Nodular disease is a non-caseating granulomatous disease of unknown cause, predisposed to young and middle-aged people, with multi-system organ involvement and a tendency to self-resolve. It is characterized by the development of extensive non-caseating epithelioid cell granulomas, with more than 90%; clinical changes in the lungs. It presents with bilateral hilar lymph node enlargement, pulmonary infiltrates, eye and skin damage, and other systems may also be involved.
The first description of nodular disease was in 1889 when Besnier and Tenneson each reported a case of cutaneous frost-like lupus with pathological changes of granuloma without Mycobacterium tuberculosis, after which there were successive case reports, and by 1940 the name Sarcoidosis was used, and in 1976 a clear definition of nodular disease was given at the 7th International Congress of Nodular Diseases, and in 1999 The American Thoracic Society, the European Respiratory Society and the World Association of Nodular Diseases (ATS/ERS/WASOG) made further changes to the definition of nodular disease.
In China, one case of childhood sarcoma-like tumor, later called nodular disease, was first reported in 1958, and in 1978, Lin Yaoguang et al. at Peking Union Medical College Hospital reported a controlled clinical, chest X-ray and pathological study of nine cases of nodular disease [1]. By now, more than 5000 cases of nodular disease have been reported in China.
Section 6 Treatment of nodular disease
Since the vast majority of patients with nodular disease can achieve remission on their own without treatment, and since treatment itself can bring about many adverse effects, it is important to first consider whether nodular disease can be observed without treatment before starting treatment, especially for patients with stage 1 nodular disease. It is generally accepted that treatment may be considered, with oral adrenocorticosteroids preferred, when the following conditions are present. These indications include severe ocular, neurologic, or cardiac nodal disease, malignant hypercalcemia, symptomatic stage 2 nodal disease, progressive stage 2 nodal disease (manifested by progressive decline in pulmonary function), and stage 3 nodal disease. The goal is to control nodular disease activity and protect vital organ function.
1 Hormones
In 1952, Siltzbach performed a series of pathological sections of nodular lesions and found that the lesions gradually shrank or even disappeared with hormonal treatment and that the histological changes paralleled the clinical manifestations. Since then, studies have also continued to confirm the effectiveness of hormones in nodular disease, making hormones the classic drug for nodular disease treatment. However, as the number of treated cases increased, it was found that the clinical manifestations of nodular disease were again diverse, and the natural course of the disease and the long-term effects of hormone therapy were unclear, making the treatment of nodular disease still highly controversial.
The primary question of treatment is which patients need treatment. The progression of nodular disease tends to be benign, with nearly half of patients being asymptomatic or only mildly symptomatic and less than 10%; of patients having a more severe clinical presentation. And about 30% to 50% of patients can resolve on their own without treatment. When nodular disease manifests itself as erythema nodosum or acute arthritis, the possibility of self-resolution is high, but when the liver, nervous system, upper respiratory tract, etc. are involved, treatment is mostly required. As for pulmonary nodular disease, 50%; to 70%; of patients with stage I can heal spontaneously and less often recur; 50%; to 70%; of patients with stage II can be in remission, but most of them need to be treated; less than 30%; of patients with stage III are cured;; and the chance of curing patients with stage IV is very small.
Johns et al. conducted a review of nodular disease cases at Johns Hopkins Hospital in the United States over the last 50 years. concluded that hormones are still the most effective drugs available for the treatment of nodular disease. However, given that some patients are self-remitting, an observation period of about 2 years is recommended for asymptomatic patients [8]. The joint American Thoracic Society (ATS)/European Respiratory Society (ERS)/WASOG guidelines on nodular disease state that systemic treatment with hormones is needed when there is cardiac or neurological involvement, or hypercalcemia, or ocular involvement and local medications are ineffective, and that fatigue is a common symptom and should be treated if it interferes with life. The aim of treatment is to alleviate symptoms and reduce irreversible organ damage. The indication for treatment of pulmonary nodular disease is usually based on the presence or absence of pulmonary symptoms. Hormone therapy is not recommended for asymptomatic patients, and is not recommended for patients with only chest imaging or pulmonary function changes but no symptoms unless the disease progresses. The ideal dose and duration of hormone therapy is inconclusive and should be developed on an individual basis.
Although the efficacy of hormones is currently controversial, corticosteroids remain a primary treatment for nodular disease. If immediate treatment is not indicated, a period of observation may be considered, but there is no consensus on how long to observe. The initial dose of corticosteroids is 0.5 to 1.0 mg/kg.d, and a higher dose is rarely needed. The usual starting dose for adults is 30-40 mg/d. According to observations, the starting dose of hormones for nodular disease treatment is not the most important, but the key is the control of the reduction and maintenance dose during the treatment process and the duration of maintenance therapy. If the efficacy is significant, the dose can be reduced. If the efficacy is average, the treatment can be continued for 2-4 weeks and then the dose can be reduced. Inhaled corticosteroids can reduce the adverse effects of systemic administration by obtaining higher local concentrations in lung tissue. One study found that for stage 2 nodular disease budesonide (budesonide) 1600 μg/d, nebulized inhalation, 10%; of the drug was deposited into the alveolar region, and the improvement of X-ray chest and pulmonary function was not significant after 8-10 weeks of inhalation, but after 6 months of treatment, there was significant improvement in symptoms and pulmonary function, but some scholars have come up with different results.
1.The dosage of hormone in patients with relapsing nodular disease is still inconclusive, most authors believe that a low dosage is appropriate, usually 10-15mg/d
2.Methotrexate
Methotrexate is one of the most commonly used second-line drugs for the treatment of nodular disease, and the commonly used dose is 5-25mg/week. Low-dose methotrexate alone or in combination with hormone for 6 months to 2 years is effective and safe for nodular disease that is not treated with hormone therapy and for relapsed refractory nodular disease.
3. Azathioprine
Azathioprine can inhibit the activation and proliferation of T cells at a dose of 50-200 mg/d. The dose should be increased gradually from a small dose at the beginning, and the effect should be seen within 2-4 months. It is mostly used in chronic nodular disease or refractory nodular disease with multiple systemic lesions. It can be used alone or in combination with hormones.
4.Chloroquine or hydroxychloroquine
It is an antimalarial drug. Mostly used for refractory nodular disease with multi-system damage. The dose is 200-400mg/d. It has been reported that it is used in combination with hormones to treat neurological and cutaneous nodular diseases, and has achieved certain efficacy.
5.Cyclophosphamide
Commonly used at a dose of 50-150mg/d. Mostly used for extra-thoracic nodular disease (neurological or cardiac nodular disease) that is ineffective to hormones or severe. Can be used alone or in combination with hormones. But the side effects are large, should be strictly control the indications, and should further determine the efficacy.
6.Nitrogen mustard phenylacetate
It has been reported to be used in the treatment of nodular disease at a dose of 4-6 mg/d. It has been reported that the combination with low-dose hormones may be effective in relapsing refractory nodular disease. However, its efficacy and safety need to be further verified.
7.Hexketone cocaine
It is a kind of vasodilator drug. By inhibiting the production of tumor necrosis factor, it reduces the formation of granulomatous nodules. The dose of 25mg/kg.d , treatment for 6 months, can improve the symptoms and lung function.
8. Lung transplantation can be considered for patients with advanced pulmonary nodules. Indications for lung transplantation in nodular disease: (1) forceful lung volume <;1 .5L; (2) stage IV patients; (3) need for hormone amount >;20mg/d; (4) lung carbon monoxide diffusion reduced to <;30%;; (5) <;span=";"; >; need for oxygen to sustain life; (6) presence of pulmonary arterial hypertension.