Sarcoidosis is a condition that can affect many organs of the body. It can be fatal if it affects the heart or lungs. Patients now have medicines to relieve suffering. More specific treatments will bring hope to patients.
Sarcoidosis, also known as Boeck’s sarcoid, is an inflammatory disease characterized by the development of granulomas (masses of inflamed tissue, or lumps) that may affect any organ system of the human body. Sarcoidosis was first identified over 100 years ago by two dermatologists working independently, Dr. Jonathan Hutchinson in England and Dr. Caesar Boeck in Norway. Boeck coined the name sarcoidosis which stems from the Greek words “sark“ (meaning flesh) and “oid“ (meaning like) and refers to the flesh-like tumours that were first observed on the skin of patients with the disease.
The disease most commonly involves granuloma formation in the lungs. Other organ systems include the lymph nodes, especially the nodes of the thorax, the skin, the eyes, the liver, the heart, and the nervous and musculoskeletal system. Chest radiography is used in staging the disease. Stage I disease shows bilateral swelling of hilar lymph nodes. Stage II is characterised by lymphadenopathy and pulmonary infiltrates. Stage III is defined by pulmonary infiltrates and stage IV shows pulmonary fibrosis.
The cause of the disease is still unknown, but several immune aberrations are thought to play a role in its pathogenesis. Studies have revealed an increase of B-cell activity with elevated plasma levels of immunoglobulins and immune-complexes in about 50 per cent of patients. Reduced T-cell mediated immune response is also found in many patients. Two-thirds do not react to tuberculin intradermal testing. Dysregulation of the immune system has been suggested to be due to a persistent antigen of low virulence that is poorly cleared, leading to a chronic T-helper cell response which results in granuloma formation.
Numerous geographically localised outbreaks have been reported and suggest the possibility of an infectious agent or shared environmental exposure as the causative agents. Granulomatous inflammation can be induced by infectious organisms and environmental factors. Infectious organisms suspected to sustain the disease are: (i) typical and atypical mycobacteria, corynebacteria species, Borrelia burgdorferi, spirochetes, and others; (ii) viruses, such as herpes simplex, Epstein-Barr, cytomegalovirus, coxsackie and rubella; (iii) fungi, such as histoplasma and cryptococcusspecies; or (iv) various parasites. Environmental antigens that have been implicated include metals, organic and inorganic dusts.
The course of sarcoidosis is variable, ranging from a self-limited acute form to a chronic progressive disease that may result in death. Patients most commonly present in winter and early spring. Often, the onset is insidious, and findings may be discovered on routine chest radiographs. About 30 per cent of patients complain about elevated body temperature, fatigue and weight loss. Cutaneous involvement is seen in 25 per cent of patients. Erythema nodosum (EN) – a cutaneous hypersensitivity reaction – is the main non-specific manifestation of the skin. The combination of EN in conjunction with swelling of the thoracic lymph nodes, inflammatory reaction of the eye (anterior uveitis), and the joints (polyarthritis) is known as Löfgren syndrome.
Spontaneous remissions occur in about 60 per cent of cases, but the other patients may experience a more chronic course. The mortality rate is one to six per cent. Sarcoidosis leads to death from severe involvement of lung tissue which results in pulmonary fibrosis and respiratory failure, or from myocardial problems leading to arrhythmias and cardiac failure. Other causes of mortality include involvement of the central nervous system, renal insufficiency and affection of the liver.
How is sarcoidosis diagnosed?
About 95 out of every 100 people who have sarcoidosis have an abnormal chest X-ray.
• Stage I: Chest X-ray showing enlarged lymph nodes but otherwise clear lungs
• Stage II: Chest X-ray showing enlarged lymph nodes and shadows in lungs
• Stage III: Chest X-ray showing shadows in lungs, but the lymph nodes are not enlarged
• Stage IV: Chest X-ray showing scars in the lung tissue.
The annual incidence rate of sarcoidosis varies between one to 40 cases per 100,000 population. In Europe, the disease affects Western Europeans more than European living in the East. Scandinavians have a rather high incidence rate, at 64 cases per 100,000 population, whereas in Poland the incidence is three cases per 100,000 population. Although sarcoidosis can appear in children and in elderly people, most cases present in early adulthood in people aged 20-40 years.
In the USA, the annual incidence rate is 11 cases per 100,000 population for whites, whereas in African Americans the rate is 36 cases per 100,000 population. Sarcoidosis affects both men and women, with a higher prevalence in women. The incidence is highest in African American women, followed in order by African American men, white women, and white men.
Familial clustering of cases has been reported. Monozygotic twins are more likely to be affected than dizygotic twins. Certain human leukocyte antigen (HLA) associations have been demonstrated. The most common allele found is HLA-B8. Other associated alleles include HLA-A1 and HLA -DR3.
Not everyone with sarcoidosis will need treatment. The goals of treatment are to maintain good lung function, lessen symptoms and to prevent organ damage. Corticosteroids are the treatment of choice for patients with neurological, cardiac, or ocular involvement and symptomatic stage II and all stage III pulmonary disease.
Corticosteroids — either ointments or tablets — are also used to treat patients with cutaneous sarcoidosis; in severe cases, immunosuppressant medicines, disease-modifying anti-rheumatic drugs (DMARDs) or cytotoxic molecules are given. Symptomatic relief can be obtained by using non steroidal anti-inflammatory drugs (NSAIDs).
Corticosteroids work by decreasing the inflammatory reaction, especially suppressing white blood cell functions, i.e. T-lymphocyte mobility and antibody production by B-lymphocytes. Cytotoxic agents, such as antimetabolites, may be given in combination to decrease the dose of corticosteroid needed to control the disease. Cytotoxic agents decrease the proliferation of immune cells by inhibiting the synthesis of DNA, RNA, and proteins. DMARDs have immune-modulating effects by blocking the locomotion of white blood cells and impair complement-dependent immune-complex reactions.
Research groups are looking into the development of targeted treatment alternatives to corticosteroids that are more specific. Exaggerated tumour necrosis factor (TNF) release from the alveolar white blood cells of patients with sarcoidosis who do not respond to corticosteroids suggests a potential role for TNF. Therefore, several TNF antagonists are being studied for the treatment of pulmonary progressive forms of the disease.
As genetic predisposition plays a major role in the development of the disease, accurate clinical phenotyping of subjects with sarcoidosis and the avoidance of environmental impacts will be critical to the success of future clinical trials.
In March 2005, researchers reported a newly identified subset of T-cells with immune regulatory functions. In animal studies, the cells have been shown to protect against disorders with increased T-cell responses. It was found that these cells were absent or greatly reduced in patients with sarcoidosis. The scientists concluded that the loss of immune regulation by these cells could explain the amplified and persistent T-cell activity in sarcoidosis.
Also in 2005, investigators published a genetic survey demonstrating that a single gene mutation on human chromosome six augments an individual’s susceptibility to develop sarcoidosis by 60 per cent. The aberration leads to a deficient synthesis of signal protein BTNL2 which under normal circumstances modulates specific T-lymphocyte response.