Pulmonary Sarcoidosis: Understanding a Multisystem Inflammatory Disease

Sarcoidosis may present acutely with bilateral hilar lymphadenopathy (BHL) on chest x-ray, sometimes accompanied by inflammatory eye disease (anterior uveitis) and red, warm, tender papules (erythema nodosum).

On the contrary, a significant minority presents:

• Pulmonary infiltrates on chest x-ray with or without symptoms and/or involvement of one or more organs (skin, liver, kidney, heart) or
• metabolic complications (hypercalcemia).

There is a certain correlation between the initial symptoms and radiological presentation of sarcoidosis and its subsequent evolution, prognosis and treatment. Patients who initially present with LHB, with or without NE or uveitis, rarely require treatment with oral corticosteroids, presenting high rates of spontaneous remission.

Sarcoidosis is rare as, in the UK, a general practitioner caring for a population of 1,500-2,000 patients is expected to receive a new case every 2 years. In mass radiographic studies, the prevalence of intrathoracic sarcoidosis per 100,000 population examined ranges from <10 in Australia, Italy, and Spain to 40 in Scandinavia, Ireland, and Germany. High rates are seen in urban black Americans and black West Indians in London.

Specific outbreaks have been recorded in some occupational groups and different geographical areas. In European populations with  bilateral hilar lymphadenopathy ( BHL) and  erythema nodosum (EN), a seasonal peak is observed in the spring. These observations suggest that some environmental triggers could be involved.

This hypothesis is reinforced by a large US epidemiological study (ACROSS) that found associations between the onset of sarcoidosis and agricultural work or exposure to microbial aerosols or insecticides at work. Although these associations are compatible with an infectious etiology, no convincing evidence has been found to incriminate atypical mycobacteria, herpesviruses or Propionibacterium spp.

Genetic susceptibility is increasingly evident through family and twin group studies, candidate genes, genetic linkages, and limited genome-wide association studies. The best evidence is established for major histocompatibility complex class II alleles, including HLA-DRB1*03 (associated with a more favorable course of the disease), HLA-DRB1*14/15 (associated with a chronic course of disease) and other loci , including replicate data for BTNL2 and ANXA11 across multiple ethnicities. High-density genetic mapping has shown a different genetic susceptibility for the favorable prognostic phenotype of Löfgren’s syndrome compared to other sarcoidoses.

The classic non-caseated granulomas of sarcoidosis can be distributed in the lymph nodes, lung, liver and spleen.

This raises the hypothesis that some external antigen causes the onset of the disease, and some data suggest agents such as Propionibacterium or or mycobacteria. However, it is likely that a variety of antigens, microbes and non-microbes, can trigger the disease in genetically susceptible hosts, with a T helper type immune response program . The type 17 helper T cell subset and interactions with regulatory T cells are also involved in pulmonary sarcoidosis.

To date, no clinically applicable serum marker (angiotensin-converting enzyme, interleukin-2 receptor, chitotriosidase, neopterin, KL-6, and lysozyme) has been identified that would allow prospective differentiation of patients whose alveolitis will experience spontaneous healing from those that will develop fibrosis and subsequent organ damage.

The most common clinical presentation in white patients is asymptomatic BHL incidental to chest radiography or associated with Löfgren’s syndrome and anterior uveitis.

A rule of thumb is that NE that presents in the second or third decade of life is sarcoidosis until proven otherwise.

A warning sign is pretibial EN lesions, as they are distinctive, and patients usually have marked arthralgias in the knees and ankles with swelling and pain.

EN is a panniculitis, often with secondary vasculitis, and associated with elevated erythrocyte sedimentation rate and concentrations of C-reactive protein and circulating immune complexes. If the patient is between 20 and 30 years old, the ophthalmologist should suspect sarcoidosis and request a chest x-ray and a clinical examination. The second most common presentation is symptomatic lung disease.

The initial symptoms , cough or dyspnea, should lead to the request of a chest x-ray, in search of pulmonary infiltrates, with or without LHB. It is prudent to check for the presence of lymphadenopathy, hepatosplenomegaly, and skin or ocular lesions, although these are often absent.

A European multicenter study of white individuals used relatively low-bias clustering analysis to define 5 organ involvement phenotypes: abdominal, oculo-cardiac-cutaneous-central nervous system, musculoskeletal-cutaneous, pulmonary/intrathoracic lymph nodes and extrapulmonary. The importance of these findings in other ethnicities is unknown.

>  Patients with pulmonary infiltrates : in these patients the following studies are added.

• Complete pulmonary function testing in a typical patient with a diffuse pulmonary infiltrate associated with restriction (reduced FVC and total lung capacity) with impaired gas exchange (reduced TL CO ).

Airflow obstruction, with a reduced FEV 1 /FVC ratio, is seen in patients with evidence of chronic fibrobullous disease in the upper lobes or granulomatous bronchial obliterans disease.

>  High-resolution computed tomography: the perilymphatic distribution of reticulonodular infiltrates around the bronchovascular bundles and/or the symmetric hilar and mediastinal lymphadenopathy that appear in sarcoidosis contrasts with the juxtapleural reticular (honeycomb) pattern of idiopathic pulmonary fibrosis. Computed tomography can also help detect intracavitary aspergillomas or cicatricial bronchiectasis of fibrobullous disease. Peribronchiolar airway thickening may correlate with objective airflow obstruction.

>  Biopsy : The diagnosis should be confirmed by biopsy (e.g., transbronchial fine-needle aspiration with endobronchial ultrasound guidance, transbronchial biopsies) unless high-resolution computed tomography shows classic signs associated with a plausible clinical picture, which It has high diagnostic performance. Compared with other biopsies, the aforementioned, which replaced surgical mediastinoscopy for sampling the mediastinum, has a yield of 80% (endobronchial biopsies: (53%) in stage I/II sarcoidosis.

>  Positron emission tomography with 18F-fluorodeoxyglucose (FDG 18 -PET)

This technology appears to be superior to Ga 67 citrate scintigraphy . It can be used to detect occult diseases in difficult cases, as well as predict lung deterioration at 1 year and the expected lung improvement after therapy.

The management of sarcoidosis covers a broad spectrum, from no requirement for oral corticosteroid therapy (e.g., LHB/EN) to corticosteroid-dependent disease. However, there is considerable controversy in the literature and in clinical practice about the approach to be adopted in patients with variable patterns and combinations of symptomatology, pulmonary infiltration and lung function states.

The result of this analysis will indicate whether or not treatment is started. Follow-up over several months or years can detect serial changes in symptoms, lung function, and radiographic staging to guide therapeutic decisions. This approach reduces the risk of 2 therapeutic problems, such as the following.

>  Overtreatment : involves inappropriate and unnecessary prolonged use of corticosteroids in patients with mild infiltrates or small reductions in lung function. In many of these patients, the untreated disease remits spontaneously or does not progress during the observation period.

>  Undertreatment : occurs when corticosteroids are inappropriately discontinued. Some asymptomatic patients with pulmonary infiltrates show an insidious and silent decline in lung function and eventually only have symptoms when pulmonary fibrosis has already reached significant and irreversible severity.

Corticosteroids are also incorrectly discontinued in some patients who already present with fibrosis at first presentation and are then mistakenly labeled as "burned" sarcoidosis. However, these patients often have coexisting reversible symptoms, such as active alveolitis. They may then respond to corticosteroids and show useful and clinically meaningful increases in lung function, despite concurrent established fibrosis.

The treatment, required by 20-70% of patients, is effective but must continue for years or even decades.

Patients with significant organ dysfunction (usually lung) who initially require corticosteroids should continue treatment for a minimum of 2 years before attempting to discontinue treatment. This discontinuation of corticosteroids should be monitored based on symptoms, chest x-rays, and pulmonary function tests every 4-6 months.

Validated tools that use patient-reported outcomes, such as the Sarcoidosis Assessment Tool and the King’s Sarcoidosis Questionnaire, may be useful in clinical decision making.

Up to 50% of patients may relapse within 1 year of stopping corticosteroids, even while the dose is being tapered. Relapses accompanied by the reappearance of pulmonary infiltrates and decreased lung function require immediate restoration of the full dose of corticosteroids.

A course of high-dose corticosteroids is restarted and then slowly tapered to the previously successful maintenance dose (usually prednisolone 5-15 mg). In some patients, relapses occur every time weaning is attempted, sometimes for decades.

It has been suggested that if relapses are severe and recurrent in some patients, they may have the potential for a long-term persistent inflammatory response. This is based on the fact that it was found that fresh granulomas can occur in the allografts of patients with sarcoidosis who have had a lung transplant for end-stage fibrosis.

Corticosteroid doses vary based on several factors, including corticosteroid experience and body weight. The timing of dosing can be adapted (single or divided daily dose or, every other day). The most convenient regimen is a single daily dose, but patients who develop mood swings, hyperactivity, or depression may benefit from multiple divided doses. Prudent management includes:

• Ophthalmological examination to rule out cataracts and glaucoma, annually in older people.
   
• Measurements every 2 years of bone mineral density, to detect osteoporosis.
   
• Prophylactic treatment with bisphosphonates if indicated.
   
• Serial monitoring of body weight, blood pressure and blood glucose.

These drugs may be useful in patients who do not tolerate or are refractory to corticosteroids. Inhaled corticosteroids have not shown significant benefit with respect to diffuse pulmonary infiltrates. As a rule, corticosteroid substitutes are less effective and cause specific adverse effects.

Corticosteroid-sparing agents have been used: methotrexate, azathioprine, hydroxychloroquine (used off-license in the United Kingdom for sarcoidosis) and leflunomide, cyclosporine, mycophenolate mofetil and thalidomide.

The purpose is to reduce the dose of corticosteroids and not to completely suspend them. The authors have mainly used methotrexate or hydroxychloroquine. Methotrexate is widely used, often at doses similar to those used for refractory rheumatoid arthritis (e.g., 15 mg/week); shows a similar corticosteroid-sparing effect and on lung function similar to those of azathioprine, with lower infection rates.

Hydroxychloroquine is started at a dose of 200 mg/day and increased as tolerated, to an average of 300 mg after a few months, reaching 400 mg/day after several months. This regimen is well tolerated, but annual liver function tests and ophthalmologic examination (to detect pigmentary retinopathy) are required.

Based on the British National Formulary recommendations for disease-modifying antirheumatic drugs, the authors propose reducing the corticosteroid dose by half and combining it with 200-400 mg/day of hydroxychloroquine.

Data suggest that infliximab, which neutralizes anti-tumor necrosis factor, may be beneficial in refractory sarcoidosis, especially in patients with positive pulmonary FDG 18 -PET and in patients who received <20 mg/day of prednisone. Recently, a biosimilar of infliximab has demonstrated similar efficacy and safety to the original biologic used as a third-line treatment of severe sarcoidosis.

Adalimumab, but not etanercept or golimumab, may also have therapeutic value. JAK inhibitors are gaining attention based on favorable case reports in pulmonary and cutaneous sarcoidosis.

The occurrence of pulmonary hypertension (PH) in sarcoidosis is increasingly recognized.

Terminal parenchymal pulmonary fibrosis is the most common cause of sarcoid-associated PH, a complication that correlates best for severity with TL CO . There is evidence that PH may also be due to left ventricular dysfunction, granulomatous vasculitis, or intrinsic sarcoid vasculopathy, or secondary to severe sarcoid-related portal hypertension.

Agents such as epoprostenol, sildenafil and bosentan (in the UK, licensed for some non-sarcoid-related but non-sarcoid-related PH) have shown some beneficial effects in non-sarcoid PH. Therefore, a careful therapeutic trial of these agents alone or in combination for sarcoid-associated PH would seem justified. A multinational registry showed lower rates of specific treatment for sarcoid-associated Hp in the US versus elsewhere.

Currently, lung transplantation is an established option for end-stage fibrotic sarcoid in patients who meet criteria for transplantation. The success rate is similar to that of other fibrotic diseases, but fungal contamination of fibroampullary cavities increases the risk of postoperative morbidity and mortality. In some patients, lymphocytic infiltration and granulomas may emerge in the allograft.

About 50-70% of patients report significant fatigue, which can affect overall functional status. There is some evidence that neurostimulants, including methylphenidate, may be useful in treating sarcoidosis-related fatigue.

Complications that warrant specific intervention include:

• Bronchiectasis and aspergilloma in end-stage bullous disease (antibiotics, antifungal therapy, transcatheter arterial therapy, embolization).
   
• Recurrent pneumothorax caused by fibrosis-induced traction blisters (drainage tube, pleurodesis).
   
• Cryptic coincident asthma, often overlooked because airflow obstruction is attributed to fibrobullous disease.
   
• In these patients, provocation with a bronchodilator (inhaled corticosteroids, bronchodilators) is always indicated.
   
• Massive hemoptysis (bronchial artery embolization).
   
• Serious airflow obstruction that is poorly reversible.
   
• Corticosteroid-induced obesity (diet, exercise).

Data from recent Swedish cohorts showed that, in individuals with pulmonary sarcoidosis who do not require treatment at diagnosis, there may be a marginally increased risk of death, while those who require early treatment when diagnosed appear to have a twofold increased risk. of the risk of death compared to the general population. Some patients with cardiac, neurological, skin or bone sarcoidosis may be poor responders or even refractory to all therapeutic measures.

Ancestral genetic factors have a great influence on black patients with more aggressive refractory disease. Individuals with delayed diagnosis of advanced pulmonary fibrosis may develop severe pulmonary dysfunction and present with complications such as bronchiectasis, aspergilloma, recurrent pneumothorax, and eventually PH and cor pulmonale . When PH and cor pulmonale appear, mortality is high.

Life expectancy can be increased by the use of oxygen, vasodilators, angiotensin-converting enzyme inhibitors, iloprost, diuretics, bronchodilators for reversible asthma symptoms, antibiotics for associated bronchiectasis, and lung transplantation. The evidence for these interventions is largely extrapolated from patients with other associated forms of lung disease or is based on surrogate endpoints for sarcoidosis, such as improvement in pulmonary hemodynamics.