In every decade, sarcoidosis makes a chameleon-like change so its profile needs to be updated. It was first recognised as a dermatological curiosity which evolved into a multisystem disorder with bone cysts, uveitis, and intrathoracic involvement. New dimensions were uncovered by biochemistry and immunology, bringing it still nearer the elusive enigma, namely the cause of sarcoidosis. Aetiology includes an understanding of a genetic predisposition and environmental trigger factors. What was left undone in the 20th century will become evident in the 21st century with more sophisticated technology. Likewise, conventional treatments of the past will be superseded by cytokines and other magic bullets of the millennium.
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In Jonathan Hutchinson's day sarcoidosis was a dermatological curiosity which gradually evolved into a multisystem disorder with skin lesions and bone cysts.1 Still later, the introduction of radiography delineated pulmonary involvement, and thereafter it has been recognised to involve all systems of the body. New dimensions were uncovered by biochemistry and immunology, bringing us still nearer the enigma that continues to elude us—namely, the cause of sarcoidosis.
What was left undone in the 20th century will surely come to light during the 21st century for the will to solve the problem is now harnessed to more sophisticated technology.
Sarcoidosis is a multisystem disorder of unknown cause(s) most commonly affecting young adults, and frequently presenting with hilar lymphadenopathy, pulmonary infiltration, ocular and skin lesions. The diagnosis is established most securely when well recognised clinicoradiographical findings are supported by histological evidence of widespread epithelioid granulomas in more than one system. Multisystem sarcoidosis must be differentiated from local sarcoid-tissue reactions. There is imbalance of CDT4:T8 subsets, an influx of Th1 helper cells to sites of activity, hyperactivity of B cells, and circulation of immune complexes. Markers of activity include raised 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.
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 normalise both levels of SACE and the uptake of gallium. A synthesis of clinical features, radiology, histology, biochemical changes, and immunological abnormalities helps to distinguish it from non-specific local sarcoid-tissue reactions.
Genetic and other molecular probes may help to define a sarcoidosis terrain or diathesis and what antigens have a causative role in that susceptible soil.
Granulomas form by a stepwise series of events, starting when T helper cells recognise protein peptides presented to them by antigen presenting cells bearing histocompatibility class II molecules. Immunological reactivity or inflammation attract monocyte macrophages which fuse to form multinucleated giant cells and onwards to epithelioid cells. Granuloma formation is aided by a cavalcade of chemotactic factors; Th1 cells induce interleukin (IL)-2, interferon gamma, and tumour necrosis factor (TNF) with the help of IL-12 and costimulator B7. The resulting exuberant granuloma formation is associated with active cell mediated hypersensitivity and tissue destruction. This framework is also remodelled by chemokines, adhesion molecules, matrix receptors of the integrin family, costimulators B7 and CD28, IL-12, and RANTES (regulated on activation normal T cells as secreted).
Bronchoalveolar fluid (BALF) reveals this macrophage class II-CD4Th1 cell synergy with its awesome cytokine cascade. Angiotensin converting enzyme is generated within mature epithelioid granulomas; monocyte chemoattractant protein-1 is detected in macrophages peripheral to the granuloma but not within it. Antigen presenting cells and monocyte chemoattractant protein-1 should not be confused for they act at different stages of granuloma formation. Both reflect early sarcoid activity and are likely to be undetected at the late fibrotic stage. Interferon-inducible protein-10 correlates with activated Th1 cells in BALF.2-8
Anergy is an exquisite form of immune apathy due to cytokine dysregulation and signal transduction. With CD28 mediated costimulator there is active T cell proliferation; without it there is ignorance, apathy, and anergy. CD28 and B7 are transmembrane glycoprotein signals on helper T cells and antigen presenting cells respectively. The signals induce the T cell to produce IL-2, which in turn activates the T cell to proliferate and interact with B cells and cytoxic T cells. In due course this costimulation must end and the activated helper T cells are brought under control. This is done by cytotoxic T lymphocyte antigen 4 gene (CTLA-4) a regulatory molecule on the surface of activated T helper cells.9 10
Apoptosis is another mechanism to switch off granulomatous inflammation, achieved via Fas antigen (Fas) and Fas ligand (Fas L). Fas, a cell surface protein that mediates apoptosis is a member of the TNF receptor family. Fas L is expressed in activated T lymphocytes. The Fas/Fas L combination mediates apoptosis of Fas bearing cells, eliminating unwanted inflammatory cells during repair after injury. In this way, apoptosis may be regarded as an useful mechanism resolving granulomatous inflammation and preventing postinflammatory scarring and fibrosis.11
Granulomatous inflammation is usually self limiting with spontaneous resolution. It remains a mystery why some patients with sarcoidosis behave in this way whereas in others there is uncontrolled progress to fibrosis. Could one aspect of the puzzle be homoeostasis?
Armstrong et al have demonstrated an important inter-relationship between TNF-α and TNF soluble receptors in pulmonary sarcoidosis.12 Alveolar macrophages were cultured in the presence and absence of lipopolysaccharide. There was significant more immunoreactive TNF-α in the BALF than in controls. TNF-α bioactivity was inhibited by increased soluble TNF receptors (TNF-R), particularly in early stage 1 intrathoracic involvement, suggesting a homoeostatic mechanism protecting the lung from excessive TNF production. Indeed, this mechanism may provide one explanation which may prevent subsequent on-going pulmonary fibrosis.
The CD4:CD8 ratio and TNF-α levels in induced sputum correlate with those in BALF and also parallels changes with steroid treatment.13 The raised CD4:CD8 ratio and increased TNF-α levels in induced sputum in pulmonary sarcoidosis falls towards normal after six months' treatment with oral prednisone. This should prove to be a popular non-invasive method of assessing activity and a monitor of progress with treatment.
The road from granuloma to fibrosis
The most sinister clinical complications or sarcoidosis are the irreversible fibrosis causing glaucoma, cataract, and blindness; nephrocalcinosis; crippling pulmonary failure; hydrocephalus, lupus pernio, and myocardial damage. Indeed, but for fibrosis, sarcoidosis would be clinically insignificant. It is important to explore every antifibrotic avenue of prevention as early as possible in the disorder. The road from granuloma to fibrosis may be accelerated or inhibited by various chemicals and cytokines, and these mechanisms have been expertly discussed in a recent review (table 1).14Pirfenidone ameliorates bleomycin fibrosis, inhibits transforming growth factor, and blocks profibrotic cytokines.15
Markers of activity
The need for steroid therapy depends whether sarcoidosis is active. Clinical features of activity are erythema nodosum, uveitis, rashes, polyarthralgia, dactylitis, myopathy, neuropathy, lymphadenopathy, parotid and lacrimal gland enlargement, red scars, and cardiac arrhythmia.
It is helpful to complement these clinical features with new techniques. All available data are used to assess activity and serial measurements monitor progress of the disease with treatment (table 2).
Conventional treatment of the past comprised steroids followed, if necessary, by methotrexate or hydroxychloroquine (table 3). But this often proved insufficient, and the combined use of all three drugs came into use. This is to be encouraged so that different influences—anti-inflammatory and antifibrotic—are brought into play. Early treatment is the key to the prevention of sinister fibrosis; and hopefully it will make transplantation less necessary.
We must also look beyond our present drugs for additional cytokine therapy for they and their antagonists are the antibiotics and magic bullets of the future (table 4). Nature has herself curbed the overactivity of TNF by producing neutralising TNF-R. It is suggested that this homoeostasis is responsible for the more benign course of early rather than late sarcoidosis. Other TNF blockers include thalidomide and pentoxyfyline. Infliximab is a human-mouse chimeric anti-TNF-α IgG antibody which has been successful in the management of rheumatoid arthritis, Crohn's disease, and psoriasis. Etanercept is a fusion protein made up of two recombinant p75 TNF receptors fused with the Fc portion of the human IgG1. Infliximab is an antibody against TNF-α whereas etanercept is a receptor for TNF; the former is a human-mouse chimeric product whereas the latter is a fully human protein.
The causes of sarcoidosis comprise two interwoven factors, namely the genetic background and the environmental operative target.
The genetic background is often referred to under the terms terrain, diathesis, and constitution. Erythema nodosum is seen most frequently in Irish women, Puerto Ricans reaching New York, and Martiniques migrating to Paris. Sarcoidosis is more common in Afro-Americans and in the West Indies. It is common in the Japanese but infrequent in Chinese, Greeks, and Cypriots. A recessive mode of inheritance is evident in familial sarcoidosis. There is some correlation between genetic predisposition and whether the course of the disease carries a good or poorer prognosis (table5).16
Takemoto et al have noted an association between angiotensin II receptor gene polymorphism and SACE activity in patients with sarcoidosis.17
It is equally important to investigate triggers which may set in motion the disorder in predisposed individuals. Many different antigens have been suspected including bacteria, fungi, viruses, and chemicals (table 6).5 Dr C G Teo of the Public Health Laboratory, Colindale has identified human herpes virus 8 genome by the polymerase chain reaction amplification in the blood of 78% of patients with sarcoidosis compared with 7% in controls (personal communication).
Is sarcoidosis an autoimmune disorder?
There are several pointers to an autoimmune disorder including erythema nodosum, uveitis, sarcoid thyroiditis, Sjogren's syndrome, hypergammaglobulinaemia, the occasional presence of odd non-specific circulating antibodies, overlap syndromes with recognised autoimmune disorders; and finally an impressive response to corticosteroid therapy. However true sarcoid autoantibodies have not been regularly noted, and sarcoidosis does not share the female preponderance which is a feature of all autoimmune disorders.