Sarcoidosis

The definition of sarcoidosis has changed over time. The histological hallmarks of granuloma, unknown cause and multisystem involvement emerged as the three essential defining features, and later the heightened Th1 immune response at sites of disease was added. The history of sarcoidosis started >150 years ago with early observations made on patients with skin disease. By 1915, the systemic nature of sarcoidosis became evident. Since the 1940s, our knowledge of the disease including potential causes, epidemiology, immunology, genetics and clinical presentation has undergone remarkable changes. The history of the immunology of sarcoidosis is a good example of the change of dogmas in our understanding of disease concepts. In the 1960s, the dogma was that sarcoidosis is a disease of decreased immune functions. With the use of BAL as a research tool since the 1970s, the concept changed to a disease of immunological hyperresponsiveness characterised by an exaggerated Th1 immune response at sites of disease activity.

Cite as: Costabel U, Nagai S. Definition and history. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 1–7 [https://doi.org/10.1183/2312508X.10031020].

In the last decade, our knowledge of sarcoidosis pathobiology has improved substantially, yet its aetiology remains elusive. Immunological features of sarcoidosis include, among others, enhanced expression of Th1 (and often Th17) cytokines at disease sites, abnormal regulatory T-cell responses, oligoclonal expansion of CD4⁺ T-cells consistent with persistent antigen exposure and granuloma formation. An emerging body of literature suggests that B-cells and antibody responses may also be involved in disease pathogenesis. Multiple environmental agents have been associated with sarcoidosis, including mycobacterial or propionibacterial organisms, but the mechanisms through which microbial infection may cause sarcoidosis remain speculative. Identification of the inciting agent(s) and insight into the immunological events that determine granuloma formation and evolution to fibrosis will inevitably facilitate the development of more efficacious therapies.

Cite as: Spagnolo P, Grunewald J. Aetiopathogenesis, molecular determinants and immunological features. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 25–40 [https://doi.org/10.1183/2312508X.10015621].

The diagnosis of sarcoidosis is tentative and has a higher likelihood of being correct if a compatible clinical and radiological presentation is supported by evidence of non-necrotising granulomatous inflammation in at least one organ/tissue. However, some clinical scenarios (Löfgren syndrome, Heerfordt syndrome, lupus pernio, and asymptomatic bilateral hilar lymphadenopathy) are thought to be so specific that they allow a presumptive diagnosis of sarcoidosis to be established without a biopsy. When histological confirmation of the clinical suspicion is needed and an easily accessible superficial lesion is lacking, bronchoscopy with its ancillary sampling techniques is commonly performed, because the thorax is involved in the vast majority (>90%) of sarcoidosis patients. The exclusion of alternative diagnoses is imperative, even when pathological examination of the biopsy sample reveals a non-necrotising granulomatous inflammation, as several infectious, inflammatory and even malignant conditions (i.e. lymphomas) may have a granulomatous component.

Cite as: Trisolini R, Spagnolo P, Baughman RP. Principles of diagnosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 57–74 [https://doi.org/10.1183/2312508X.10031420].

Pathologists are frequently involved in the diagnosis of sarcoidosis when tissue specimens are required to confirm the presence of sarcoid granulomas. In general, this occurs when the clinical and imaging features are atypical for sarcoidosis. In this setting, evaluation of granulomas in the lung is related to their qualitative characteristics (well-formed aggregate of epithelioid histiocytes lacking necrosis and surrounded by few lymphocytes and fibrotic tissue) and anatomic involvement (lymphatic distribution along the subpleural space, the interlobular septa and around the bronchovascular bundles). The pathological differential diagnoses mainly include infections, hypersensitivity pneumonitis, autoimmune diseases and a drug reaction, particularly with novel immunotherapeutic agents. Transbronchial biopsy/fine-needle aspiration of the lung parenchyma and/or mediastinal lymph nodes usually results in an accurate final diagnosis when interpreted within the appropriate clinical, laboratory and radiological findings.

Cite as: Rossi G, Farver C. Pathological features and differential diagnosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 91–106 [https://doi.org/10.1183/2312508X.10031620].

The lung is the most common organ affected by sarcoidosis. Multiple tools are available to assist clinicians in assessing lung disease activity and in excluding alternative causes of respiratory symptoms. Improving outcomes in pulmonary sarcoidosis should focus on preventing disease progression and disability, and preserving quality of life, in addition to timely identification and management of complications like fibrotic pulmonary sarcoidosis. While steroids continue to be first-line therapy, other therapies with fewer long-term side-effects are available and should be considered in certain circumstances. Knowledge of common clinical features of pulmonary sarcoidosis and specific pulmonary sarcoidosis phenotypes is important for identifying patients who are more likely to benefit from treatment.

Cite as: James WE, Bonella F. Pulmonary sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 122–141 [https://doi.org/10.1183/2312508X.10031820].

Neurological complications of sarcoidosis include not only granulomatous disease but also nongranulomatous disorders such as small-fibre neuropathy (SFN) and headache. This chapter reviews the clinical manifestations of both types of disorder as well as updated diagnostic criteria, and describes newer diagnostic studies including SFN testing and details regarding current treatment options. In the last few years, there have been several reports demonstrating the beneficial effects of infliximab in treating neurosarcoidosis. Similarly, intravenous immunoglobulins may be helpful with sarcoidosis-associated SFN.

Cite as: Tavee J, Voortman M. Granulomatous and nongranulomatous neurological sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 160–173 [https://doi.org/10.1183/2312508X.10032020].

Sarcoidosis can lead to abnormal calcium metabolism in up to one-quarter of patients. This can lead to hypercalcaemia and nephrocalcinosis. Both of these may lead to renal dysfunction. Direct renal involvement from sarcoidosis occurs in a smaller proportion of patients. Granulomatous interstitial nephritis has been associated with hypercalcaemia. The interaction between calcium and renal dysfunction should be evaluated in all sarcoidosis patients as part of their initial evaluation and on a regular basis as clinically indicated. Bone health in sarcoidosis patients can be impacted by abnormal calcium metabolism and anti-inflammatory therapy, especially glucocorticoids. Evaluation of the calcium–kidney–bone axis is an important aspect of the management of sarcoidosis.

Cite as: Baughman RP, Lower EE. The calcium–kidney–bone axis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 193–205 [https://doi.org/10.1183/2312508X.10032220].

Hepatic and splenic sarcoidosis are detected clinically in about 10% of sarcoidosis patients but are asymptomatic in up to 79% of cases. Splenic involvement is usually asymptomatic, and hepatic involvement can vary from asymptomatic to showing nonspecific symptoms to presenting with signs and symptoms of cirrhosis and portal hypertension. Diagnostic criteria mainly rely on compatible clinical variables in the setting of established sarcoidosis, and occasionally on pathological findings. The differential diagnosis for both hepatic and splenic involvement is wide, and careful assessment is needed to avoid misdiagnosis, as sarcoidosis is a diagnosis of exclusion. Various imaging modalities reveal organ enlargement and nodularity, but the findings are not pathognomonic for sarcoidosis. Treatment is indicated in symptomatic cases and when there is evidence of significant organ dysfunction. Ursodeoxycholic acid is a therapeutic option in predominantly hepatic sarcoidosis, and splenic and hepatic involvement tend to respond to standard anti-sarcoidosis regimens. Careful monitoring for potential complications is imperative. Liver transplantation has been successful in cases of end-stage liver disease due to sarcoidosis.

Cite as: Jeny F, Hamzeh N. Hepatic and splenic involvement. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 223–233 [https://doi.org/10.1183/2312508X.10032820].

Musculoskeletal complaints are commonly present in sarcoidosis and can range from nonspecific arthralgias and myalgias to well-defined findings, such as overt arthritis, sacroiliitis, bone sarcoidosis or myositis. Further adding to the complexity of the disease, sarcoidosis may mimic other rheumatic diseases that need to be ruled out before a diagnosis of sarcoidosis can be made. A frequent presentation is Löfgren syndrome (erythema nodosum, bilateral ankle periarthritis and bilateral hilar lymphadenopathy). To control Löfgren syndrome, anti-inflammatory drugs are often required, but the prognosis is usually good. Chronic sarcoidosis can involve the joints with arthritis, dactylitis, bone sarcoidosis or sacroiliitis. Therefore, treatment decisions need to take into consideration which organ systems are affected and require treatment. While no therapies are approved explicitly for sarcoid arthritis, glucocorticoids and disease-modifying anti-sarcoid drugs (conventional or biological) are used sequentially as needed to control symptoms.

Cite as: Korsten P, Sweiss NJ. Rheumatological manifestations. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 256–266 [https://doi.org/10.1183/2312508X.10033020].

Sarcoidosis is very rare in children, with an estimated prevalence of 0.40–0.80 per 100 000 children. Teenagers are more affected, but the disease can be observed in children of all ages. The pathophysiology of paediatric sarcoidosis is likely to be similar to that of adults, including an aberrant inflammatory and granulomatous response to an antigenic trigger (organic or mineral, especially dusts) in genetically predisposed patients (genes involved in autophagy and mitophagy). The disease is often severe at presentation, with general signs (fever, weight loss, asthenia) and multiorgan involvement, with the lungs, liver and eyes predominantly affected. Diagnosis requires an exhaustive workup to exclude other causes of granulomatous disorders. Corticosteroids are the first-line treatment, either orally or intravenously (high-dose pulses) for months to years, with immunosuppressive drugs as a second-line treatment. The course of sarcoidosis is unpredictable, and relapses are frequent in adulthood. This argues for long-term follow-up of patients and an optimal transition of care from paediatric to adult departments.

Cite as: Nathan N, Hadchouel A. Paediatric sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 285–294 [https://doi.org/10.1183/2312508X.10033220].

Sarcoidosis treatment is initiated for two major reasons: threat of severe organ dysfunction (danger) or to improve quality of life when bothersome symptoms dominate the presentation. While there are few data to suggest a major impact of treatment on the likelihood of long-term disease remission, reducing inflammation with prednisone and other therapies is likely to prevent progressive, organ-threatening disease, and may be useful to restore symptomatic organ dysfunction. As most death and major morbidity from sarcoidosis occur in patients with extensive pulmonary disease, pulmonary hypertension, cardiac sarcoidosis, neurological disease, uveitis and calcium derangements, danger indications for treatment are typically present when these organs are substantially affected. Management involves prognostic assessment of the likely natural history of the disease and often entails relatively aggressive immunosuppressive therapy, with a more proscriptive role for the physician in the decision to treat. In contrast, treatment of bothersome symptoms typically revolves around a patient-centred, individualised discussion, considering the relationship of the symptoms to granulomatous inflammation, likelihood of response to therapy and risks of medications. Therapy may be much less aggressive when treating quality of life. Corticosteroid therapy is associated with significant toxicity, probably accounting for a proportion of sarcoidosis mortality. Longitudinal care of the patient includes recurring assessments of the risk–benefit balance of treatment, likelihood of remission, screening for new evidence of dangerous sarcoidosis and consideration of emergent comorbidities.

Cite as: Culver DA, Wells AU. When to treat sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 316–327 [https://doi.org/10.1183/2312508X.10033520].