Introduction
Sarcoidosis is a multisystem, inflammatory disease characterized by the development of noncaseating granulomas in affected organs. The lungs and intra‐thoracic lymph nodes are the most common sites of involvement. Extrapulmonary disease can affect several organ systems, including the skin, joints, eyes, liver, kidneys, heart, nervous system, and many others.
While most cases involve the pulmonary system, sometimes the disease initially presents in other organs, making diagnosis more difficult. Treatment requires the use of corticosteroids and steroid‐sparing agents including conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) and/or monoclonal tumor necrosis factor‐alpha (TNF‐α) inhibitors. Several other options for refractory disease have also been studied, including rituximab, an anti‐CD20 monoclonal antibody.
We present a case of probable sarcoidosis without typical pulmonary involvement in a patient who initially had recurrent optic neuritis requiring steroid therapy to control her symptoms. Despite the addition of rituximab, she was unable to achieve sustained control of the neuro‐ophthalmic symptoms and developed inflammatory cardiac disease with lymphadenopathy.
Case Presentation
A 61‐year‐old woman presented to the emergency room after a near‐syncope event at home. Her only symptom during the event was dizziness; no chest pain, fevers, cough, dyspnea, or neurologic deficits were reported. On exam, she was bradycardic without pulmonary, neurologic, or cutaneous findings.
EKG demonstrated complete heart block resulting in admission for further management.
Past medical history was notable for hypertension, hyperlipidemia, and a relapsing left‐sided optic neuritis over the past 2 years of unknown etiology. The initial presentation of optic neuritis consisted of the acute onset of blurry vision, visual color loss, and eye discomfort. MRI brain reported enhancement of the left optic nerve consistent with left optic neuritis and two small foci of hyperintensity in the right mesial temporal lobe and left anterior commissure.
Serum labs revealed glucose level of 85 and were negative for antinuclear antibody (ANA), varicella serology, syphilis serology, Quantiferon‐Tb Gold, antibodies to myelin oligodendrocyte glycoprotein (anti‐MOG) and aquaporin‐4 (anti‐AQP4). Subsequent lumbar puncture showed cerebrospinal fluid protein of 45 mg/dL (reference range 15–25 mg/dL), glucose of 59 mg/dL (reference range 40–70 mg/dL), no RBCs or WBCs, and no oligoclonal bands. Her symptoms responded to repeated high dose steroid tapers starting from prednisone 50 mg a day and sometimes preceded by pulse dose steroids with IV methylprednisolone, but returned when the prednisone dose was below 20 mg daily.
Repeat brain MRIs were unchanged and she was evaluated by Neuroimmunology, who started IV rituximab 1000 mg every 6 months for a working diagnosis of chronic relapsing inflammatory optic neuropathy (CRION). At that time, the CT chest showed no evidence of lymphadenopathy or parenchymal lung disease to suggest sarcoidosis. She continued to develop flares of optic neuritis despite over a year of treatment with rituximab, only responding to high dose steroid tapers.
Three weeks prior to the current hospital admission, she had tapered off prednisone after receiving an infusion of rituximab. One day before admission, the optic neuritis had flared and prednisone was restarted.
The patient had no relevant cardiac history, and this was her first near syncopal event resulting in the current presentation and discovery of a new complete heart block. Given the ambiguity surrounding her ophthalmic history, there was a question of whether her cardiac symptoms were related. Cardiac MRI was performed, which showed focal acute myocardial inflammation compatible with sarcoidosis (Figure 1).
Rheumatology was consulted to assist with additional evaluation. Pertinent findings included elevated inflammatory markers and soluble interleukin‐2 receptor (sIL‐2R) levels (Table 1). Infectious Disease was also consulted, and extensive testing did not identify any pathogenic organisms.
PET/CT with sarcoidosis protocol again showed evidence of focal acute myocardial inflammation (Figure 2). Additionally, there was uptake within the left hilar (Figure 3), retroperitoneal, porta hepatis, and left external iliac lymph nodes. These findings in the context of her symptoms narrowed the differential to probable sarcoidosis.
She continued prednisone at 20 mg daily and was discharged after pacemaker placement. Two weeks later, bronchoscopy with endobronchial biopsy was performed. Unfortunately, the biopsy yield was insufficient for tissue diagnosis, likely due to ongoing steroid use.
Outcomes and Follow‐Up
Oral weekly methotrexate and infliximab infusions were added while prednisone was slowly tapered off, resulting in resolution of adenopathy without recurrence of her cardiac or neuro‐ophthalmic symptoms. She is now in disease remission on steroid sparing agents.
Discussion
While the majority of cases of sarcoidosis manifest within the pulmonary and lymphatic systems, sarcoidosis can affect several other organs. Cardiac sarcoidosis has a reported prevalence of 3%–39%; however, the true prevalence is thought to be higher based on autopsy studies [1]. Ocular or neuro‐ophthalmological sarcoidosis can either be the initial manifestation of sarcoidosis or may present later along the course of the disease, and optic nerve involvement occurs in 1%–5% of patients [1].
While tissue biopsy provides the greatest diagnostic yield, areas of disease activity can be difficult to biopsy, and the diagnosis may ultimately rely on supportive imaging and comprehensive laboratory evaluation [2].
In our patient, the cardiac MRI and PET scan showed active inflammation without scarring, but in combination with high‐degree heart block, elevated serum sIL‐2R, and the exclusion of other etiologies, the findings were supportive for cardiac sarcoidosis. The affected sites were difficult to biopsy, leading to delay in diagnosis. By the time active pulmonary lymph nodes were identified, the patient had already been immunosuppressed, limiting the diagnostic yield of the tissue sampling.
Given the challenges of obtaining histologic samples, newer guidelines have broadened the diagnostic criteria for sarcoidosis. The American Heart Association (AHA) classifies the diagnosis of cardiac sarcoidosis based on a spectrum of probability, which can include patients without histologic confirmation of noncaseating granulomas [3]. The most recent Japanese Circulation Society (JCS) criteria also separate the diagnosis into a histologic or clinical group [4].
A recent single‐center retrospective observational study by Tanabe et al. evaluated patients for suspected cardiac sarcoidosis with pacemaker implants. Using the newer JCS criteria, more patients were diagnosed with cardiac sarcoidosis without requiring biopsy and a subset of these patients received corticosteroids without adverse outcomes [5]. In our patient, the ability to make a clinical diagnosis of sarcoidosis enabled the initiation of appropriate treatment and the achievement of long‐term disease control with methotrexate and infliximab.
Although our patient initially presented with an isolated neuro‐ophthalmic manifestation, the clinical response to immunosuppressive therapy directed towards sarcoidosis and exclusion of alternative etiologies favored her optic neuritis as associated with sarcoidosis, rather than her previous working diagnosis of CRION.
Several biomarkers are associated with sarcoidosis, but their utility as a diagnostic tool is limited. Serum angiotensin converting enzyme (ACE) is one of the most‐well known biomarkers in sarcoidosis. However, its sensitivity remains low, partially due to its presence in other inflammatory diseases.
Lysozyme is another biomarker associated with sarcoidosis, but also carries a low sensitivity. Both serum ACE and lysozyme were normal in our patient while her sIL‐2 receptor level was elevated. Although sIL‐2R is nonspecific and can be seen in other diseases, it can correlate with active systemic inflammation as is seen in sarcoidosis [6].
Overall, these biomarkers are best utilized as evidence of inflammation rather than pathognomonic tests [2].
While the exact cause of sarcoidosis is unknown, it is widely accepted that a combination of genetic and environmental factors contributes to the etiology. Specific alleles for human leukocyte antigen (HLA) have been shown to increase the risk for developing sarcoidosis, although other non‐HLA genes have been implicated in the disease process as well [7]. Genetic variation predisposes patients to the different presentations associated with sarcoidosis [8].
The hallmark pathology of sarcoidosis is the formation of noncaseating granulomas, which involves multiple classes of immune cells, cytokines, and chemokines in response to an antigen [9]. One specific pro‐inflammatory cytokine, TNF‐α, is key to both the development and maintenance of granulomas in sarcoidosis. Animal studies have shown that deficient expression of TNF‐α or its receptors leads to impaired granuloma formation [10].
While the mainstay of treatment for sarcoidosis includes steroids and csDMARDs, TNF‐α inhibitors are a reliable third‐line treatment option.
Although sarcoidosis is well‐known as a T‐cell‐mediated disease, studies have supported B‐cell activity in its pathogenesis as well [2]. Rituximab, an anti‐CD20 monoclonal antibody, is one of many agents being studied in treatment‐refractory sarcoidosis. One single‐center study in 2022 identified seven patients who received rituximab for the treatment of cardiac sarcoidosis after failing prior immunosuppressive therapy, including steroids [11].
6 out of 7 patients responded to rituximab with decreased inflammation as assessed by cardiac FDG PET/CT, demonstrating promise for rituximab in cardiac sarcoidosis management. Our patient, unfortunately, did not achieve sustained steroid‐sparing disease control after receiving therapy for over a year, emphasizing the need for further data on the utility of rituximab for sarcoidosis.
Conclusion
The diversity in the presentation of sarcoidosis can make diagnosis challenging. It is important to consider sarcoidosis as a differential in the presence of unexplained inflammatory conditions affecting several organs, even without initial pulmonary involvement and especially when biopsy may not be feasible. While rituximab has been studied in refractory disease, additional data is needed to elucidate its role in the treatment of sarcoidosis.
Author Contributions
Chetan Kamath: investigation, data curation, writing – original draft, writing – review and editing. Ghassan Al‐Qaysi: investigation, data curation, writing – review and editing. Hemanta Paudel: writing – review and editing.
Jonathan Saado: writing – review and editing, data curation. Jane Nwaonu: investigation, conceptualization, supervision, writing – review and editing.
Funding
The authors have nothing to report.
Consent
Written consent was obtained from the patient for publication of case information and images.
Conflicts of Interest
The authors declare no conflicts of interest.