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MinnaPurokivi

Sarcoidosis

Essentials

  • Sarcoidosis is a systemic inflammatory disease of unknown aetiology. Granulomatous changes due to sarcoidosis may occur in virtually any organ.
  • The possibility of sarcoidosis should be considered in patients with relevant pulmonary, skin, eye or lymph node symptoms, and a chest x-ray taken. In some cases, the first manifestation of the disease may be signs or symptoms resulting from CNS or cardiac changes.
  • Patients with sarcoidosis should be monitored (for example, by chest x-ray and possibly lung function tests) for aggravation of the disease.

Prevalence

  • The annual incidence in Finland is 11/100 000, the prevalence 28/100 000.
  • Onset is most commonly between the ages of 20 and 40 years but the disease may also appear near retirement age or later. In children, sarcoidosis is very rare.

Symptoms and findings

  • About 50% of cases are diagnosed incidentally at an asymptomatic stage on the basis of a chest x-ray taken during investigations for some other disease or in routine check-ups.
  • The symptoms most commonly occur in the lungs (cough, dyspnoea) but they may appear in any organ, such as the skin (erythema nodosum, maculopapular lesions, reactivation of old scars), eyes (dry eyes, iritis, ophthalmologist-diagnosed uveitis) or lymph nodes (lymph node swelling).

Acute sarcoidosis

  • Some patients present with what is known as acute sarcoidosis in which the symptoms develop over a short period of time. Some or all of the following symptoms may be present:
    • erythema nodosum Erythema Nodosum (particularly in women; pictures 1 2)
    • arthralgia, swelling of joints
    • elevated body temperature
    • iritis or uveitis
    • salivary gland oedema
    • reddening, swelling and tenderness of old scars (scar sarcoidosis; pictures 3 4)
    • cough and dyspnoea
    • enlarged lymph nodes.

Chronic sarcoidosis

  • Dyspnoea, cough
  • Various types of papular skin lesions (pictures 5 6)
  • Chronic uveitis, glaucoma
  • Hypercalcaemia
  • Renal insufficiency as a result of nephrocalcinosis
  • Arrhythmias and conduction abnormalities (also in the acute stage)
  • Hypersplenism
  • Neurological symptoms

Neurosarcoidosis

  • Neurosarcoidosis may mimic virtually any neurological disease. It occurs in 5-15% of patients with sarcoidosis.
  • Symptoms of neurosarcoidosis may include, for example,
    • cranial nerve symptoms (most often peripheral facial paresis or optic neuritis)
    • aseptic meningitis
    • mental or cognitive symptoms
    • hormonal insufficiency due to damaged pituitary gland or hypothalamus
    • symptoms of peripheral small-fibre neuropathy Polyneuropathies.
  • In practice, the diagnosis is based on the clinical picture, MRI and cerebrospinal fluid sample.

Cardiac sarcoidosis

  • In cardiac sarcoidosis, active myocarditis or subsequent fibrotic scar tissue causes arrhythmia or cardiac failure. Mitral regurgitation, pericarditis and left ventricular aneurysm are also possible.
  • In patients with sarcoidosis that appears in one or more organs, cardiac sarcoidosis has been observed clinically in about 2-5%, but pathoanatomically in as many as 25%.
  • The diagnosis is based on myocardial imaging (ultrasound imaging, MRI and PET) and cardiac muscle biopsy. Abnormal ECG findings are common (in about half of patients) but unspecific.
  • If a patient with sarcoidosis is treated by a physician other than a cardiologist, cardiac sarcoidosis should be suspected if there is any symptom of clearly cardiac origin, such as arrhythmia, chest pain or dyspnoea not explained by pulmonary findings and, additionally, abnormal findings in at least one of the following examinations:

Initial investigations in primary health care

Chest x-ray

  • 90-95% of patients show changes in the chest x-ray (pictures 7 8).
  • A radiologist should be consulted, mentioning the suspicion of sarcoidosis.
  • Classification of radiological findings
    • Type I: enlarged hilar lymph nodes
    • Type II: as above + parenchymal abnormalities
    • Type III: Only parenchymal abnormalities
    • Type IV: Pulmonary fibrosis
  • At the erythema nodosum stage, the initial chest radiograph may be normal; if there are symptoms suggestive of sarcoidosis, the chest x-ray should be repeated after one month.

Laboratory tests

  • There are often no abnormal findings in blood or urine tests.
  • Basic blood count with platelet count (leuco- and thrombocytopenia may occur)
  • ESR (increased in a number of patients mainly at the onset of the disease)
  • Serum and 24-hour urinary calcium (some patients have increased concentrations)
  • Serum ACE (may be elevated in about 2/3 of patients at the onset and active stages of the disease, in which case it supports the diagnosis; Patients using an ACE inhibitor should have a break of at least 1 week in the medication before the sample is taken)
  • Plasma soluble interleukin-2 receptor
  • ALT (alanine aminotransferase) and ALP (alkaline phosphatase) concentrations increase in association with liver changes, and creatinine increases in association with kidney changes.

Differential diagnosis

  • Consider other differential diagnostic alternatives.
    • Tuberculosis
    • Allergic alveolitis
    • Rheumatoid arthritis or other collagenosis
    • Drug-induced sarcoid reaction: TNF-alpha inhibitors, HIV drugs
    • Bacterial or viral infection
    • Malignancies, especially lymphomas.

Examination in specialized care

  • Further investigations should be performed and the diagnosis confirmed in specialized clinics, usually of pulmonary diseases or internal medicine.
  • All patients with sarcoidosis except those who have the quickly resolving acute form of the disease should be seen by an ophthalmologist at least once and, if the disease continues for long, yearly even if there are no eye symptoms.
  • If ordinary chest x-ray is difficult to interpret, a typical finding in pulmonary high resolution computed tomography (HRCT) will serve to confirm the diagnosis.
  • If the diagnosis is not clear based on the clinical picture and findings from other examinations, a positive tissue sample should be obtained to confirm the diagnosis.
    • The sample can be taken from any organ manifesting the disease, wherever it is easiest to obtain. Ultrasound-guided spleen, liver or kidney biopsy may also lead to diagnosis.
    • Samples from the bronchial mucosa and, by transbronchial biopsy, from the lung parenchyma can be obtained by fibre optic bronchoscopy. Bronchoalveolar lavage (BAL) can also be performed in connection with bronchoscopy.
  • Neurosarcoidosis
    • MRI is the only reliable imaging method but even a negative finding will not exclude neurosarcoidosis.
    • The diagnosis can only be confirmed by taking a biopsy.
    • Findings from cerebrospinal fluid samples are unspecific (slightly elevated leucocyte levels, elevated protein and ACE levels).
    • Polyneuropathy and myopathy can be shown by ENMG. Small-fibre neuropathy can be shown by quantitative sensory testing (QST).
    • PET scanning is increasingly used for investigation and treatment response evaluation particularly in patients with multi-organ sarcoidosis.

Treatment Immunosuppressive and Cytotoxic Therapy for Pulmonary Sarcoidosis

  • The aim of the treatment is to prevent damage and fibrosis in the lungs and other central organs and to alleviate the symptoms, i.e. to improve the quality of life.
  • Acute sarcoidosis usually clears spontaneously. NSAIDs can be used to alleviate the symptoms.
  • A specialist can start glucocorticoid therapy, as necessary Corticosteroids for Pulmonary Sarcoidosis. Treatment should be started in any patient with diagnosed or suspected cardiac sarcoidosis, neurosarcoidosis, ocular, renal or upper respiratory tract sarcoidosis or symptomatic and/or progressive pulmonary sarcoidosis.
  • There are no controlled studies of the doses or the duration of treatment required. Prednisolone is usually given at a dosage of 20 mg daily for about 1 month, and the dose subsequently reduced. The aim is to achieve the maintenance dose (usually about 5-10 mg/day) within 3-4 months; treatment at that dosage is continued for a total of at least 6-9 months. In severe cases, as well as in neurosarcoidosis or cardiac sarcoidosis, for example, higher doses are used. Topical treatment is usually sufficient for ocular sarcoidosis.
  • If there is no response to glucocorticoid therapy or if it cannot be used, there are other alternatives, such as azathioprine, methotrexate, mycophenolate or leflunomide. The newest drug used for the treatment of severe extrapulmonary sarcoidosis is infliximab, and there is increasing evidence that it is beneficial in the treatment of patients with severe sarcoidosis. Adalimumab, rituximab and JAK inhibitors have been tried in persistent and recurring disease.

Follow-up

  • Follow-up of active disease, whether stable or progressive, most often takes place in specialized care, initially every 1 to 4 months, considering the disease activity and treatment choices.
  • The responsibility for follow-up is usually not transferred to primary health care until after about one year with no disease activity. If reactivation of the disease is suspected at the health centre, diagnostic tests may be repeated.
  • In some cases, the family physician may coordinate the treatment in a way agreed with specialized care, especially if very many organs are affected.

Prognosis

  • Patients with acute sarcoidosis associated with changes due to erythema nodosum and enlarged hilar lymph nodes have the best prognosis. 80 to 90% of these recover spontaneously, usually within a period of 1-2 years.
  • More than 50% of all patients with sarcoidosis recover spontaneously.
  • 50% are left with radiological pulmonary changes but in the Finnish population respiratory insufficiency rarely develops.
  • About 15% develop chronic sarcoidosis with variable prognosis depending on the spread of the disease in the body.
  • 50 to 80% of patients with neurosarcoidosis recover completely.
  • Of Finnish patients with cardiac sarcoidosis, 90% survive 5 years and 83% 10 years after diagnosis, without cardiac transplantation.

    References

    • Vorselaars AD, Crommelin HA, Deneer VH et al. Effectiveness of infliximab in refractory FDG PET-positive sarcoidosis. Eur Respir J 2015;46(1):175-85. [PubMed]
    • Kandolin R, Lehtonen J, Airaksinen J ym. Cardiac sarcoidosis: epidemiology, characteristics, and outcome over 25 years in a nationwide study. Circulation 2015;131(7):624-32. [PubMed]
    • Ramos-Casals M, Retamozo S, Sisó-Almirall A et al. Clinically-useful serum biomarkers for diagnosis and prognosis of sarcoidosis. Expert Rev Clin Immunol 2019;15(4):391-405. [PubMed]
    • Drent M, Crouser ED, Grunewald J. Challenges of Sarcoidosis and Its Management. N Engl J Med 2021;385(11):1018-1032. [PubMed]
    • Baughman RP, Valeyre D, Korsten P et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J 2021;58(6):. [PubMed]