoidosis involves steroids but occasionally other medications may be needed (105). Often a pacemaker and/or AICD (automatic implantable cardioverter defibrillator) may be required while awaiting cardiac transplant (100, 106). Use of steroids improves outcome dramatically even with the aforementioned devices (106, 107).

g. Gastrointestinal Tract

Other than the liver and spleen (see above), the gastrointestinal tract is infrequently involved in sarcoidosis. Minor labial salivary glands may be affected up to 60% of the time, major salivary glands are affected in Heerfordt's syndrome as described above (12). Parotid swelling occurs in about 4 % of cases. Oral, small intestinal (108) and colonic and appendiceal (109) cases are very rare. The stomach may be involved in 10% of cases (110)) but if the esophagus is involved with granulomas, Crohn's disease must be considered in the differential diagnosis (12, 111). The pancreas is very rarely involved but in some series can have granulomas in up to 6% of cases (112).

h. Kidneys

Kidneys are affected in up to 20% of cases. The involvement ranges from hypercalciuria, to glomerulonephritis, and interstitial nephritis (113-115). Therapy with steroids may have dramatic beneficial effects (116).

i. Endocrine System/Reproductive Organs/Pregnancy (117, Table 9)

Pituitary and pancreatic sarcoidosis have already been mentioned above. The thyroid gland may be involved in up to 4%, however thyroid function usually remains normal (12).

Breast is rarely involved (12) and when it is there may be a nodule that remains localized for a long time. Uterine involvement is rare (118). The endometrium can become involved following previous surgery. The ovary is occasionally involved. Pelvic involvement is usually self-limiting.

Testicular involvement is possible (12, 117) . It must be distinguished form other causes, e.g. seminoma, tuberculosis, and idiopathic granulomatous orchitis. Epididymitis (117) has been described. Prostatitis is only occasionally mentioned (117).

Pregnancy in sarcoidosis presents a curious phenomenon. During pregnancy sarcoidosis in many sites including the lungs may actually regress, presumably due to endogenous steroid production. In the postpartum period various organ system involvement may again reappear (117).

j. Muscles (119, 120)

Sarcoidosis is common in skeletal muscle. It is more likely to occur than in peripheral nerves (11,12). Proximal myopathy with muscle weakness, tenderness and pain may be present. It is more often seen in females and Afro-caribbean individuals (11, 12).

k. Joints

Burman first described sarcoid arthritis arthroscopically (33, Figure 30). Martenstein was the first to describe tenosynovitis (121) in association with lupus pernio. Sokoloff described the histology of joint involvement (122). Joints are often affected in the acute syndromes. Kaplan described three settings (123). When migratory arthritis is associated with erythema nodosum and hilar nodes the prognosis is good (124). However, if there are single or recurrent episodes of monoarticular or polyarticular arthritis with or without migratory components or persistent arthritis, complete clearing is unlikely. However, frank arthritis, i.e. the latter two forms, is not common. There are unusual some forms that are extremely destructive (125). Caplan described a syndrome consisting of hilar adenopathy associated with periarticular inflammation with granulomas consistent with sarcoidosis (126). Joint destruction may occur as described below in association with lupus pernio (10). There is also a peculiar syndrome of sarcoidosis, psoriasis and gout (127) but there is controversy as to its actual existence (128). It is of note that the first description by Hutchinson was initially believed to be a case of gout and the patient actually did die with renal failure (129). It is also of interest that most bone disease does not encroach upon the joints (130, 131).

l. Bone

Kreibich probably was the first to describe the cystic bony changes that occur in the hand with lupus pernio (26). Schaumann actually described bone involvement in 1926 (132). Bone involvement occurs with chronic skin disease such as plaques, nodules, and lupus pernio (10). Often there is a peculiar cystic or trabecular appearance to the phalangeal bones (10, Figures 31-34) so characteristic for sarcoidosis that the diagnosis can occasionally be made by an astute radiologist. Often the bone involvement will spare the intervening joint (133, Figure 35). Multiple unusual sites have been reported in isolated cases such as skull (134,135, Figure 36), vertebral (136, 137), and bone marrow (138) . Several excellent reviews are available (12,133,139, 140).

Bone Marrow is common involved but less often recognized. Drug hypersensitivity reactions may be confused with this lesion but show less-well-formed granulomas (103).

VI. Epidemiology (141-142)

Epidemiologic studies can tell us a great deal about entire populations of individuals with various diseases. They tell us nothing about individuals with the diseases. Modern techniques have allowed predictions about the etiology of sarcoidosis. This section explores a little of each of these attributes and demonstrates how powerful epidemiologic principles and studies can be.

First lets define a few terms. Incidence refers to the number of new cases of a disease that occur during a particular interval of time, for example per year. Prevalence describes the number of cases of a disease that exist at a given point in time (143).

In order to discuss the magnitude of the problem Figure 37 displays the proliferation of articles written about the topic. This figure was generated from data obtained by performing a literature search using Internet Grateful Med, which searches the National Library of Medicine database. From 1966 until 1985 there was a 46% increase in the number of articles published from 325 to 475 per year (incidence per year). Then the number appeared to plateau at about 440 per year thereafter. The total number of articles found in this search reached 12,492 which averages 390 per year for the entire period. Searches older than this were not possible using that database and search engine. Based on the number of references generated the problem is significant and warrants a major investigative effort.

Using data from various worldwide studies, James and Hosoda (141) put together some incidence and prevalence data for a few countries. The prevalence per 100,000 population in the Nordic countries is about 28, for Japan it is 3 to 5. The incidence rate for the Nordic countries is 12 and for Japan is 1.3. In the United States, based on data from Israel (Figure 10) in1971, the prevalence among blacks is 27-47 and for whites about 2 to 4. Geographic distribution coupled with temperature variations suggests increased incidence in northern cooler areas of Japan just before the warmer months. This pattern seems to replay itself among other countries as well, with emphasis on the temperature variations.

Over the years a number of strange relationships have been observed based on various ethnic groups living in native compared with foreign countries (142). In England the prevalence per 100,00 among natives born in Britain is 27 (males and females); those born in Ireland 97 for males, 213 for females; and those born in the British Caribbean 197 for males, 170 for females. The data demonstrates that prevalence varies from one ethnic group to another living in the same country and within each ethnic group the prevalence is quite different among the sexes.

Various organ involvement various substantially among different countries as well. Erythema nodosum is quite common in the Scandinavian countries (53%) as well as Britain (31%) and Barcelona (33%). Eye disease is common in London (27%), Tokyo (32%) and New York (20%). However, even in the same country, in Los Angeles eye disease is much less common (11%) as is the case in Paris (11%) and Europe as a whole (4%).

Hosoda (143) divides a number of other features into two broad categories Host Related and Time-Space Factors. Among Host Related factors, age, gender, race and family clustering (to be discussed in the genetics section) have been evaluated. Among Time-Space Relationships, overall incidence, geographic distribution, migration effects, seasonal differences, and possible local outbreaks have been discussed but none provides conclusive evidence of a specific cause.

On the other hand, based on the available epidemiological data such as described above, Hosoda suggests that a hypothesis of the causative agent can be deduced. After providing a disclaimer that statistical methods can not establish proof of a causal relation ship in an association, Hosoda states that sarcoidosis may be triggered by an infectious agent or more than one agent. These may be commonly prevalent in most parts of the world but not virulent enough to cause local outbreaks. The agent(s) may be more active in cooler climates and may be more obvious in the wake of waning epidemics of tuberculosis, plague and cholera, allowing these weaker agents to become manifest. Furthermore, environmental factors may be joined by increased susceptibility of certain people by their age, gender, race, familial predisposition and genetic immune and humoral makeup. He recommends that members of various disciplines such as molecular biology, microbiology, clinical medicine and epidemiology should put forth an effort to work together toward a better understanding of this disease. This in fact is being done (see Etiology/Future/Summary below).

One other area in which epidemiologic studies have helped is in the determination of mortality from sarcoidosis. Reich (144) recounts Gideons article in which mortality from sarcoidosis was counted as 5% (145). The values require careful interpretation since they are derived from a tertiary care center and may be biased. Other studies may show values as low as 0.6% based on whole populations. Ethnic or geographic factors may be confounding variables.

The 5% figure is fairly consistent among many epidemiologic studies but increases to about 10% for neurosarcoidosis (144, 146).

Perry (146) in a small autopsy study (38 cases) demonstrated that the cause of death was sarcoidosis in 67% and incidental in 33% of the 38 sarcoid cases that came to autopsy. Furthermore, of the deaths attributable to sarcoidosis, 45% were suspected ante-mortem. In addition, 50% of the cases that died of sarcoidosis were cardiac deaths and 43% were pulmonary. Of the cardiac sarcoid deaths, 29 % were diagnosed antemortem and of the pulmonary cases 75% were diagnosed antemortem. The author makes the point that cardiac sarcoid occurs in the young and is often undetected in life but many had extracardiac manifestations and could possibly have been detected with endomyocardial biopsies.

There are a number of other interesting associations that have been presented over the years. Several isolated cases and a few small series have presented cases of sarcoidosis occurring either simultaneously or preceding the development of lymphoproliferative diseases such as lymphomas or lymphocytic or myelocytic leukemia (147) . The authors usually claim immuno-dysregulation or immunosuppression as a rationale for the increased incidence of malignancy in sarcoidosis. Sarcoidosis has been associated with common-variable hypogammaglobulinemia (148) however, many textbooks list a granulomatous disease more consistent with a granulomatous bronchiolitis which may be different from sarcoidosis. The distinction needs to be made since some of these are believed to develop into lymphomas. Sarcoidosis has been associated with lung cancer also (149-155) and some cite a sarcoid reaction in which there is local granuloma formation but no systemic disease (156).

Sarcoidosis has been reported in a patient with multiple sclerosis, the distinction from which would be difficult if considering the diagnosis of neurosarcoidosis (157). Sarcoidosis has been reported in association with tuberculosis (which is hard to diagnose especially if the tuberculosis occurs first) and various fungal diseases most often Aspergillus (71) but occasionally Nocardia (158). It is unclear what these associations mean since cause and effect can not be inferred but perhaps they are related to the immunologic events involved in the development of granulomas in sarcoidosis.

VII. Genetics

Although no definite genetic marker or link has been determined there is indirect evidence of genetic predisposition for sarcoidosis. Support comes from several lines of data spanning over fifty years. In 1923 Martenstein described two affected sisters (159). In 1947 two sets of brothers were described by Robinson and Hahn (160). In 1973 the British Thoracic and Tuberculosis Association did a huge survey finding 59 families with 121 cases (161).

The medical literature contains over 450 families in which two or more members have sarcoidosis (162). Several patterns have surfaced. Familial cases are more common among women. Same-sex pairs are more common than non-same sex cases. Monozygotic twins have a higher incidence than dizygotic twins although the numbers are small. There is a tendency toward mother-child cases more than father-child cases. Heading estimated 60-70% heritability of disease liability (163). The British survey (above) cited 14% had first or second degree relatives with sarcoidosis. Familial sarcoidosis occurred 17% in African-Americans compared with 6% in whites. The conclusions were that familial sarcoidosis is common in hospital outpatient-based population of cases and that African Americans are more likely to have affected relatives.

The risk in families can be due to shared environment and genetic features but there is much heterogeneity in familial risk (164). Genetic markers such as HLA class one markers on the surface of alveolar macrophages have been studied. Although some patterns emerged, no clear conclusions can be drawn.

Genes have been paired with clinical manifestations but there have not been any definitive findings (165). Some HLA alleles appeared to predispose to erythema nodosum, arthritis, and a good prognosis whereas others appeared to protect against getting sarcoidosis. Others appeared to predict a poor prognosis. But again, the data is inconclusive.

Evans derived four arguments that might be used to explain the genetics of sarcoidosis (162) 1. family studies demonstrated a Mendelian pattern of inheritance, 2. HLA typing may be used to determine the disease severity, 3. HLA typing may be used to determine the incidence of sarcoidosis, and 4. defects in genes may occur that normally protect the host from infectious granulomatous diseases.

On the basis of the evidence to date no clear answer as to how genetic makeup predisposes to sarcoidosis can be offered (162). The NIH study described in the section below on future events is based on the above hypotheses. In summary we need large studies using phenotypic stratification with genetic markers and environmental data. Until then we are left with a disease with interesting patterns in families and uncertain allelic associations (165).

VIII. Immunology

It is perhaps the study of immunology that has given the best insight into mechanisms of this disease and helped to elucidate granuloma formation and development of fibrosis. The earliest immunologic findings were of hypergammaglobulinemia (32) and cutaneous anergy (166). This always seemed paradoxical until fairly recently when the complex series of events of granuloma formation have been studied and the mystery unraveled.

The real progress in understanding this disease appeared to come after studies of bronchoalveolar lavage (BAL) fluid demonstrated lymphocytic alveolitis and localized the immune response to the lung (167-170). However, this procedure has its pitfalls as well discuss later.

B Lymphocytes

There is a polyclonal hypergammaglobulinemia yet circulating B cells have impaired proliferative response to mitogens. In the granulomas however, there is increased local production of immunoglobulins (mainly IgG) by B cells in response to release of soluble mediators by T helper cells surrounding sarcoid granulomas (171). B cells in between granulomas may be responsible for the local production. (50).

T Lymphocytes

T suppressor cells (CD8) comprise most of the circulating lymphocytes yet T helper cells (CD4) pervade the granulomas and BAL fluid in an active alveolitis. Peripheral lymphocytes are less responsive to mitogenic stimulation than normal. CD4 paucity peripherally results from compartmentalization of CD4 cells at sites of ongoing inflammation (172). This is not specific for sarcoidosis but can occur in other interstitial diseases such as tuberculosis, berylliosis, and asbestosis). Furthermore, not all sarcoid alveolitis is CD4 predominant, some contain more CD8 cells than CD4 cells (173, 174). BAL helps with the diagnosis but is not conclusive, Costabel estimated that it helps in 50-60% of cases (175).

T cells in sarcoidosis consist of the memory variety as opposed to the naive type (171). Data suggests that a discrete number of lymphocytes are stimulated to transform from naive to memory secondary to continuous antigenic stimulation. IL-2 is released and soluble IL-2 receptors (sIL2r) circulate in active disease. Soluble IL-2 receptors can also be found in BAL fluid (176-178). It is unclear where the sIL2r is coming from but it appears to interfere with normal IL-2 action, causing peripheral blood lymphocytes to respond poorly to mitogenic stimulation (179). It is likely that CD4 cells are not randomly activated but are responding to specific unknown antigen (171) or, preferential expansion of particular V region of T effector cells that require a peculiar tropism for the pulmonary tract (171).

Alveolar Macrophage

Monocytes in bone marrow serve as precursors of the alveolar macrophage (AM) (171). In response to a series of cytokines the transformation occurs to tissue macrophage and the cell loses the marker CD14. Lung AM also have increased mRNs for Class II Major Histocompatibility Complex (MHC) products and therefore have increased antigen-presenting capability which increases with disease (171).

Alveolar macrophages release a number of cytokines, which play a major role in this form of inflammatory response. Alveolar macrophages spontaneous release IL-1, which favors granuloma accretion and development of fibrosis. (171). Interferon (IFN) gamma is made by AM in sarcoidosis as well as by pulmonary T cells and type II epithelial cells. Its role in the pathogenesis is unclear due to confusing data (171). Tumor necrosis factor (TNF) alpha is released by sarcoid AMs after in vitro activation. Not much is known about its in vivo involvement. It is involved in experimental lung fibrosis (171).

Mechanisms

PHA (phytohemagglutinin) is a nonspecific mitogen capable of stimulating T cells. In sarcoidosis PHA is still capable of normal stimulation of cutaneous T cells. In contrast, purified protein derivative (PPD) is a specific antigen that stimulates only antigen-specific memory T cells, many of which have been recruited to distant sites of granulomatous inflammation. This may explain the paradox of cutaneous anergy in the setting of an overall heightened immune response. This is discussed further below (50).

Antigen Processing and Presentation

Granuloma formation is initiated when antigen presenting cells (macrophages) present processed antigen in association with MHC Class II gene products to clonotypic variable regions of the T cell receptor (TCR) on memory T-helper lymphocytes. This causes amplification of the immune response and a series of events with signal transduction and release of lymphokines, especially IL-1. In sarcoidosis Kvein - Siltzbach (K-S) antigen (an extract of sarcoid tissue, usually spleen, liver or lymph node (51-53) can cause a granuloma 4 weeks after injected in the skin. This activity can be passed from one granulomatous skin reaction to the next (50, 180). It is believed that granulomas may wall off the antigen so that it cant be eliminated by other immunologic means. BAL cells can be extracted in the same way as in the preparation of K-S antigen and the resulting material injected in skin causing granulomas 4 weeks later. Kataria proposes two possibilities as an explanation for these findings:

1. The increased antigen presentation may be a nonspecific hyperactive immune phenomenon of sarcoidosis.

2. The granulomatous cascade in sarcoidosis is triggered by antigenic stimulus specific to sarcoidosis.

Other findings of significance include results of antigen presenting cell (APC)-lymphocyte conjugation, which transduces a signal to the lymphocyte causing it to express IL-2 receptors on T cell surface and release of IL-2. This is key to maintaining the granuloma. Proliferating T cells ensure the assembly of the granuloma. Furthermore, monocytes made in the bone marrow accumulate in 24 hours in various tissues. Sarcoid T cells release a soluble chemoattractant for monocytes (MCF). Lung T cells make 25 times as much MCF as blood T cells therefore there is a gradient toward the lung. Hydrocortisone suppresses release of MCF. Migration inhibition factor (MIF) prevents migration of monocytes-macrophages, which then accumulate at sites of granulomatous inflammation. It too is suppressed by hydrocortisone. Once recruited, the monocytes differentiate into macrophages, epithelioid cells and Langhans giant cells (181-183). Further development requires adhesion molecules such as LFA-1 and ICAM-1. IFN gamma mediates that process. In all this, however, a continuous supply of antigen is required to maintain the granuloma.

CD4 T cells can be subdivided into Th1 and Th2 subtypes based on the cytokines they release. Th1 cells produce IL-2, fibronectin (FN), IFN gamma, and TNF beta and express CD30. Th2 cells produce IL-4, IL-5, IL-10 and IL-13. Uncommitted (Th0) cells differentiate into Th1 or Th2 after external activation conditions not by the nature of the T cell receptor. Moller studied BAL cells and found Th1 phenotypes and IL-12 production. He postulated that Th1 mediated disease is driven by chronic dysregulated production of IL-12 (184).

Cutaneous Anergy

Anergy can be defined as a loss of immunological energy (50, 185). Now this can be explained as discussed by Kataria (50, 186). The proposed mechanism includes: 1. At the site of granulomatous inflammation, T cells proliferate and secrete lymphokines including IL-2, MCF, and MIF. 2. These lymphokines induce and amplify the immune response by enhancing T cell proliferation and recruit and retain monocytes from the circulation. 3. This leads to increased T suppressor cells in the peripheral blood and decreased (depleted) T helper cells and monocytes available to sites of Delayed Type Hypersensitivity (DTH) (manifested by cutaneous anergy). 4. Eventually the modulatory mechanisms lead to suppressor/cytotoxic T cells, immune complexes and serum factors that inhibit function of T cells and monocyte-macrophages. Thus cutaneous anergy can be described as a loss of competition for mononuclear cells between a robust and persistent systemic granulomatous process and the comparatively weak and transient site of soluble recall antigen. Cutaneous anergy is an epiphenomenon of active sarcoidosis, a non-specific process that is seen in other vigorous granulomatous inflammations and that resolves when the underlying granulomatous disease activity wanes.

A further study of the Kveim reagent has localized the active ingredient to the membrane fractions (187). Furthermore, similar preparations of membranes from BAL cells caused granulomas when introduced into skin and sampled 4 weeks later (188). Other studies demonstrate the almost absence of B cells, CD4 preponderance, and presence of IL-2r in both granulomas from K-S antigen and lysosomal membrane fractions of BAL cells. Resulting conclusions suggest that the K-S reaction in sarcoidosis is not just an alloantigenic peculiarity but seems to be a sarcoidosis specific immune response (50). The membrane fractions appear to cause granulomas when taken from active disease but not in chronic stable disease although Kveim was still positive in the latter. Kataria makes the statement again that although skin testing with lavage cells reflects the granulomagenic activity of the alveolitis, it does not necessarily reflect the activity of parenchymal granulomas, as the sarcoid spleen does."(50). This latter statement is consistent with this author's views about BAL discussed below and urges caution in interpreting results from this technique as representing interstitial mechanisms.

It is through the study of immunologic mechanisms that we now are able to understand what activity means and can approach therapeutic interventions targeted toward specific pathways.

IX. Disease Activity/ Tests

Despite the tremendous knowledge gained about disease mechanisms and what features could be monitored during active granuloma formation and the development of fibrosis, none of the biochemical tests so far available is useful clinically to determine with any degree of certainty the activity of the disease.

Using bronchoalveolar lavage as described above and finding a lymphocytic alveolitis, especially with lymphocytes grater than 28% of the total cells counted suggest increased activity. BAL samples fluid on epithelial side of the airway (189). This data is very interesting and opened up a wide range of subsequent investigative endeavors but there is a conceptual flaw with using the information as originally presented. Sarcoidosis is an interstitial disease. Granulomas form inside the alveolar wall separated by a basement membrane from the epithelial surface. To what extent does BAL fluid represent events that occur on the other side of the membrane? (Author's comments). In support of this concept, Kataria stated that B cells are not harvested by lavage in a representative manner but are stimulated to produce immunoglobulins by activated a T-helper cells in an attempt to explain in situ production of immunoglobulins yet the lack of B cells in BAL fluid (50).

Costabel (175) uses the following to determine activity: 1. Recent or increased cough, 2. Recent or progressive dyspnea 3. Systemic symptoms (weakness, fever, arthralgia), 4. Radiographic progression. However, he goes on to state that BAL percentage of T4 cells is proportional to activity and T4 percentage is proportional to total lung capacity (TLC), PaO2, PaO2 with exercise, and DLCO/LV. He further states that T4 is not proportional to SACE, or gallium scans nor is SACE proportional to gallium scans. He believed that the percentage of T4 cells in BAL fluid is helpful in determining activity, although other investigators do not mirror this.

Numerous biochemical parameters have been used to predict activity of the disease, including serum levels of angiotensin converting enzyme (SACE), alpha-one antitrypsin (190), IgG (191), lysozyme (192) , thermolysin-like metalloendopeptidase (193), neopterin (194,195), IL-2 receptors (177) and many others. Angiotensin converting enzyme levels also can be elevated in numerous other diseases (Table 10). In Young's study (190), alpha-one antitrypsin levels appeared to correlate with active disease, but this antiprotease is also an acute phase reactant and may become elevated nonspecifically in many diseases. Gallium scan may detect active disease but it is unreliable in this regard and very expensive. In comparing gallium scans to BAL lymphocytosis Wallaert (196) found the latter to be more sensitive especially during the early alveolitis phase and often positive when plain chest radiographs and pulmonary function tests were normal. High-resolution CT scans detect alveolitis when a ground glass density is seen but this does not always correlate with active disease. On the other hand, Turner-Warwick did not find any of the newer modalities to be more sensitive or helpful in determining active disease than pulmonary function tests and plain chest radiographs (197).

The best approach to determining disease activity may be to focus mainly on clinical features of the disease and occasionally use functional and radiographic tests to determine progression, stability or improvement. Biochemical or other imaging tests may be used as adjuncts to the other data just mentioned but clearly can not be used to make a diagnosis of sarcoidosis. Their use for detecting activity is doubtful.

X. Therapy Including Steroids, Non-steroidal Drugs, And Unconventional Therapy (Tables 11 and 12)

Only after the diagnosis is evident and some degree of activity manifested, should therapy ensue. This seems a contradiction after stating that none of our tests accurately predict disease activity. Nevertheless, the time honored diagnostic tools consisting of symptoms, physical findings, pulmonary function tests and radiographic patterns still provide the best indicators of disease activity and of the need to treat the patient.

Steroids

The first ten choices of therapy for sarcoidosis are glucocorticosteroids! Although data is controversial (198) and inconclusive even among the few clinical trials that have been performed (199-204), most physicians treat symptomatic sarcoidosis with anti-inflammatory drugs. If there is evidence or even a suggestion of end-organ damage then corticosteroids are used initially. Prednisone orally and methylprednisolone intravenously are the most frequently used steroids. Steroids such as these cause many side effects including sodium and fluid retention, increased fat deposition, altered mood, vascular fragility, and often acute calcium loss from bones. The osteoporosis resulting from calcium loss can be a troublesome problem that can be treated with bisphosphonates (205, 206). Patients with steroids chronically or even with large doses acutely should have adequate calcium intake and because of the changes in calcium metabolism that may lead to hypercalcemia and hypercalciuria, frequent calcium measurements may be required. In order to minimize the negative side effects of systemic steroids, inhaled steroids such as budesonide (207,208) and deflazocort (209) have been used with limited success.

Alternative Drugs

When steroids do not appear to be working or when the side effects of steroids begin to be intolerable alternative drugs are used. Methotrexate (210-213) and azathioprine (214) appear to be the most commonly used. Hydroxychloroquine and chloroquine have been used with some success (211, 215-217). Cyclophosphamide (5,12) does not work as well as it does for other interstitial lung diseases. Cyclosporine A has been used with neurosarcoid but the side effects are often devastating. Kataria describes success using chlorambucil often in conjunction with small doses of corticosteroids (218, 219).

Cutaneous sarcoidosis has been treated with a number of agents including chloroquine or hydroxychloroquine (220, 221) often when it occurs in conjunction with upper respiratory tract disease and lupus pernio (222). Cutaneous sarcoidosis has also been treated with methotrexate (223-225), cyclophosphamide (214), mepacrin (226) , clobetasol propionate under occlusion (227), and isotretinoin (228).

Methotrexate has been used to treat neurosarcoidosis (95) and laryngeal sarcoidosis (225). Chlorambucil has been used for neurosarcoidosis (95). Chloroquine has been used to treat hypercalcemia (229) and bone involvement (230). Of interest is the finding by O'Leary that chloroquine inhibits the conversion of 25 hydroxy-vitamin D to 1, 25 dihydroxy-vitamin D (231).

Sarcoidosis causes a heightened immune system not a suppressed one and leads to granulomatous inflammation that we wish to suppress. This inflammatory response appears to cause most of the symptoms and structural derangements in the disease. Based on this pathogenesis, it seems reasonable to target therapy against several places along the pathway of granuloma formation (232). If we can prevent cytokine release, prevent collagen synthesis and prevent inflammatory cell accumulation we will be attacking three separate lines of action that lead to granuloma formation and eventually to fibrosis. If we can attack all three processes simultaneously then we have a better chance of accomplishing our goal than if we cut off only one pathway. On this basis Kataria has proposed using one or more drugs that can block all three types of pathways. This may explain why often we have been able to lower the dose of prednisone while cytotoxic drugs are added to the regimen and why indomethacin can often help in the early stages of acute disease.

Kataria further notes two experiments of nature:

1. Recurrence of sarcoidosis after bone marrow transplantation into a normal individual from one in whom sarcoidosis subsequently developed.

2. Recurrence of sarcoidosis in normal allograft transplanted into individual who has sarcoidosis.

If one can interfere with three processes one can impair or reverse granuloma formation.

Steroids interfere with lymphokines by altering a portion of DNA leading to decreased lymphokine synthesis. Chlorambucil (Leukeran) interferes with antigen processing by the macrophage. Cytotoxic drugs depress bone marrow, which lowers the supply of antigen presenting cells. Understanding the pathogenesis of the disease helps present a rational approach to the treatment of sarcoidosis.

Baughman (233, 234) classifies the drugs as established and not established. Established drugs include topical systemic glucocorticosteroids, methotrexate, azathioprine, hydroxychloroquine, and cytoxan. Not established drugs include cyclosporine A, pentoxyphilline, thalidomide, and inhaled glucocorticosteroids. Kataria uses chlorambucil as a second line drug after steroid failure or as a steroid sparing agent. Indomethacin (see algorithm, Figure 38) and oxyphenbutazone are also not on his list but the former is used only to help with symptoms early in the course and the latter is more of historic interest (201).

Methotrexate is used only if the patient has been on steroids for a considerable period of time (Baughman says 1 year) with little or no help or if side effects are a problem and steroids need to be tapered. 10 mg/week is used and may take 6 months or more to have peak or any effect. 60-80% respond after 6 months. This will allow decrease or discontinuation of steroids. 20% can decrease prednisone to less than 10-20 mg/d. After 2 years is crisis time when some liver disease may manifest but usually this occurs in years 5-10. Liver biopsy is done every 2 years and if damage is observed, the drug is discontinued. If one waits until clinically obvious liver damage occurs it may be too late. In over 90 biopsies, only 8 required discontinuation of the drug and none got irreversible liver damage (234). If one discontinues the drug after 2 years not all patients get sick again. 20% do well. Pulmonary toxicity can occur in up to 1% but may really be 0.1% if large enough series are reported. Cough is the tip-off and usually the drug needs to be stopped.

Azathioprine is used mostly for neurosarcoid (234) but James used it as the first of the alternative drugs added to steroids (5). There is no hepatotoxicity but it may be carcinogenic. Arthritis patients, but not transplant patients receiving azathioprine have rarely developed tumors. Toxicity includes leukopenia and nausea. It is steroid sparing and over 50% respond.

Hydroxychloroquine is used for skin disease, hypercalcemia and sometimes for neurosarcoid (234) but also for upper airway disease, such as laryngeal sarcoid. It is safer than methotrexate and azathioprine and works in 1/3 to 1/2 of all patients.

Cytoxan is more toxic than the others and is carcinogenic as well as having bladder toxicity.

Baughman's general scheme in acute moderately severe disease with vital capacity (VC) < 80% of predicted, posterior uveitis, or hypercalcemia is to use prednisone first. Alternative drugs include hydroxychloroquine, methotrexate, and azathioprine. For chronic moderately severe disease with lupus pernio, bone cysts, arthritis, chronic uveitis, pulmonary fibrosis, or cardiomyopathy use prednisone and if fails use methotrexate, azathioprine, hydroxychloroquine or cytoxan. If refractory with cor pulmonale, cardiac involvement, neurosarcoid there is a long list of alternative drugs which includes bolus methylprednisolone, and even melatonin, but none work well in this setting.

Unconventional Therapy

Unconventional therapies have been tried but no studies are available to substantiate their use. Thalidomide is the most recent one that has been used and is brought up here because of its notorious history. There is only one recent report and no confirmation studies (235). Melatonin has been tried (236) but the only reference is in the form of a letter. Even magnetism has been used (237).

The Ultimate Therapy - Lung/Heart-Lung Transplantation and Putting it all Together

An algorithmic approach to therapy can be seen in Figure 38. This represents a rather conventional approach developed by DG James and modified by this author. However, many current recommendations include more rapid tapering of steroids if possible. Furthermore, some authorities use methotrexate instead of azathioprine and also use hydroxychloroquine more readily for acute symptoms not responsive to steroids. If alternative agents are used due to steroid failure, then rapid tapering and eventual discontinuation of steroids may be in order.

When patients fail all medical therapy and their pulmonary function continues to decline lung transplantation may be beneficial (238, 239). Several problems exist with lung transplantation. One is that endotracheally intubated patients may have infected airways and may not be candidates for transplantation. Furthermore, lung function has to be sufficiently poor to be placed on the transplant list, yet it often takes two years to obtain a transplant after being placed on the list (240). Despite reports of significant success in selected patients the long-term outlook is still unclear (239). In addition, sporadic cases have recurred in the transplanted lungs (241, 242).

XI. Etiology/Future/Summary

Due to the multifaceted nature of sarcoidosis and the fact that its etiology has eluded investigators for over one hundred years, current scientists believe that it will take a multidisciplinary approach involving geographic, infectious, occupational, epidemiologic, immunologic, and genetic/ familial, data to figure out the cause of this enigmatic disease.

Despite the fact that we still dont know the cause of sarcoidosis, there are some excellent clues that can be obtained from recent studies. Hosoda (143) started with information such as seen in the classic paper by Siltzbach in which the course was charted and the radiographic stages described (243, Figure 39). He used similar but updated information to perform a very sophisticated analysis of epidemiological data to arrive at some interesting conclusions describing the nature of the purported cause of the disease. Kataria (50,186) and Semenzato (46,171,176, Figure 40) have utilized immunologic information and genetic information to propose major contenders for the causative agent in sarcoidosis.

Moller espouses an infectious disease hypothesis naming diagnosis fungus or TB but noting clinical overlap (184). He also states an epidemiologic hypothesis, and an environmental hypothesis. There is an autoimmune hypothesis noting that the disease is antigen driven and cites recurrences after transplantation. He speculates that sarcoidosis likely has more than one cause. Aggressive anti-mycobacterial response predisposes to an autoimmune T-cell response. If the antigen is not removed a chronic response ensues manifested by persistent dysregulation of cytokines, e.g. IL12 and interferon gamma, production. Identification of responsible the local antigenic stimulus is likely to lead directly to the cause of sarcoidosis.

Immunologic studies focus on phenotypical and functional evaluation of mononuclear cells in blood of sarcoidosis patients (46). Relationship between lymphocytes and macrophages and MHC/ T-cell receptor studies allow understanding of factors leading to granuloma formation. Factors causing lymphocytes and macrophages to become activated, inflammation etc, mainly cytokines, increased our understanding of the process and my ultimately lead to the cause. Some of these factors might even be used to assess disease activity.

The causative agent in sarcoidosis is likely an inhaled agent based on the fact that the lungs, eyes, and skin are so frequently involved. These areas are exposed to the environment. Why the gastrointestinal tract, also exposed to the environment, is not more involved must related to the lack of ingestion of the agent. Because the course is so variable there are likely to be multiple potential causes and there must be different susceptibilities. Various ethnic backgrounds (genetics) must play a role. As an example, Puerto Ricans who move to New York have a high incidence but not those who live in Puerto Rico. These individuals must have a genetic make-up that allows development of the disease when exposed to the antigen that must be present in New York but not in Puerto Rico. The same goes for Irish women. Race is important because of the high incidence in blacks in this country. Scandinavians are also susceptible even though there are not many blacks in those countries. Genetic bias must also account for the increased incidence among some families. Development of sarcoidosis in recipients (who never had sarcoidosis) of bone marrow transplants from those who had sarcoidosis implies transmission of a causative agent, although genetic transmission by abnormal cells could also be responsible. Similarly, occurrence of sarcoidosis in lungs transplanted from normal individuals into patients who had sarcoidosis suggests a transmissible agent as well. Autoimmunity could be playing a role in all of these situations as is suggested by recent lines of investigation. The mechanisms of granuloma formation have been studied extensively and many of the pathways are now known. Being able to curtail granuloma formation may help slow or halt the development of sarcoidosis; however, caution is advised whenever blocking a natural process designed to contain an antigen. It is possible that by preventing granulomas to form, the antigen may be free to cause further damage. Only by identifying and eliminating the antigen will the disease be cured ultimately.

Based on the immunologic studies described above, the granulomagenic factor may be a ligand of MHC class 2 molecules (50) and in this way allow immunopurification of these molecules. When the inciting molecule can be isolated further studies can determine if it is an abnormally expressed or posttranslationally altered endogenous protein or a foreign nucleic acid product, for example a monocytotropic virus.

Studies of the Th1 and Th2 subtypes of CD4 lymphocytes will allow targeting of these mechanisms by therapeutic agents to prevent the continuation of granuloma formation. In this way the nature of the antigen and its disposition by the immune system might influence the clinical prognosis and therapy (184).

To sum up all the work to date, it is likely that sarcoidosis has multiples causes, influenced by environmental exposures, autoimmune mechanisms and genetic susceptibility. Continuous antigenic stimulation must occur to perpetuate granuloma formation and progression to fibrosis.

On the basis of these findings, there are a number of ongoing studies, recently presented at a National Conference on Sarcoidosis held in Memphis, Tennessee. The presenter, Dr. Robert Mussan, Ph. D. is from the National Institutes of Health, Bethesda MD (244).

ACCESS (A Case Control Etiologic Study of Sarcoidosis) is designed to study the incidence, prevalence, and progression of the disease and elucidate further mechanisms and therapeutic modalities combating sarcoidosis. This study was initiated in 7/95, at 10 clinical sites. The purpose is to investigate etiology and characterize the clinical course. The hypothesis is that 1. There is a genetic component, 2. There is a non-infectious environmental agent or agents, and 3. There are infectious agents as a cause. A wide range of clinical, microbiological, biochemical, and molecular biological data will be collected.

Anticipated results: 1. Estimate the effect of many exposures/agents 2. Generate specific hypothesis of relationship to sarcoidosis of individual factors and combinations 3. Identify likely causes.

Dr. David Moller is involved in a study of granuloma formation by investigating the regulation of Th1 responses in pulmonary sarcoidosis. There are two major legs of the study a. to investigate immunologic and inflammatory responses b. to test the hypothesis that sarcoidosis is a Th1 lymphocytic disease driven by IL-12. IL12 leads to a Th1 response that causes inflammation then granuloma formation. As a corollary and based on these results, means for preventing granuloma formation by blocking specific pathways of inflammation will be formulated.

Dr. Ianuzzi will undertake a study of genetic epidemiology. Using a large sample of patients and family members he plans to look for association of specific genes. He will compare affected and non-affected family members and look at specific genes he's chosen. Environmental agents and genes may also play a role in the development of disease. This is an interesting and novel approach and if successful could help define the antigen. In this novel approach, by studying the families with sarcoidosis both affected and non-affected members he may be able to identify genetic abnormalities peculiar to patients and potentially may help define the antigen.

Dr. Mussan stated that there will be a conference 10/7/98-10/8/98 on the pathogenesis of sarcoidosis and related disorders. Sponsored by NHLBI, NIAD, and the NIH office of rare diseases. This will bring together wide range of clinicians and scientists. He predicts that in the future environmental exposure, infectious agents, genetics, and interactions of environmental, infectious, and genetic elements will be found to contribute in some way to the cause the disease, and will require a study of molecular immunology and inflammation.

Author's Last Words

With a disease that has such protean manifestations and limited therapeutic modalities, often the best we can do for our patients is to help them deal with the problems they encounter with the disease and the repercussions of the medications used to treat it. In this regard support groups often help as much as do health care professionals. Information on how to establish a support group can be obtained from the Sarcoidosis Center (SARCOIDOSIS CENTER, Figure 41) email or by linking to other sites displayed on their website.

At this time the author (Figure 42 and Figure 43) would like to solicit the help of any physician subspecialist who routinely treats patients with sarcoidosis. The goal is to set up a registry of physicians who have a particular interest in and who specialize in treating sarcoidosis. Physicians' names, qualifications, business addresses and (if desired) office phones, fax numbers and e-mail addresses will be included in a separate section of the SARCOIDOSIS CENTER's web page. The list will be grouped geographically to help patients find an expert in their location. Web pages which have sections devoted to sarcoidosis will be listed as links also. Please contact the author to express your interest in this endeavor. If you do not have e-mail please write to Norman T. Soskel, MD, FACP, 6005 Park Avenue, Suite 501, Memphis, TN 38119. Please respond only if you are an expert in this area and desire to be listed in the registry. Include as much information as possible for inclusion or questions you wish to raise.

Acknowledgments and Permissions

I would like to acknowledge the help of my school teacher wife, Judith, who has read this entire review several times and has pointed out that the initial reference has no corresponding citation listed in the bibliography. However, having left out reference number one I have decided not to renumber all the remaining references but will list number one here: Melville, H. Moby Dick, Richard Bentley, London, 1851, p.1.

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