Clinical Manifestations of Sarcoidosis

Abstract

Sarcoidosis is a granulomatous disease characterized by granulomatous inflammation in affected tissues. Any tissue may become affected and so different symptoms can occur. There can also be asymptomatic organ involvement. It may present as a multisystem disease or individual organ involvement and it is also associated with general symptoms like fever, weight loss, night sweats or fatigue. Clinical onset may be acute or subacute and clinical course may be self-remitting or chronic. Most commonly sarcoidosis affects the lungs (manifesting as dyspnea, chest pain or cough) and/or thoracic lymph nodes. Extrapulmonary sarcoidosis includes peripheral lymphadenopathy, abdominal (including renal, hepatic, splenic, gastrointestinal), neurological, musculoskeletal, ocular, cardiac, cutaneous and head and neck sarcoidosis (including nose/paranasal sinuses, salivary glands). Less commonly, sarcoidosis can affect bone marrow. Multiple associations of organ involvement occur to configure clinical phenotypes (based on organ manifestations that frequently occur together) and syndromes like Löfgren’s or Heerfordt-Waldenström’s.

1. Introduction

Sarcoidosis is a granulomatous disease of so far unknown etiology [1] that is characterized by the development of noncaseating [2] granulomatous inflammation in affected tissues [3]. Any tissue may become affected [3] and so different symptoms/signs can occur leading to a wide range of clinical manifestations. It may present as multisystem disease or individual organ involvement and there can also be asymptomatic organ involvement.

Sarcoidosis cohorts are not homogeneous, and differ in terms of age, sex, ethnicity, type of onset and organ involvement. Clinical onset may be acute or subacute, acute onset is nevertheless rare [3]. There are more female patients affected by sarcoidosis (3:2 female/male ratio) but in patients aged ≤40 years or with subacute onset, the ratio is almost 1:1. Sarcoidosis is not only a disease of young adults, it is also frequently diagnosed in middle-aged and elderly patients. However, there are more females diagnosed during the fifth decade while males are diagnosed earlier, between the third and fourth decades [1].

The clinical course of sarcoidosis ranges from spontaneous resolution to disabling chronic disease, with lung transplantation as the last resort [1]. Around 30% of cases resolve within 2 years, particularly with single system involvement, 30% have a relapsing form and 30% progressively deteriorate. Over time, the mortality rate is greater than in the general population, relating predominantly to the severity of the disease in those with respiratory, cardiac and neurological involvement, but also to an increased risk of infection. Patients with sarcoidosis also have several other morbidities, such as venous thromboembolism, cardiovascular disease and hematological and skin cancers and a higher prevalence of other autoimmune diseases, in particular thyroid disease, connective tissue diseases and multiple sclerosis [3]. The prognosis is worst for African Americans, those with multiorgan involvement and disease onset after the age of 40 years [4].

2. Clinical manifestations of sarcoidosis

Clinical manifestations of sarcoidosis differ according to the type of onset [1], race, sex, age [5] and organ involvement.

Regarding the type of onset, patients with acute sarcoidosis significantly report more fatigue, fever, night sweats and arthralgia, but less cough and dyspnea than patients with subacute sarcoidosis. Patients with acute sarcoidosis are younger, female and more often have bronchial and musculoskeletal involvement, a radiologically normal lung and better lung function. These patients also have less frequent cardiac, hepatic or splenic involvement [1].

The extent and frequency of organ involvement varies in different ethnicities [1]. For example, African Americans suffer more often from ocular, bone marrow, extrathoracic lymph nodes and skin involvement other than erythema nodosum (NS) [5] and the disease was also found to be more severe in these subjects [6].

Male and female patients’ characteristics also differ significantly: female patients suffer less from fever but suffer more from fatigue, arthralgia, chest pain, and from eye, salivary gland and skin involvement than males.

Age is an important factor influencing the clinical phenotype of patients with sarcoidosis: younger patients present predominantly with Scadding type I, whereas higher frequencies of Scadding type III or IV are noted in older patients. Patients aged ≤40 years are more prone to fever, eye, intrathoracic lymph node and bronchial involvement, but suffer less from dyspnea and heart involvement compared with patients aged >40 years [1]. Sarcoidosis has distinct characteristics in elderly people compared with younger subjects. The female-to-male ratio is higher in elderly-onset sarcoidosis (onset of sarcoidosis in people over 65 years of age), constitutional symptoms, specific skin lesions and uveitis are more frequent and erythema nodosum or asymptomatic chest X-ray abnormalities are less common compared with younger patients [7].

Finally, regarding organ involvement, pulmonary and extrapulmonary sarcoidosis can be distinguished [1]. Within pulmonary sarcoidosis, lung affection and mediastinal/hilar lymphadenopathy can be distinguished and within the extrapulmonary group it is possible to distinguish between peripheral lymphadenopathy, abdominal sarcoidosis (including renal, hepatic, splenic, gastrointestinal), neurological, musculoskeletal, ocular, cardiac, bone marrow, cutaneous and head and neck sarcoidosis (including eyes, nose/paranasal sinuses, salivary glands). Multiple organ involvement associations even configure clinical phenotypes and syndromes.

2.1 Pulmonary sarcoidosis

Most commonly sarcoidosis affects the lungs followed by mediastinal and/or hilar lymphadenopathy [1].

2.1.1 Lung sarcoidosis

Pulmonary manifestation is by far the most common organ involvement in sarcoidosis [1]. At some point, 90% of patients have abnormal chest radiographs [8].

Lung involvement is characterized by cough, breathlessness and chest tightness or stabbing pains, but is often asymptomatic [3]. Scadding’s classification defines five stages of sarcoidosis on a chest radiography [9]. The most frequent type is Scadding I (bilateral hilar lymphadenopathy (BHL)) or II (BHL and pulmonary infiltrates in upper lobes). A significant number of patients do not have sarcoidosis-associated chest radiography findings (Scadding type 0) and the less frequent Scadding types are III (pulmonary infiltrates without BHL) and IV, with the latter being the least frequent, which means that signs of lung fibrosis are the least frequent finding in patients with lung sarcoidosis [1]. Pulmonary nodules tend to be termed “micronodules,” ranging from 2 to 5 mm, typically located along the bronchovascular bundles, interlobular septa, interlobar fissures and subpleural regions [9]. Pulmonary function is only marginally impaired, with forced expiratory volume in 1 second (FEV1) [1] and forced vital capacity (FVC) [9] being the most reduced measures. The more advanced the radiological stage, the greater the decline in functional status [2]. Pulmonary arterial hypertension can be a serious complication in sarcoidosis [9] and occurs in 1 to 6% of patients [8].

2.1.2 Thoracic lymph nodes

Bilateral hilar lymphadenopathy is the most frequent mediastinal lymphadenopathy, configures Scadding I stage and is part of Scadding II stage. Right paratracheal and aortopulmonary locations are commonly observed on chest computed tomography (CT) and calcifications of lymph nodes may also occur [9].

2.2 Extrapulmonary sarcoidosis

After lung and mediastinal/hilar lymphadenopathy, skin, eye and joint are the most common sites of tissue affection [1].

2.2.1 Peripheral lymphadenopathy

More than 20% of patients have peripheral lymphadenopathy (cervical, axillary, inguinal and epitrochlear). The affected lymph nodes are moderately swollen and are usually painless [9].

2.2.2 Abdominal sarcoidosis

Sarcoidosis of the gastrointestinal (GI) tract is extremely rare: esophageal involvement in sarcoidosis may manifest as dysphagia and weight loss; the stomach, particularly the antrum, is the most frequently affected hollow organ in sarcoidosis. The main symptom is postprandial epigastric pain and there may be early satiety, nausea, vomiting and weight loss. Ulcerations may cause upper GI bleeding and mucosal enlargements may cause antral narrowing, leading to gastric outlet obstruction; sarcoidosis of the small bowel is the least common form of GI sarcoidosis. Patients present with diarrhea, malabsorption, protein-losing enteropathy, periumbilical or epigastric pain, or hemorrhage. There may be associated folate deficiency or malabsorption of vitamin B12 with terminal ileal disease or achlorhydria; colonic sarcoidosis presents as multiple nodules, polyps, stenosis, obstructive lesions, aphthous erosions or small punctuate bleeding sites. Symptoms include abdominal pain in over 50% of cases [4].

Liver is a frequently affected site in sarcoidosis. It occurs in 20 to 30% of cases and is rarely severe [4]. However, a cluster of patients may develop severe complications such as cirrhosis and portal hypertension [10]. Jaundice is a rare symptom of liver disease, with pruritus and abdominal pain being seen more often; fever, although seldom a predominant feature, may be more common in patients with hepatic affection. Up to 35% of patients with sarcoidosis have abnormal liver function tests but these liver function tests are unrelated to the degree of aggression and extent of disease. Hepatomegaly can be found clinically and on abdominal computed tomography (CT) scan [4].

The spleen is enlarged on physical examination in 5–14% of patients with sarcoidosis. Involvement of the spleen causes symptoms in 15% of patients and is associated with hypersplenism in 20% of cases, most of whom have giant splenomegaly. In the majority of patients with splenomegaly, hepatomegaly and abnormal liver function tests are performed. Patients may develop splenic nodules and those patients with splenic nodules or hepatosplenomegaly are more likely to have symptoms than those without these findings [4]. Diffuse spleen involvement is a significant risk factor for a severe prognostic outcome in sarcoidosis [11].

Peritoneal sarcoidosis is a very rare disease whose symptoms include abdominal pain and ascites [12]. The clinical course of sarcoid-induced ascites not associated with portal hypertension is benign, with the condition resolving in the majority of patients. However, chylous ascites may develop because of obstruction of mesenteric lymphatics by sarcoid lymphadenopathy or by a fibrotic process [4].

Symptomatic pancreatic involvement usually occurs due to parenchymal disease or duct obstruction. Symptoms include abdominal pain, weight loss, jaundice, nausea and anorexia; and findings include a mass, usually in the head or a diffusely firm, nodular pancreas [4].

Acute cholecystitis as a complication of sarcoidosis may occur because of extrinsic compression of the cystic duct by granulomatous lymph nodes or by granulomatous inflammation of the gallbladder; obstructive jaundice may be due to granulomatous involvement of the common hepatic duct and surrounding lymph nodes; subacute or chronic cholecystitis with granulomas in the gallbladder wall is also described; chronic cholestasis related to cholangitis or extrahepatic bile duct involvement with typical findings of pruritis and jaundice has been reported less frequently [4].

Abdominal adenopathy is characterized by an increased number of normal-sized nodes, generally less than 2 cm in diameter. The nodes are most commonly found in the porta hepatis and less commonly involve the retrocrural area [6].

Renal sarcoidosis is likely underreported but isolated renal forms of sarcoidosis without extrarenal manifestations have been described. Renal involvement of sarcoidosis represents a relevant organ manifestation including granulomatous tubulointerstitial nephritis (the most typical form of renal sarcoidosis), secondary forms of glomerulonephritis and disorders in calcium homeostasis that can lead to nephrocalcinosis and nephrolithiasis. Renal masses and amyloid A (AA) amyloidosis are considered rare manifestations. There is a marked renal impairment [6].

2.2.3 Neurological sarcoidosis

Sarcoidosis affects the nervous system in 10% of cases [3] and approximately 5–7% of patients with systemic sarcoidosis [13] manifest symptoms of central or peripheral nervous system involvement, the so-called neurosarcoidosis (NS) [14]. Patients affected by sarcoidosis may also have subclinical neurological involvement in up to 26% of cases [13]. It can affect any part of the nervous system with all degrees of severity and may be very difficult to diagnose without histological confirmation [3]. NS may manifest as:

2.2.3.1 Cranial neuropathy (CN)

Cranial neuropathy is the most prevalent symptom of NS [13]. Within CN, facial nerve is the most affected, as it accounts for 70% of isolated CN. Most of the symptoms are unilateral and occur at the onset of disease [3].

Optic neuropathy is also common. A subacute optic neuritis is the most common presentation and it presents in an identical way to a demyelinating optic neuritis with pain being less prevalent, and the nadir acuity slightly less [3]. Synchronous bilateral optic neuritis is uncommon, but sequential optic neuropathies occurred in 30% in one study, and the same study showed 36% of concurrent intraocular inflammation development [15]. The associated field defects are central, centrocecal or altitudinal. An optic perineuritis can occur and lead to visual field constriction, disk swelling and pain. Chiasmal involvement is common when a basal leptomeningitis involves the hypothalamus and adjacent structures. Finally, a compressive optic neuropathy may arise when a dural inflammatory mass, usually at the orbital apex, involves the optic nerve. There may also be sensory loss and pain [3].

Isolated CN other than optic and facial are less common: the oculomotor, trochlear and abducens are relatively frequently involved, the trigeminal often alongside other nerves [16] (inflammatory masses within the orbit, at the orbital apex and cavernous sinus or spread from an adjacent basal leptomeningitis may cause diplopia, trigeminal sensory loss and pain, and proptosis [3]). The vestibulocochlear nerve is less frequently affected [16]. In fact, eighth nerve involvement is found in 1–7% of NS patients. Isolated hearing loss is uncommon in sarcoidosis. It occurs suddenly, often alongside a vestibular syndrome [13]. Spread from mastoid sinuses into the middle ear may also occur and the vestibulocochlear nerve may be involved as part of a spreading pachymeningitis or a leptomeningitis, often with accompanying facial nerve palsy. Isolated CN of the lowest cranial nerves are uncommon, but a bulbar disorder characterized by progressive dysphonia and dysphagia has been seen. Occasionally, there is weakness and atrophy of one side of the tongue. Involvement of these nerves may also form part of a more widespread disorder due to a basal meningitis [3].

2.2.3.2 Peripheral neuropathy

Peripheral neuropathy, not associated with concomitant central neurological disease, is uncommon in sarcoidosis, accounting for <5% of all cases. Symptoms are sensorimotor or purely sensory and they may manifest as mononeuritis multiplex, asymmetric neuropathy and mononeuropathies, particularly of the radial and ulnar nerves. Thoracic radiculopathy appears to be exclusive to sarcoidosis, presenting as burning numbness of the chest wall. Rarely, acute inflammatory demyelinating polyradiculoneuropathy can occur [3]. However, small fiber neuropathy is a common complication of sarcoidosis [17]. It is associated with a severe and very poor treatment responsive to distal neuropathic pain [3], somatic paresthesia and/or dysautonomia [17].

2.2.3.3 Pituitary and hypothalamic involvement

Prevalence of hypothalamic-pituitary (HP) involvement is estimated at 2.5% in patients with NS, which may lead to pituitary hormone abnormalities. Central hypogonadism occurred most frequently in a case series, followed by hypothyroidism, low insulin-like growth factor 1 (IGF-1) and corticoadrenal insufficiency. Diabetes insipidus was frequent (66%), but primary polydipsia leading to hyponatremia had also been reported. Primary polydipsia as well as obesity and behavioral changes are a reflection of hypothalamic involvement by NS and may contribute to some of the metabolic changes observed in these patients [14]. Hypogonadism was also the most frequently reported endocrine disorder in HP sarcoidosis in a multicenter study, followed by thyroid-stimulating hormone (TSH) deficiency, diabetes insipidus, hyperprolactinemia, adrenocorticotropic hormone (ACTH) deficiency and growth hormone (GH) deficiency (GHD). Panhypopituitarism had also been described [18]. At last, optic neuropathy may occur in HP NS due to mass effect or direct involvement of the optic chiasm [14].

2.2.3.4 Involvement of the brain

Involvement of the brain can be observed to take place through a pachymeningitis, a leptomeningitis and a vasculitis [3].

Pachymeningitis: Patients present with headache and focal neurological signs, often with seizures. If the cavernous sinus and orbital apex are involved, patients may present with pain, diplopia and optic neuropathy [16].

Leptomeningitis: In a prospective study, 75% of cases showed features of an invasive and destructive meningoencephalitis. Two-thirds presented with signs of diencephalic dysfunction and hydrocephalus, while a third had signs of involvement of the brainstem, with associated hydrocephalus. The disease course is subacute but increasingly rapid, and these patients are more disabled than those with a pachymeningitis (the two processes do not seem to overlap) [16].

Vasculitis: Vascular involvement does occur but it rarely has a direct clinical consequence [16]. Vascular involvement may be as infarction due to large vessel occlusion occurring without prelude [3], a crescendo series of transient ischemic attacks culminating in infarction [19] or by raised intracranial pressure and transient neurological deficits [20]. Intracranial hemorrhage (ICH) in NS is rare, probably as uncommon as cerebral infarction. According to a systematic literature review, 20% of patients had no prodromal symptoms before ICH, one-third of patients had one or a combination of prodromal symptoms for days to months: mostly new or worsening headaches, in some cases ataxia or cognitive difficulties and rarely daytime somnolence or seizures. At presentation, most patients had worsening or acute severe headache or seizures, some patients had acute posterior fossa syndrome and two patients presented with coma [21]. The hemorrhage is mostly supratentorial, followed by infratentorial and less frequently subarachnoid [8]. There may be multiple simultaneous intracerebral hematomas or a single intracerebral hematoma [22] and an intramedullary spinal cord hemorrhage was also described [23].

2.2.3.5 Spinal cord and cauda equina involvement

Although less common than in leptomeningeal and pachymeningeal forms of the condition, isolated disease of the spinal cord and cauda equina does occur. Most symptoms present with a subacute spinal cord lesion, in which there is a single cervical or thoracic longitudinally extensive lesion. Half of those with lower dorsal lesions also have cauda equina lesion whose signs are early sphincter disturbance and a predominantly sensory disorder; it is rarely painful. However, a motor disorder comprising a single motor root usually is painful. When there is an accompanying amyotrophy due to root involvement, it may be difficult to distinguish it from a motor neuron disease. A progressive cord lesion is less common [3].

2.2.3.6 Clinically isolated NS

Patients may present with neurological symptoms consistent with NS with no clear evidence of systemic sarcoidosis [19]. From those symptoms, systemic disease might or not be found and can even develop later [3].

2.2.4 Musculoskeletal sarcoidosis

Musculoskeletal manifestations of sarcoidosis occur in one-quarter to one-third of sarcoidosis patients [24] and can take place in multiple forms: bone involvement, sarcoid arthropathy and sarcoid myopathy [9].

Bone sarcoidosis is usually asymptomatic and its lesions are more often cystic than sclerotic or lytic. Bone involvement is often accompanied by overlying skin disease and is reported most frequently in the proximal and middle phalanges. Skull, nasal bones, maxilla, sternum, ribs, vertebra, pelvis, tibia and femur may also be affected. Spinal lesions may appear lytic, sclerotic or both and can involve any segment of the spine but spinal involvement is often asymptomatic [24].

The most common manifestation is sarcoid arthropathy [9] in the form of an acute arthritis that occurs as part of Löfgren’s syndrome (LS). The ankles are the most frequently involved joint, bilateral in the majority of patients. Joint involvement can extend to other sites including the knees, wrists, elbows and metacarpophalangeal joints. Tenosynovitis and periarticular swelling are more common than true synovitis. Chronic sarcoid arthritis is characterized by symmetric, medium to large joint oligoarthritis [24] and is usually associated with extra-articular sarcoidosis [9]. Destructive arthritis is less frequently described and there are case reports of sarcoid monoarthritis, although it is rare. Jaccoud’s arthritis has been described in case reports and it usually presents in the context of extensive internal organ involvement later during the disease course. Dactylitis is almost exclusively associated with chronic systemic involvement and is a common form of musculoskeletal involvement. It is associated with swelling and erythema and typically develops in a symmetrical pattern, most often affecting the second and third phalanges, preserving the metacarpophalangeal joints [24].

Skeletal muscle involvement occurs in as many as half of all sarcoidosis patients [25]. Asymptomatic granulomatous muscle involvement in sarcoidosis is more common than symptomatic one. Muscle involvement includes a nodular type, an acute sarcoid myopathy type and a chronic sarcoid myopathy type (the most frequent type of sarcoid myopathy [25]) [24]. The main symptom is weakness, followed by myalgia [25] and reduced exercise capacity [24]. Nodular sarcoid myopathy is characterized by symmetrical limb involvement with single or multiple nodules in the muscles [24] that may cause pain and stiffness with cramps [25]. Acute myopathy is the least common form of sarcoid myopathy. It occurs early in the course of sarcoidosis and in patients <40 years of age. It presents with rapid onset of proximal weakness and myalgia associated with elevated creatinine kinase levels. Chronic sarcoid myopathy is reported in female patients between the ages of 50 and 60 years [24]. It is a slowly progressive symmetrical disease involving the proximal muscles of the extremities, trunk and neck, often with muscle wasting [25].

2.2.5 Ocular sarcoidosis

Ocular involvement manifests in 25–60% of patients with systemic sarcoidosis in two peaks of incidence, the first at 20–30 years and the second at 50–60 years [26]. Any structure within the eye may be involved, but uveitis is the most frequent form of ocular manifestation and may affect up to 20–30% of patients with sarcoidosis [9]. After uveitis, the most frequent feature is conjunctival involvement. Lacrimal gland or conjunctival involvement is usually asymptomatic, although extensive granulomas leading to diplopia or severe keratoconjunctivitis sicca may develop. Eyelid granulomas were repeatedly reported while corneal involvement by granulomas is extremely rare [26]; orbital symptoms mimic other inflammatory syndromes manifesting in the orbit (diffuse orbital inflammation, usually unilateral, which can result in ptosis, limitations of ocular movements and diplopia [27]). At scleral level, there may be scleritis or episcleritis and sarcoid-induced inflammatory myositis may resemble Graves’ ophthalmopathy [26].

Acute signs of uveitis as pain, photophobia, lacrimation or redness might be absent, so that the patients with sarcoid-associated “silent uveitis” may develop permanent ocular damage before the intraocular process is diagnosed and treatment initiated [26]. Sarcoid uveitis is generally bilateral with the same findings and clinical course in both eyes [28]. Anterior uveitis is the most common anatomical form of intraocular inflammation, followed by posterior uveitis, intermediate uveitis and panuveitis [9]. Classic sarcoid-associated anterior uveitis may either present as an acute self-limiting [29] iridocyclitis or as a chronic granulomatous uveitis with keratic precipitates. Chronic anterior uveitis may lead to secondary cataract, glaucoma and cystoid macular edema. Intermediate uveitis with vitritis and genuine snow banking may be occasionally encountered but more frequent is the presence of vitritis with peripheral vasculitis and snowball infiltrates. This type of intermediate uveitis may precede more severe posterior segment changes [26]. Characteristic findings of posterior uveitis include retinal periphlebitis associated with segmental cuffing, extensive sheathing and perivenous infiltrates, referred to as “candle-wax drippings” [28]. The association of posterior segment and neurological involvement in sarcoidosis has been reported to be as high as 27%. The most frequent complications of posterior segment involvement in sarcoidosis include cystoid macular edema, cataract, glaucoma, retinal ischemia and neovascularizations. Poor visual prognosis is associated with advanced age, African-American ethnicity, female sex, chronic systemic disease and also with posterior segment involvement, the presence of cystoid macular edema and glaucoma [26].

2.2.6 Cardiac sarcoidosis

Cardiac involvement affects approximately 3 to 39% of patients with systemic sarcoidosis [9]. The cardiovascular involvement is usually associated with a bad prognosis. The most frequent clinical symptoms are palpitations, lipothymia and syncope. Among all arrhythmias, the most represented are those secondary to alterations of the conduction pathways (atrioventricular node, bundle of His and intraventricular pathways) which can progress toward a complete atrioventricular block that can lead to clinical symptoms such as syncope, sudden death and also to ventricular tachyarrhythmias. Atrioventricular block is the most common clinical manifestation of disease onset followed by ventricular tachyarrhythmias. Supraventricular tachyarrhythmias have a prevalence three times greater in cardiac sarcoidosis than in sarcoidosis patients without cardiac involvement and the most frequent supraventricular tachyarrhythmia is atrial fibrillation, followed by atrial tachycardia and atrial flutter [30].

Heart failure is an onset manifestation of the disease in 16% of cases, less frequently than arrhythmias. However, it is the second cause of death, only after sudden death from ventricular arrhythmias. Asthenia, dyspnea and orthopnea are related to heart failure, and the involvement of the ventricle can lead to the onset of cardiomyopathy at a young age. Patients with sarcoidosis also have an increased risk of cardiovascular events compared to the control population [30].

2.2.7 Cutaneous sarcoidosis

Cutaneous sarcoidosis is the initial manifestation of the disease in nearly one-third of patients. The skin is most often involved in African Americans [8].

Specific sarcoidosis lesions have granulomas on histological examination and apple-jelly coloration characteristic of granulomatous skin lesions on diascopy. Depending on the skin color, specific lesions range from flesh tinted to brown, to pink or violaceous. Specific sarcoidosis lesions include maculopapular sarcoidosis (lesions not only on the face, especially on the nasal folds, eyelids and orbits but also on the nape of neck, back, buttocks and extremities); the very common papular sarcoidosis (discrete papules measuring ≤1 cm that are commonly present on the face, especially around the eyelids and nasolabial folds. Papules can coalesce into plaques, are often associated with minimal to no systemic disease and may resolve spontaneously); the very common plaque sarcoidosis (single or multiple round, oval or annular plaques on the face, back, buttocks and extensor surface of the extremities. The plaques are thick and indurated and often heal with scarring or pigmentary changes); the common lupus pernio (reddish purple to violaceous brown, shiny, indurated plaques frequently over the central face, especially on the nasal alae, cheeks, lips and ears, and rarely on dorsal face of hands and feet. Lupus pernio lesions, predominantly occurring in African Americans, enlarge and are progressively disfiguring, causing nasal ulceration, septal perforation and obstruction); the common subcutaneous sarcoidosis (single to multiple asymptomatic to mildly tender, indurated skin-colored, panniculitic plaques or nodules characteristically on the extremities, particularly the forearms); the common scar sarcoidosis (granulomatous infiltration of surgical scars, tattoos, skin piercings and other sites of trauma); the common nodular sarcoidosis; and other uncommon or rare specific lesions of cutaneous sarcoidosis like annular, angiolupoid, verrucous, lichenoid, psoriasiform, hypopigmented, atrophic, ulcerative, ichthyosiform, erythrodermic, morpheaform, photodistributed, sarcoidal alopecia, oral, genital and nail sarcoidosis [8].

Nonspecific sarcoidosis skin lesions lack granulomas and are caused by inflammatory reactions to sarcoidosis. Erythema nodosum (EN) is the most common nonspecific sarcoidosis skin manifestation, occurring in 10% of patients [8]. EN is a form of panniculitis (inflammatory processes that affect the subcutaneous cellular tissue) characterized by tender erythematous nodules mainly in the lower limbs on the pretibial area [31]. On histology, lesions show a septal panniculitis without granulomas [8]. EN is considered a hypersensitivity response to a variety of antigenic stimuli which can be infections, inflammation, neoplastic disease, pregnancy and/or drugs [31]. Other nonspecific manifestations of sarcoidosis include Sweet syndrome, erythema multiforme, pyoderma gangrenosum, prurigo, calcinosis cutis, vasculitis and digital clubbing [8]. All these nonspecific skin manifestations (EN included) can be a skin manifestation of a non-sarcoidosis disease and so, although they can be associated with sarcoidosis, their presence does not mean cutaneous sarcoidosis.

Although most lesions have distinct features that allow recognition or at least enable a high level of suspicion, sarcoidosis skin manifestations can mimic nearly any skin disease [8]. Some patterns of cutaneous involvement may be associated with specific extracutaneous manifestations of sarcoidosis, while other patterns may predict systemic disease severity and response to treatment [9].

2.2.8 Head and neck sarcoidosis

Multiple manifestations are possible in the head and neck region (HNR), such as lymphadenitis colli, acute or chronic sinusitis and swelling of the parotid glands, as part of Heerfordt’s syndrome or xerostomia. The clinical findings are often nonspecific. The most frequent manifestation of sarcoidosis in the HNR is cervical lymphadenopathy, followed by nose or parasinusal affection, cervical skin or parotid gland affection [32]. Larynx is the less frequently involved organ in the HNR [9]. While the major salivary gland involvement most frequently follows a benign course, sinonasal and laryngeal sarcoidosis are usually severe [9]. Patients with sinonasal disease have nonspecific upper respiratory symptoms like nasal obstruction, rhinorrhea, anosmia, crusting rhinitis, epistaxis and facial pain [33]. Laryngeal sarcoidosis usually involves the supraglottis (epiglottis, then arytenoids) and does not affect the vocal cords [9]. The symptoms range from hoarseness, inspiratory dyspnea, dysphagia, chronic cough and obstructive sleep apnea to airway obstruction requiring a tracheotomy [33].

2.2.9 Bone marrow sarcoidosis

Bone marrow involvement is a rare extrapulmonary sarcoidosis tissue affection. It is present in approximately 6% of cases of pulmonary sarcoidosis [34], but isolated sarcoidosis of the marrow as an initial presentation, without involvement of other organ systems, is not as common [35].

Although peripheral blood tests may show evidence of anemia, leukopenia or lymphopenia [35], bone marrow involvement can present with normal hematological parameters [36].

2.3 Clinical phenotypes and clinical syndromes

Multiple manifestations and associations of organ involvement occur to configure clinical phenotypes/syndromes.

2.3.1 Clinical phenotypes

A European multicenter study [1] identified five distinct phenotypes based on predominant organ involvement and organ manifestations that frequently occur together:

Cluster (1) Abdominal organ involvement (liver, spleen, kidney): in patients with liver involvement, there was often spleen, kidney and intrathoracic lymph node involvement. These patients experienced weight loss, night sweats and presented significantly more often with impaired lung function.

Cluster (2) Ocular-cardiac-cutaneous-central nervous system (CNS) disease involvement (eye/heart/skin/salivary glands/CNS): In cardiac and skin sarcoidosis, fatigue and arthralgia were more prevalent than in patients without these organ manifestations. In patients with eye involvement, there was also a higher rate of arthralgia but a reduced frequency of fever. In NS, fatigue was also more prevalent.

Cluster (3) Musculoskeletal-cutaneous involvement: patients with arthritis or musculoskeletal involvement presented significantly more often with an acute onset and suffered more from fever, night sweats, weight loss and arthralgia. These patients showed more often involvement of the skin, intrathoracic lymph nodes and kidneys but less often of the lungs or bronchi. Patients with musculoskeletal sarcoidosis also suffered significantly more often from eye involvement.

Cluster (4) Pulmonary and intrathoracic lymph node involvement: patients with lung involvement had worse lung function and presented more often with dyspnea, cough, chest pain and fatigue. These patients suffered more often from bronchial and intrathoracic lymph node involvement, but less often from skin or musculoskeletal involvement.

Cluster (5) Extrapulmonary involvement: the extrapulmonary phenotype had the highest frequency of kidney involvement.

These phenotypes are only applicable in Caucasian cohorts and might be different in African or Asian populations [1].

Another cohort study [37] identified six discrete phenotypes of sarcoidosis: C1 (pure LS with BHL and erythema nodosum), C2 (febrile LS), C3 (nonfebrile LS with periarticular ankle inflammation), C4 (exclusive pulmonary sarcoidosis), C5 (pulmonary sarcoidosis and abdominal involvement) and C6 (organ involvement different from the lungs, including: skin lesions, peripheral lymph nodes and neurological and ocular involvement).

Lastly, a multicenter study [38] identified five clinical phenotypes of extrapulmonary sarcoidosis: (1) erythema nodosum, joint involvement and hilar lymph nodes, mainly in European/Caucasian female patients; (2) neurological, digestive and/or kidney involvement; (3) parenchymal lung involvement and fibrosis, cardiac and skin involvement, mainly in non-European/Caucasian patients; (4) lupus pernio and severe involvement; and (5) parenchymal pulmonary involvement, peripheral nodes, and hepatic, splenic and bone involvement, mainly in non-European/Caucasian patients. This study also identified a preferential association of organ involvement: erythema nodosum with joint involvement; hepatic, splenic, bone and peripheral node involvement; pulmonary with cardiac involvement; kidney with digestive involvement; lupus pernio with ear, nose and throat involvement; and uveitis with neurological involvement [38].

2.3.2 Clinical syndromes

Löfgren’s syndrome is a well-differentiated form of sarcoidosis with characteristic epidemiological, clinical, radiological and prognostic features. LS is the triad of bilateral hilar lymphadenopathy with erythema nodosum and/or articular involvement (usually periarticular ankle inflammation) and/or fever. Patients typically experience an acute onset of the disease, is more frequent in females and it usually occurs between the age of 25 and 40 years, with a second peak around the age of 45 to 60 years [39]. The different manifestations of LS differ according to sex: EN is found predominantly in women while arthropathy/arthritis is more common in men [9]. Other extrapulmonary manifestations were observed in a cohort of patients with LS: granulomatous skin lesions, hepatomegaly, ocular involvement, splenomegaly, salivary gland hypertrophy and CNS involvement. LS is usually a self-limiting disease but some patients develop chronic disease [40].

Heerfordt-Waldenström’s syndrome, also called uveoparotid fever as it is associated with low-grade fever [9], comprises a granulomatous uveitis, parotid and submandibular salivary gland swelling and cranial neuropathy (usually but not always the facial nerve) [3]. LS and Heerfordt’s syndrome are considered to be highly specific of the disease and do not require histological confirmation [9].

3. Conclusion

Sarcoidosis is a granulomatous disease of unknown etiology that is characterized by the development of granulomatous inflammation in affected tissues. Any tissue can be affected and the same organ involvement may be presented in multiple ways. Also, sarcoidosis may be asymptomatic or cause a symptomatic multisystem disease. To add on to the variability of clinical presentation, clinical manifestations vary with race, sex, age and type of disease onset. Female patients are globally more affected. Clinical onset may be acute or subacute and clinical course self-remitting or chronic.

The most common manifestation is pulmonary sarcoidosis, followed by skin, eye and joint involvement. Respiratory and cardiac sarcoidosis contribute to the greater mortality rate associated with sarcoidosis compared to the general population and these patients also have more other morbidities.

It is important to be aware of sarcoidosis’ wide range of manifestations in order to achieve diagnosis so that patients can be followed and treated.

Acknowledgments

No funding was received for the development of this paper.

Conflict of interest

The authors declare no conflict of interest.