Sarcoidosis: Rheumatology perspective




Abstract


Sarcoidosis is a systemic inflammatory granulomatous disease for which rheumatologists are uniquely trained and qualified to treat. Historically, sarcoidosis has been managed within silos of medical subspecialties, but with increased appreciation of the systemic nature of this disorder and the availability of more therapeutic options, it is clear that a multidisciplinary approach, with the rheumatologist as a key component, can offer more optimal care. This manuscript reviews clinically relevant immunology and pathophysiology, diagnostic issues, management decision-making, and therapeutics in the care of patients with sarcoidosis. Issues particularly relevant to rheumatologists are highlighted. These include aiding in establishing diagnosis; recognition of disease manifestations involving bone, joint, and muscle; management of calcium metabolism and metabolic bone disease; and formulation and implementation of anti-inflammatory and immunomodulatory therapies.


Introduction


Sarcoidosis is a systemic inflammatory disorder that can potentially affect any organ system, notable for great variability in clinical presentation and clinical course. Since its first description, attributed to Norwegian dermatologist Caesar Boeck in the late 19th century, sarcoidosis remains a fascinating and enigmatic condition, which by its very nature of unpredictability can be unsettling for the afflicted patient and the treating physicians. Cases can range from asymptomatic individuals diagnosed after incidental findings of radiologic abnormalities that require no specific treatment to severely affected individuals with potentially life-threatening situations that demand aggressive therapy from the outset.


Historically, the care of sarcoidosis patients has understandably tended to be compartmentalized according to the specific organ systems that are affected. Hence, for example, patients with isolated cutaneous sarcoidosis will often be seen solely by dermatologists. This compartmentalization quite naturally extends into research as well, in which therapeutic trials will often be restricted to relatively narrow spectrums of patients with isolated organ system involvement such as lung, eye, or skin.


There are estimates that lung involvement is present in up to 90% of patients with sarcoidosis, and as a result, much of the important work in the understanding and treatment of this disease is credited to the efforts of the pulmonary medicine community. For example, the classic staging of sarcoidosis devised by Scadding half a century ago assesses pulmonary and intrathoracic involvement and is still widely cited today . However, the Scadding staging system all but ignores extra-thoracic disease, and so today, with increasing acknowledgment of the systemic nature of sarcoidosis and the development of newer approaches to treatment, interdisciplinary approaches to the management of sarcoidosis have aptly become more standard.


From the standpoint of sarcoidosis, the production of this volume is timely. The role of the rheumatologist in the management of this disease has been less fully defined historically. However, it takes little stretch of imagination to recognize that sarcoidosis bears striking similarities to the many inflammatory diseases such as systemic lupus erythematosus (SLE) for which rheumatologists are relied on for their expertise. It was not surprising, then, that when one widely respected veteran pulmonologist was asked to give a presentation at the 2015 Annual Conference of the American Association of Sarcoidosis and Other Granulomatous Disorders on novel approaches to the treatment of sarcoidosis, he said that the first thing he did to prepare was “to talk to my colleagues over at the Division of Rheumatology.”


Preliminary data from an ongoing study of rheumatology trainees at Hospital for Special Surgery/Weill Cornell Medicine show that advice and assistance from the rheumatology community are regularly being sought in the care of patients with sarcoidosis. While this monograph offers a broad overview of the management of this disorder, special attention is given to topics that may be of particular relevance in the involvement of the rheumatologist.




Immunology and pathogenesis


The pathologic signature of sarcoidosis is noncaseating granulomatous inflammation ( Fig. 1 ). The compact and highly organized sarcoid granuloma is formed by lymphocytes, macrophages, multinucleated giant cells, and fibroblasts. The core comprises macrophages and epithelioid cells and is classically noncaseating, although cases with varying degrees of necrotic features are not rare. Also seen are multinucleated giant cells, formed by the fusion of giant cells within the granuloma, which is encircled by a halo of lymphocytes, predominantly CD4-positive.




Fig. 1


Muscle biopsy of a patient with sarcoid myositis demonstrates characteristic granulomas containing macrophages and multinucleated giant cells within the endomyseal connective tissue, adjacent to muscle fibers. A thin ring of lymphocytes can be seen around the granuloma at the upper left part of the photomicrograph.


Any tissue may become involved, accounting for clinical variability in presentation. While no single etiologic trigger has yet to be identified, the pathogenesis of the sarcoidosis involves the contributions of many cellular arms of the immune system, including lymphocytes, macrophages, and antigen-presenting cells, the activities of which are mediated and coordinated by various cytokines and chemokines . The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α), in particular, has emerged as a central orchestrator in the disease process. In animal models, deficient expression of either TNF-α or of its receptors results in impaired granuloma formation in response to antigen stimulation . Other data suggest that TNF-α is required not only to induce the formation of granuloma but also for their maintenance. In an in vivo murine model of granulomatous disease, anti-TNF-α antibodies suppress the expression of TNF-α mRNA in stimulated macrophages . At the same time, they cause the regression of pre-existing granulomas and the inhibition of new granuloma formation. These observations raise the intriguing hypothesis that TNF-α has a stimulatory autocrine effect on granuloma development. In theory, then, sufficiently maintained disruption of this positive feedback loop may not only result in the dissolution of established granulomas in human sarcoidosis but also in the removal of an important driver for their reformation. This is an important consideration, as will be discussed later, in light of commercially available monoclonal antibodies against TNF-α for therapeutic use.




Immunology and pathogenesis


The pathologic signature of sarcoidosis is noncaseating granulomatous inflammation ( Fig. 1 ). The compact and highly organized sarcoid granuloma is formed by lymphocytes, macrophages, multinucleated giant cells, and fibroblasts. The core comprises macrophages and epithelioid cells and is classically noncaseating, although cases with varying degrees of necrotic features are not rare. Also seen are multinucleated giant cells, formed by the fusion of giant cells within the granuloma, which is encircled by a halo of lymphocytes, predominantly CD4-positive.




Fig. 1


Muscle biopsy of a patient with sarcoid myositis demonstrates characteristic granulomas containing macrophages and multinucleated giant cells within the endomyseal connective tissue, adjacent to muscle fibers. A thin ring of lymphocytes can be seen around the granuloma at the upper left part of the photomicrograph.


Any tissue may become involved, accounting for clinical variability in presentation. While no single etiologic trigger has yet to be identified, the pathogenesis of the sarcoidosis involves the contributions of many cellular arms of the immune system, including lymphocytes, macrophages, and antigen-presenting cells, the activities of which are mediated and coordinated by various cytokines and chemokines . The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α), in particular, has emerged as a central orchestrator in the disease process. In animal models, deficient expression of either TNF-α or of its receptors results in impaired granuloma formation in response to antigen stimulation . Other data suggest that TNF-α is required not only to induce the formation of granuloma but also for their maintenance. In an in vivo murine model of granulomatous disease, anti-TNF-α antibodies suppress the expression of TNF-α mRNA in stimulated macrophages . At the same time, they cause the regression of pre-existing granulomas and the inhibition of new granuloma formation. These observations raise the intriguing hypothesis that TNF-α has a stimulatory autocrine effect on granuloma development. In theory, then, sufficiently maintained disruption of this positive feedback loop may not only result in the dissolution of established granulomas in human sarcoidosis but also in the removal of an important driver for their reformation. This is an important consideration, as will be discussed later, in light of commercially available monoclonal antibodies against TNF-α for therapeutic use.




Diagnosis


The diagnosis of sarcoidosis is made on the cumulative evidence obtained clinically, pathologically, and radiologically, specific for any given case. To ensure proper diagnosis, therefore, emphasis must be placed on thoroughness and accuracy in data collection. It is also perhaps wise, even in the most seemingly obvious of cases, to always maintain a level of vigilant skepticism, as there are many conditions that can mimic various manifestations of sarcoidosis. In 1999, an international consensus statement (A Case Controlled Etiology of Sarcoidosis Study (ACCESS)) was issued jointly by the American Thoracic Society, European Respiratory Society, and World Association for Sarcoidosis and Other Granulomatous Disorders (WASOG) to aid in ensuring diagnostic specificity . The ACCESS instrument highlighted two key elements. Firstly, emphasizing the systemic nature of sarcoidosis, the statement required convincing evidence of involvement of at least two organ systems for diagnosis. Secondly, recognizing the phenotypic variability of the disease, other causes of granulomatous disease were needed to be excluded.


In principle, then, if biopsies from two organ systems showed noncaseating granulomatous inflammation and if no other etiology can be identified (e.g., infectious, neoplastic), then the diagnosis of sarcoidosis can be reasonably accepted. The choice of biopsy sites should be those that would expose the patient to the least risk for morbidity, regardless of whether that particular organ was symptomatic. Hence, suspicious skin lesions or accessible peripheral lymph nodes may often be safe and convenient sites for sampling, even if the patient’s primary complaint is respiratory.


Of historical interest, the Kveim test is an intriguing diagnostic test that involves the intradermal injection of a splenic extract from a patient with sarcoidosis . After several weeks, a skin nodule may form at the site of inoculation. In some patients with sarcoidosis, biopsy of the nodule may reveal noncaseating granulomas. The Kveim test lacks sensitivity, is not approved by the Food and Drug Administration, and is not generally available, but it continues to tantalizingly suggest promise for the identification of a “sarcoid-antigen.”


Some sarcoidosis phenotypes such as Lofgren’s and Heerfordt’s syndromes have been considered to be so stereotypical that some authors feel that tissue sampling may not always be necessary . Lofgren’s syndrome is the triad of erythema nodosum, periarticular inflammation (typically the ankles), and hilar lymphadenopathy. Although quite painful and debilitating at times, Lofgren’s syndrome is usually self-limited . Heerfordt’s syndrome is the triad of acute parotitis, uveitis, and fever. Certain clinico-radiologic patterns such as asymptomatic bilateral hilar lymphadenopathy on conventional radiography or the Panda sign (parotid and lacrimal gland uptake) or the Lambda sign (bilateral hilar and right paratracheal lymph node uptake) on gallium-67 radionuclide scanning may also preclude the need for biopsy in many cases.


While the concepts behind the ACCESS tool remain important and valid, advances in diagnostic technology and recognition of certain deficiencies of the tool (such as the omission of some important organ systems) have led to a recent update by WASOG to help the clinician incorporate newer information and knowledge in the diagnostic process . It is of no small significance that contributors to the update came from a more diverse group of subspecialists, thereby adding a wider breadth of clinical expertise. From a pragmatic standpoint, the end result of this effort was the identification of clinical, laboratory, or radiologic findings that could act as “highly probable,” “probable,” and “possible” surrogates for a biopsy of the organ in question, as long as pathologic specimens from another site showed typical findings of noncaseating granulomatous inflammation. Some findings that were deemed “highly probable” for the diagnosis of sarcoidosis are as follows:



  • 1.

    Lung: bilateral hilar lymphadenopathy on chest X-ray ( Fig. 2 ), perilymphatic nodules on chest computed tomography (CT), symmetrical hilar/mediastinal lymphadenopathy on chest CT, or mediastinal/hilar enhancement on gallium-67 or positron emission tomographic (PET) scanning.




    Fig. 2


    Chest X-ray of a patient with stage II pulmonary sarcoidosis demonstrates both bilateral hilar lymphadenopathy and diffuse interstitial lung disease.


  • 2.

    Skin: lupus pernio.


  • 3.

    Eye: uveitis, optic neuritis, mutton-fat keratic precipitates, iris nodules, or snowballs/strings of pearls.


  • 4.

    Salivary glands: positive gallium-67 or PET scanning of the parotid glands.


  • 5.

    Calcium metabolism: hypercalcemia or hypercalciuria in the setting of (a) normal serum parathyroid hormone, (b) normal or increased serum 1,25-OH-dihydroxy-vitamin D, and (c) low serum 25-OH vitamin D.


  • 6.

    Bone: typical radiographic features (e.g., trabecular pattern, osteolysis, punched out/lytic lesions) ( Fig. 3 ).




    Fig. 3


    Bilateral X-rays of the hands of a patient with osseous sarcoidosis demonstrate involvement of multiple bones, most evidently in the left third distal, left second middle, and right fifth middle phalanges. Apparent are the multiple cystic lesions resulting in an overall trabecular pattern.


  • 7.

    Bone marrow: diffuse uptake on PET scanning.


  • 8.

    Nervous system: clinical manifestations consistent with inflammatory disease of the meninges, brain, ventricular system, cranial nerves, pituitary gland, spinal cord, cerebrovasculature, or nerve roots and (a) correlating findings on magnetic resonance imaging (MRI) with enhancement ( Fig. 4 ) or (b) cerebrospinal fluid analysis consistent with inflammation.




    Fig. 4


    Sagittal post-gadolinium non-fat-saturated T1-weighted MRI of the thoracic spine of a patient with transverse myelitis demonstrates ventral spinal cord enhancement from T5 through T8. The patient had tissue documentation of sarcoidosis from a peripheral lymph node biopsy.



The following case is illustrative of some of these diagnostic concepts.


A 70-year-old previously healthy woman presented with acute change in visual acuity and was diagnosed with bilateral uveitis and vitreous hemorrhage. She was treated with surgical debridement and topical corticosteroids. Several months later, the patient developed acute-onset right leg weakness, complete bilateral lower extremity paresthesia, and partial bowel and bladder incontinence. An MRI showed transverse myelitis involving levels T5–T8 ( Fig. 4 ), and the cerebrospinal fluid showed pleiocytosis. She responded partially to “pulse” intravenous methylprednisolone followed by standing high-dose corticosteroids but subsequently developed multiple poorly tolerated adverse effects, including Cushingoid changes, obesity, hypertension, diabetes, glaucoma, and cataracts. Systemic corticosteroids were discontinued, and the patient’s myelitis relapsed. She consulted several neurologists but was given no additional diagnoses and received no further treatments outside of physical therapy and eventually became confined to a wheelchair. After several months, her uveitis recurred, and she was started again on corticosteroid ophthalmic drops. More thorough investigation at this time revealed mediastinal lymphadenopathy. Lymph node biopsy showed noncaseating granulomas consistent with sarcoidosis, about 1.5 years after her initial presentation of bilateral uveitis.


Sarcoidosis should appear on the list of possible differential diagnoses in any patient presenting with uveitis or with transverse myelitis in isolation and should certainly rise to near the top of the list when they occur in the same patient. Nevertheless, laboratory and pathologic documentation is crucial not only to make a definitive diagnosis of sarcoidosis but also to exclude other possibilities such as granulomatosis with polyangiitis (Wegener’s granulomatosis) or Borreliosis (Lyme disease). Once tissue demonstration of noncaseating granulomas in the lymph node was made, the clinical and radiologic findings in the eye and in the spinal cord could be more readily accepted as highly probable evidence for additional organ system involvement.




Clinical manifestations


Although no list of potential presentations of sarcoidosis can be hoped to be completely exhaustive, certain phenotypes do occur with regularity. Patients are often asymptomatic and incidentally found to have sarcoidosis, or they may exhibit nonspecific complaints such as fatigue, weight loss, night sweats, anorexia, and fever indicative of a systemic inflammatory illness. When specific organ involvement arises, some manifestations such as sarcoid lung disease or cardiomyopathy result from direct infiltration of tissue, while other manifestations such as erythema nodosum or hypercalcemia arise indirectly from epiphenomenon of diverse inflammatory processes.


Pulmonary and intrathoracic disease


In some series, up to 90% of patients with sarcoidosis may have pulmonary involvement, over a third of whom may report chronic and insidious dyspnea on exertion, retrosternal chest pain, or dry cough. Even when the predominant clinical features are extrapulmonary, subclinical lung disease can often be revealed on investigation. More acute and rapidly progressive presentations are less frequent but may be more common in individuals of African descent. Progressive lung disease is the major cause of death due to sarcoidosis.


Pulmonary sarcoidosis is most commonly an interstitial lung disease involving the bronchioles, alveoli, and vasculature, clinically manifested by dry rales, restrictive lung disease, and gas exchange abnormalities. Airway involvement with granulomatous infiltration of the nares, larynx, trachea, and bronchi may also be present, leading to airway obstruction and occasionally bronchiectasis. In fact, up to 20% of patients may have significant obstructive pulmonary disease, airway hyperactivity, and/or audible wheezing. Accordingly, pulmonary function testing may demonstrate restrictive, obstructive, or mixed restrictive/obstructive patterns.


Pulmonary and intrathoracic sarcoidosis is routinely staged according to radiographic findings based on criteria initially proposed by Scadding : stage 0 – normal; stage I – bilateral hilar lymphadenopathy; stage II – bilateral hilar adenopathy with parenchymal infiltrates ( Fig. 2 ); stage III – parenchymal infiltrates without hilar adenopathy; and stage IV – pulmonary fibrosis with evidence of honeycombing, emphysema, bullae, or hilar retraction. While greater appreciation of extra-pulmonary disease has limited the overall utility of the Scadding classifications, they are still important prognostically. Patients with stage I and stage II disease have up to 90% and 70% spontaneous remissions, respectively. In contrast, stage III disease progresses in up to 90% of patients, and stage IV reflects near-end stage or end-stage pulmonary disease. Of note, as indicated earlier, patients with Lofgren’s syndrome (hilar lymphadenopathy, periarthritis, and erythema nodosum) have a high likelihood for remission.


Pulmonary hypertension is increasingly being recognized as a distinct important cause of respiratory morbidity and mortality and may occur in up to 20% of patients. PH in the setting of sarcoidosis is a particular challenge because it can have multiple concurrent causes in any given case, and treatment needs to accordingly address both the underlying contributing factors as well as the PH itself. Pulmonary fibrosis due to interstitial inflammation is the most common cause of PH in sarcoidosis. However, other mechanisms contributing to the development of PH include chronic hypoxia and vasoconstriction, left ventricular dysfunction secondary to cardiac sarcoidosis, pulmonary vascular compression due to mass effect from granulomas and lymphadenopathy, pulmonary veno-occlusive disease, granulomatous arteritis, and porto-pulmonary hypertension due to sarcoidosis-associated liver disease.


Less common pulmonary and intrathoracic manifestations include pleural effusions (both transudative and exudative), pneumothorax, and cavitary lung disease sometimes complicated by mycetomas.


Cardiac disease


Cardiac involvement is one of the most challenging areas in the management of sarcoidosis. Clinically evident cardiac disease is present in approximately 5–10% of patients, and it is second only to pulmonary disease as the cause of death. In the United States, up to a quarter of deaths attributed to sarcoidosis have been thought to be caused by cardiac disease. The spectrum of clinical manifestations can range from the absence of symptoms to sudden death due to malignant arrhythmias. Moreover, it is likely that the majority of patients with cardiac sarcoidosis are not even identified, since it is estimated that 25% of patients have subclinical disease, all of whom are potentially at risk for sudden death, which can be the initial presentation of sarcoidosis.


Clinical cardiac disease typically results from granulomatous inflammation of the myocardium, conduction system, or both. Patients may develop a patchy infiltrative cardiomyopathy or papillary muscle dysfunction, potentially leading to progressive heart failure. Other patients develop conduction defects such as advanced heart blocks or atrial or ventricular arrhythmias, including potentially life-threatening malignant ones.


Cardiac sarcoidosis presents many diagnostic challenges. The role of endocardial biopsy is limited. While it has high specificity, because of the patchy distribution of the disease, its yield is no more than 20%. The procedure is not devoid of potential short- and long-term complications. In lieu of endocardial biopsy then, the aforementioned WASOG update identified several findings that could be deemed “probable” surrogates for a histologic diagnosis of cardiac involvement, when noncaseating granulomatous inflammation consistent with sarcoidosis has already been demonstrated in an extra-cardiac site. These include the following:



  • 1.

    Cardiomyopathy or heart block responsive to steroid and/or immunomodulatory therapy;


  • 2.

    Unexplained reduced left ventricular function (ejection fraction < 40%);


  • 3.

    Unexplained spontaneous or inducible sustained ventricular tachycardia;


  • 4.

    Mobitz type II second-degree or third-degree atrioventricular heart block;


  • 5.

    Characteristic findings of patchy uptake on dedicated PET scanning ( Fig. 5 );




    Fig. 5


    Cardiac PET/CT of a patient with sarcoid myocarditis demonstrates mismatch uptake between metabolic and perfusion scanning in the anteroseptal wall. Images 63–67 (bottom row) show increased signaling on PET scanning, indicative of active inflammation. Images 51–55 (top row) show perfusion defects in the same anatomic distribution. It is hypothesized that the mismatch reflects local microvascular compression by local edema and inflammation.


  • 6.

    Delayed enhancement on cardiac magnetic resonance (CMR) imaging;


  • 7.

    Positive gallium scanning;


  • 8.

    Unexplained defect on perfusion scintigraphy or single photon emission computerized tomography scanning;


  • 9.

    T2-prolongation on CMR.



Recent recommendations have been published for screening of cardiac involvement in patients with sarcoidosis , but this remains an area of ongoing discussion. Class I recommendations include (1) assessment for history of unexplained syncope, pre-syncope, or significant palpitations and (2) a baseline 12-lead electrocardiogram (EKG). Class IIa recommendations include (1) echocardiography and (2) advanced cardiac imaging with CMR or PET scan in patients with one or more positive findings on clinical history, EKG, or echocardiography. Other modalities such as Holter monitoring, signal average EKG, and gallium scanning may also be useful in select situations.


Neurosarcoidosis


All parts of the neuraxis can be targets for granulomatous inflammation, and thus, the spectrum of clinical phenotypes is vast, affecting approximately 5–10% of patients with sarcoidosis. Cranial nerve, leptomeningeal, brain parenchymal, spinal cord, neurovascular, and peripheral nerve involvement has all been documented, with clinical manifestations reflecting the affected tissue. Simultaneous involvement of multiple parts of the neuraxis can also occur; therefore, unusual combinations of neurological findings (e.g., simultaneous central and peripheral nervous system deficits) should raise the suspicion of neurosarcoidosis. When accessible, histopathology will show typical granulomatous inflammation.


Occurring in about half of the cases of neurosarcoidosis, cranial neuropathies are common presentations, with the seventh, second, and eight cranial nerves most frequently involved. Facial neuropathy is seen in about half of the patients with neurosarcoidosis, of which two-thirds of the cases are unilateral and one-third of cases bilateral, and may occur as a result of either direct infiltration of the neural tissue or compression by adjacent affected tissue such as the parotid gland. Optic neuropathy may be unilateral or bilateral and may lead to permanent visual deficits when not promptly recognized and treated. Cochlear nerve disease is typically bilateral and may either be due to direct inflammation or broader meningeal disease. Involvement of the vestibular component results in vertigo and disequilibrium.


Leptomeningeal disease is another common presentation of neurosarcoidosis, occurring in as many as three-fourths of patients with neurologic disease. Most patients present with headache due to chronic or subacute aseptic meningitis. Granulomatous inflammation of the brain will usually present as focal defects or seizures due to space-occupying mass lesions. However, involvement of the hypothalamus and/or pituitary gland can present in various more subtle endocrine disorders such as syndrome of inappropriate antidiuretic hormone, diabetes insipidus, galactorrhea, and amenorrhea. Concomitant leptomeningeal and brain parenchymal disease is not rare, potentially adding to further diagnostic confusion.


As illustrated in the above case, spinal cord involvement such as transverse myelitis can be quite acute and devastating. However, more insidious presentations such as changes in bladder or bowel habits, sexual dysfunction, gait disturbances, and paresthesias can easily be overlooked or mistaken for other more common conditions. Large fiber peripheral nerve disease is a non-length-dependent polyneuropathy caused by granulomatous infiltration, extrinsic compression, or vasculitic ischemia of large nerve fibers. A painful neuropathic picture that does not follow a stocking/glove distribution should raise suspicion of this entity.


In all the above phenotypes, non-necrotizing granulomas can be demonstrated on histopathologic examination of the involved tissue. However, sampling of the suspected neural tissue, particularly in the central nervous system, is frequently not feasible. Hence, MRI has become an increasingly useful diagnostic tool, as radiologic patterns characteristic of sarcoidosis have become more widely recognized. The most common MRI finding is leptomeningeal thickening and enhancement, occurring in up to 40% of patients with central nervous system disease, most typically at the base of the brain.


Small fiber neuropathy (SFN) is an entity that merits special mention. Occurring in over half of the patients with sarcoidosis, SFN is a peripheral neuropathy affecting thinly myelinated Aδ and unmyelinated C fibers . It is distinct from other neurologic complications of sarcoidosis in that granulomatous inflammation does not appear to be directly causative. Symptoms reflect sensory and autonomic dysfunction and often include the following :


Sensory dysfunction



  • •

    Upper extremity pain


  • •

    Muscle cramps


  • •

    Chest pain


  • •

    Abnormal temperature sensation


  • •

    Hyperesthesias


  • •

    Dysesthesias and paresthesias


  • •

    Restless legs syndrome



Autonomic dysfunction



  • •

    Palpitations


  • •

    Dysphagia or gastroparesis


  • •

    Bowel dysfunction


  • •

    Bladder dysfunction


  • •

    Dry eyes


  • •

    Vision disturbances


  • •

    Orthostasis


  • •

    Flushing



Punch skin biopsy, typically taken at the distal leg and lateral thigh, shows reduced intra-epidermal nerve fiber density but no evidence of granulomatous inflammation. It is not surprising, therefore, that standard therapy with corticosteroids and immunomodulatory agents is generally ineffective in the treatment of SFN. Quality of life can be severely affected, and management is mostly palliative.


Ocular sarcoidosis


Uveitis is an extremely significant feature of sarcoidosis. Depending on the study population, the prevalence of uveitis in sarcoidosis may be as high as 70%, and in dedicated uveitis clinics, sarcoidosis may account for 10% of cases. Uveitis is often the initial presentation and may precede the diagnosis of sarcoidosis by many years. Inflammation can involve any segment of the uveal tract individually or all segments simultaneously (panuveitis) and is frequently bilateral. It is most often chronic but can also present acutely as part of Heerfordt’s syndrome (acute fever, uveitis, and parotitis).


Anterior uveitis (iris and ciliary body) typically presents with erythema, loss of visual acuity, photophobia, and eye pain, but it can also be insidious and subclinical. Hence, regular monitoring is important to ensure early identification. Progression of inadequately treated disease may lead to premature cataract formation, synechiae, and permanent anterior segment deformity. Involvement of the vitreous and peripheral retina is known as intermediate uveitis, presenting as floaters and decreased visual acuity, potentially leading to cystoid macular edema and opacification of the vitreous. A characteristic ophthalmologic finding is the accumulation of chronic inflammatory vitreous debris on the retinal surface with the appearance of “snowballs” or “strings of pearls.” Posterior uveitis (retina and choroid) is usually bilateral and can lead to permanent and severe vision loss, particularly when the posterior pole is affected or when retinal detachment occurs. Important ocular signs and features pointing toward the diagnosis of sarcoid uveitis have been proposed by an international panel of experts and include the following:



  • •

    Bilateral involvement


  • •

    Trabecular meshwork nodules and/or tent-like peripheral anterior synechiae


  • •

    “Mutton-fat” keratic precipitates and/or iris nodules


  • •

    Vitreous “snowballs” or “strings of pearls”


  • •

    Multiple chorioretinal peripheral lesions


  • •

    Optic disc nodules and/or granulomas and/or solitary choroidal nodule


  • •

    Nodular and/or segmental periphlebitis and/or macroaneuryms



Sarcoidosis of the lacrimal glands is extremely common, occurring in as many as two-thirds of patients. Clinically, the resulting eye dryness may be a simple nuisance or may lead to severe corneal injury. Conversely, inflammation of the lacrimal drainage system (puncta, canaliculi, nasolacrimal sac, duct, and nasal meatus) can lead to excessive tearing. Granulomatous inflammation of the eyelids, conjunctiva, sclera, or cornea can lead to cosmetic disfigurement, pain due to mass effects, or changes in vision. Involvement of the cranial nerves may result in vision disturbances from optic neuropathy or extra-ocular muscle dysfunction.


Dermatologic manifestations


Skin disease occurs in approximately 25% of patients, and dermatologists are often the first to identify new cases of sarcoidosis after the evaluation of atypical skin lesions. Although a myriad of macular, papular, and plaque lesions can be seen, two phenotypes are classically associated with sarcoidosis, erythema nodosum, and lupus pernio. Erythema nodosum consists of elevated, red, and exquisitely tender subcutaneous nodules characteristically on the anterior aspects of the legs ( Fig. 6 ). Gradually, the lesions darken and resemble deep purplish bruises. Erythma nodosum is a nonspecific panniculitis characterized by inflammation around the septal areas of the subcutaneous fat, typically without demonstrable non-necrotizing granulomas. It can be seen in many other settings (notably pregnancy, streptococcal infections, inflammatory bowel disease, and tuberculosis), but its presence should always raise suspicion for sarcoidosis. Erythema nodosum usually resolves spontaneously within several weeks to months, particularly when seen in the setting of Lofgren’s syndrome. As the lesions are stereotypic, biopsy is rarely necessary.


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Nov 10, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Sarcoidosis: Rheumatology perspective

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