Sarcoidosis

Right Ventricular Hypertrophy Along With Malignant Ventricular Arrhythmias An Uncommon Case of Sarcoidosis at Cardiac Magnetic Resonance Imaging

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A 51-year-old black man without a personal or family history of cardiovascular disease was admitted to our hospital following syncope. Of note, he reported several episodes of chest pain and palpitations with lipothymia in the past few years associated with progressive dyspnea reaching New York Heart Association class II. ECG showed negative T waves in the precordium (V3 through V4) without significant ST deviation, monomorphic ventricular ectopies of septal origin with bursts of rapid polymorphic ventricular tachycardia, and mild first-degree atrioventricular (AV) block (Figure 1).

Figure 1.

A, ECG on admission showing negative T waves in the precordium (V3 to V4) without significant ST deviation, polymorphic narrow ventricular ectopies, and mild first-degree atrioventricular block. After β-blocker therapy was initiated, the patient was monitored showing a lengthening or PR interval. B, The patient received corticosteroid treatment with complete LV ejection fraction recovery at 3 months and partial conduction recovery with grade I AV block. AV indicates atrioventricular; and LV, left ventricular.

Clinical examination and chest radiography were normal. Laboratory tests showed mildly elevated ultrasensitive troponin at 36 ng/mL, normal blood cell count, and C-reactive protein. Transthoracic echocardiography found interventricular septal hypertrophy (25 mm) without left ventricular (LV) dilatation or regional wall motion abnormality and no pericardial effusion, and the diagnosis of hypertrophic cardiomyopathy was suspected at the first step. β-Blocker therapy was initiated and the patient was monitored showing severe lengthening of the PR interval (Figure 1). Cardiac MRI found atypical and severe concentric right ventricular (RV) hypertrophy with diffuse elevation of myocardial signal on T2-weighted short tau inversion recovery images (Figure 2 Movies I and II in the online-only Data Supplement), and severe RV free wall hypokinesia along with global asynchrony of RV contraction. The LV ejection fraction was confirmed normal, whereas the RV ejection fraction was markedly impaired at 35%. First-pass perfusion of the RV myocardium was slightly delayed in comparison with the LV. There was an intense and diffuse delayed enhancement of RV myocardium predominant in the right side of the septal wall but no LV delayed enhancement (Figure 2). Coronary angiography revealed no coronary artery disease. A dual-chamber cardiac defibrillator was implanted.

Figure 2.

Figure 2.

Cardiac magnetic resonance (CMR) images: severe asymmetrical right ventricular (RV) hypertrophy with marked predominance of wall thickening in the mediobasal region of the interventricular septum (white star) and in the RV free wall (white arrow) in 4-chamber view steady-state free precession cine (A) and short-axis proton density image (B). Interventricular septum (white star) and RV free wall (white arrow) show intramyocardial ill-defined high signal intensity area in short-axis T2-weighted spectral adiabatic inversion recovery image (C). Postgadolinium short-axis steady-state free precession cine image shows marked RV free wall thickening (white arrow) with a intramyocardial ill-defined high signal intensity area within the interventricular septum (white star; D). Four-chamber and short-axis inversion recovery images acquired 10 minutes after gadolinium show marked delayed enhancement of the interventricular septum (white star) and RV free wall (white arrow; E-F).

 During the follow-up, the patient was admitted with electrical storm with recurrent polymorphic sustained ventricular tachycardia at 220 beats/min triggered by septal ventricular ectopies needing several appropriate implantable cardioverter-defibrillator discharges, despite that the patient was on β-blockers and amiodarone therapy. Radiofrequency ablation was performed after electrophysiological mapping of both ventricles with a primary success confirming the septal origin of ventricular arrhythmias (Figure 3). However, the condition of the patient secondarily worsened with the recurrence of ventricular tachycardia, state III New York Heart Association dyspnea, and apparition of a second-degree Mobitz 1 AV block when echocardiography revealed the reduction of LV ejection fraction at 35%. Endomyocardial biopsy from the septum was then performed revealing gigantocellular inflammatory granulomas without caseum among dystrophic cardiomyocytes (Figure 4). Computed tomography of the chest demonstrated diffuse lymphatic micronodules combined with mediastinal and right gastric lymph node hypertrophy, consistent with lung and lymph node sarcoidosis (Figure 5). The patient received daily intravenous corticosteroids followed by oral steroids at 0.7 mg·kg–1·d–1 and intravenous cyclophosphamide. Follow-up was clinically satisfactory, with complete LV ejection fraction recovery at echocardiography, disappearance of ventricular tachycardia, and partial conduction recovery with first-degree AV block along with a significant decrease in the total interventricular septum thickness (Figures 6 and 7 Movies III, IV, and V in the online-only Data Supplement).
Figure 3.

Figure 3.

Radiofrequency ablation of ventricular arrhythmias. The patient developed an electrical storm with polymorphic ventricular tachycardia triggered by narrow ventricular ectopies (*) of septal origin (A). The endocardial mapping of both ventricles was performed with the Velocity system (SJM) and showed a large scarring zone (yellow-red) at the right side of the interventricular septum (IVS) and limited zones of scar (yellow-red) at the left side (voltage map, B). Mapping of the ventricular ectopies localized them in the IVS (activation map, C) within the Purkinje system as demonstrated with the sharp Purkinje potential observed at the beginning of the electrogram (C, arrow). Radiofrequency applications (brown and red points) were performed on both sides of the IVS with progressive disappearance of the ectopies. LV indicates left ventricle; and RV, right ventricle.

Figure 4.

Figure 4.

Histological analysis (×20; A) and (×40; B) showed intramyocardial gigantocellular inflammatory granulomas (white arrow) without caseum among dystrophic cardiomyocytes (white star).

Figure 5.

Figure 5.

A, Chest radiography was normal. In particular, there were no signs of hilar lymphadenopathy, interstitial lung disease, or fibrosis. B, Chest computed tomography in the axial plane shows mediastinal lymphadenopathy (black arrow) and pulmonary micronodules located in the peribronchovascular area and along the pleural surface (white arrows). C, Abdominal computed tomography in the axial plane shows gastric lymphadenopathy (white arrow).

Figure 6.

Figure 6.

Echocardiography before and 6 months after beginning of treatment. A and D, Long-axis parasternal view. B and E, Short-axis parasternal view, pillar level. C and F, Short-axis parasternal, mitral valve level. We observed a significant decrease in the total interventricular septum thickness from 23.5 to 27 mm to 16 to 17 mm with an important decrease in the right ventricular septum thickness from 11 mm to 4 mm (long-axis parasternal view; A and D).

Figure 7.

Figure 7.

Cardiac ECG-gated computed tomography 6 months after beginning of treatment. A through C, Short-axis view, pillar level. D, Four cavities view. We observed a significant decrease in the total interventricular septum thickness from 25 mm to 13 to 15 mm with an important decrease in the right ventricular septum thickness. White arrows show the implantable cardioverter-defibrillator probes in the right ventricle. Eand F, Maximum-intensity projection in the coronal axis shows vanishing of lymphatic pulmonary micronodules in the left apical lobe (white arrows).

 Although cardiac involvement in sarcoidosis may be found in up to 40% of autopsic series, only 5% of patients presented with inaugural myocarditis in the pre-MRI era.1 Cardiac MRI has been considered as the best imaging modality for the diagnosis of acute myocarditis with sensitivity up to 100% and a specificity of 78%.2 Indeed, cardiac MRI is able to demonstrate subepicardial or transmural edema, necrosis, microvascular obstruction, and fibrosis in addition to highly accurate biventricular functional evaluation. However, such markers of tissue damage remain nonspecific with regard to etiology, and differential diagnoses such as sarcoidosis, which require a specific treatment, have to be considered. Formal diagnosis of cardiac sarcoidosis remains based on histopathologic proof of noncaseating granuloma that may be found in peripheral or cardiac tissue.2

Septal involvement in cardiac myocarditis is severe and may lead to a high mortality rate of 60% in the absence of treatment mainly owing to high-grade AV block and ventricular tachycardia or fibrillation.1 Implantable cardioverter-defibrillator placement along with medical treatment should be considered as soon as possible in the presence of ventricular arrhythmias even in the absence of severely altered LV ejection fraction.

Isolated and diffuse RV involvement in sarcoid myocarditis, such as described here, is an uncommon finding. Patchy RV delayed gadolinium myocardial enhancement may be seen in cardiac sarcoidosis, usually associated with LV involvement,2 and is thought to be a predictor of an adverse prognosis.

The presentation here is highly atypical, both in its imaging and rhythmic components with the combination of severe ventricular arrhythmia and aggravating conduction anomalies arising from the septum. Cardiac sarcoidosis presenting as severe RV myocardial hypertrophy is exceptional and has not been reported so far. RV hypertrophic cardiomyopathy could have been discussed as a potential alternative diagnosis according to the echocardiographic findings, but would have been highly unlikely without LV involvement at MRI. Both entities may present in MRI with concentric thickening of the myocardium associated with patchy late enhancement along with edema and may be associated with AV block. However, isolated RV hypertrophic cardiomyopathy is uncommon in hypertrophic cardiomyopathy and is essentially limited to focal hypertrophy and late enhancement of right-left ventricular junctions and associated to LV involvement.3,4

In conclusion, isolated RV concentric hypertrophy is an uncommon finding in cardiac MRI and, especially when associated with signs of edema and necrosis and combined with severe AV conduction and ventricular arrhythmia, should be considered as a potential cardiac sarcoidosis.

Sarcoidosis:Clinical Presentation, Immunopathogenesis, and Therapeutics

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Sarcoidosis is a multisystem granulomatous disorder that most often affects the lungs and may cause significant morbidity. Sarcoidosis can manifest as neurological disease, uveitis, blindness, end-stage pulmonary fibrosis, pulmonary hypertension, dysrhythmias, cardiomyopathy, hypercalcemia, and renal failure. Sarcoidosis persists as chronic disease in approximately one-third of those affected. Clinical pitfalls and misconceptions about the course of disease place this population at risk for delayed or inadequate care. While noncaseating granulomas are the histopathological hallmark of sarcoidosis, they also are nonspecific. No pathognomonic diagnostic test exists for sarcoidosis, so the diagnosis remains one of exclusion. While the etiology of sarcoidosis is still unknown, recent insights into its immunopathogenesis have moved investigators closer to finding more effective treatments. Corticosteroids remain the standard of care when treatment is indicated, despite their adverse effect profile. Clinical investigations of novel drugs and biological agents targeting mechanisms involving CD4 type 1 helper T cells may provide more effective, better tolerated therapies.

Can You Reduce Steroid Treatments for Sarcoidosis?

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If you have sarcoidosis, your doctor may prescribe steroids at some point during your treatment. Specific types of steroids can treat the symptoms of this inflammatory condition, which often affects the lungs.

But steroids are not for everyone. Used long-term, steroids present a long list of potential side effects. That’s why doctors often look for “steroid-sparing” treatments to address sarcoidosis over time.

Below, Daniel Culver, DO, a leader in treating sarcoidosis, describes the concerns surrounding steroids, as well as treatment alternatives.

The risks of long-term steroid use

Sarcoidosis can affect any organ, but about 90 percent of cases involve the lungs, Dr. Culver says. Cases that involve the heart or central nervous system are less common but more often need treatment.

Most clinicians look to steroids as the first line of treatment. Steroids treat inflammation quickly and effectively. Prednisone is the mainstay, but some doctors also will use methylprednisolone intravenously.

However, chronic use of steroids comes with the risk of side effects. Common issues include mood or personality changes, obesity, diabetes, infection, osteoporosis, hypertension, cataracts, glaucoma, and thinning of the skin.

“Steroids cause obesity because it makes you more anabolic, so you tend to accumulate fat and eat more,” Dr. Culver notes, addressing a common concern. And they can affect diabetes by changing your glucose sensitivity. They can either make an existing case of diabetes worse or unmask a new case.

“Steroid-sparing” treatments

Because of concerns about steroids, doctors often look for alternatives. For example, Cleveland Clinic’s Sarcoidosis and Interstitial Lung Disease Program reports that it reduced average daily steroid dose for patients by more than 80 percent through use of steroid-sparing therapies.
Because of concerns about steroids, doctors often look for alternatives.
Choosing the right treatment depends on the organ involved or target of treatment, Dr. Culver says.

For severe sarcoidosis, doctors often use cytotoxic drugs like methotrexate, azathioprine, and leflunomide. These three drugs all target roughly the same organs, and seem to work approximately equally well, he says.

More recently, clinicians have started using drugs calledTNF (tumor necrosis factor) antagonists for patients who don’t respond to moderate-dose steroids or cytotoxic drugs. TNF antagonists seem especially effective for skin and neurologic issues, Dr. Culver says. Doctors may also prescribe anti-malarial medicines such as hydroxychloroquine for skin disease or calcium problems.

Of course, any drug comes with side effects. Patients on methotrexate have reported nausea, elevation of liver enzymes, suppression of blood counts, or fatigue. Azathioprine and leflunomide can cause diarrhea or cramping, as well as abnormalities of liver enzymes and blood counts.

“Most patients don’t experience those side effects, but those are some of the things I talk to patients about when I start them on these drugs,” Dr. Culver says.

In addition to these medications, new treatments are on the horizon. Several clinical trials are underway. And Acthar gel, a clinical drug first approved by the Food and Drug Administration in the 1950s for at least 20 to 30 different uses, is getting renewed attention for sarcoidosis.

What to ask your doctor

Not all sarcoidosis patients need treatment, Dr. Culver notes. For 50 to 75 percent of patients, the condition is likely to go away on its own.

If you do need treatment, talk to your doctor about what medications would be the best for you. Those may include steroids or other medications mentioned above, or you may be a good candidate for clinical trials.

Steroids will continue to have their place as a treatment. For patients who don’t require long-term treatment, steroids might be the most appropriate option, for example. “They work more quickly and they’re more reliable than most other medications,” Dr. Culver says.

Oral Antimycobacterial Therapy in Chronic Cutaneous.

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ABSTRACT

Importance  Sarcoidosis is a chronic granulomatous disease for which there are limited therapeutic options. This is the first randomized, placebo-controlled study to demonstrate that antimycobacterial therapy reduces lesion diameter and disease severity among patients with chronic cutaneous sarcoidosis.

Objective  To evaluate the safety and efficacy of once-daily antimycobacterial therapy on the resolution of chronic cutaneous sarcoidosis lesions.

Design and Participants  A randomized, placebo-controlled, single-masked trial on 30 patients with symptomatic chronic cutaneous sarcoidosis lesions deemed to require therapeutic intervention.

Setting  A tertiary referral dermatology center in Nashville, Tennessee.

Interventions  Participants were randomized to receive either the oral concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) regimen or a comparative placebo regimen for 8 weeks with a 180-day follow-up.

Main Outcomes and Measures  Participants were monitored for absolute change in lesion diameter and decrease in granuloma burden, if present, on completion of therapy.

Observations  In the intention-to-treat analysis, the CLEAR-treated group had a mean (SD) decrease in lesion diameter of –8.4 (14.0) mm compared with an increase of 0.07 (3.2) mm in the placebo-treated group (P = .05). The CLEAR group had a significant reduction in granuloma burden and experienced a mean (SD) decline of –2.9 (2.5) mm in lesion severity compared with a decline of –0.6 (2.1) mm in the placebo group (P = .02).

Conclusions and Relevance  Antimycobacterial therapy may result in significant reductions in chronic cutaneous sarcoidosis lesion diameter compared with placebo. These observed reductions, associated with a clinically significant improvement in symptoms, were present at the 180-day follow-up period. Transcriptome analysis of sarcoidosis CD4+ T cells revealed reversal of pathways associated with disease severity and enhanced T-cell function following T-cell receptor stimulation

Source: JAMA

Sarcoidosis from bench to bedside: a state-of-the-art series for the clinician.

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First described in 1899 [1], sarcoidosis is a multi-organ granulomatous disorder that remains an enigma and challenges researchers and clinicians due to its unknown aetiology, variegated presentation and an unpredictable, and occasionally severe or even fatal, outcome despite therapy. As over 90% of patients have involvement of the lungs and thoracic lymph nodes, most chest physicians encounter sarcoidosis regularly in their practice, and have to manage this disorder with a risk of delayed or inadequate care [1].

Sarcoidosis may cause significant morbidity, as it persists as a chronic disease in approximately one-third of cases [1]. It most commonly affects individuals aged 20–39 yrs [2]. The prevalence of disease varies widely throughout the world and in ethnic groups, with a mean estimate of 15 cases per 100,000 persons, roughly corresponding to one in 6,000 persons in the general population [3]. In Ireland, England, central Europe and Scandinavia the prevalence ranges between 40 and 60 cases per 100,000 and associations with environmental and occupational exposure have been reported [4–8].

In the past, the European Respiratory Journal (ERJ) has disseminated advances in knowledge of sarcoidosis and is committed to doing so consistently. To this end, the ERJ has, in the June issue, started a new series on sarcoidosis that will provide an in-depth overview of the tremendous progress made in this field in recent years. This series of articles intends to provide readers with the most up-to-date and comprehensive reviews. The authors are among the world’s leading experts in the field of sarcoidosis, and the articles are intended to be practically oriented and relevant for practicing physicians without neglecting the cutting edge of research. Topics developed in the series were carefully chosen as those with the most recent and important developments, be it in the setting of clinical manifestations, investigations, pathophysiology or therapeutic approach; some articles are related to approaches already applicable in practice, while others are anticipating developments in the near future.

One of the highlights of the series will consist of two articles on the imaging of sarcoidosis. The diagnosis of sarcoidosis is based on compatible clinical and radiological manifestations, with histologic evidence of noncaseating epithelioid-cell granulomas in one or more organs and in the absence of identifiable cause, especially microorganism or exposure to antigens that may cause granulomas [9]. Therefore, chest imaging dominated by chest computed tomography (CT) is key to the diagnosis of sarcoidosis. T. Nunes will review the eminently variegated imaging features of sarcoidosis; the typical pattern which is highly suggestive of the diagnosis when predominant (i.e. bilateral hilar lymphadenopathy with peri-lymphatic micronodules), or bilateral hilar retractile masses with scarring and traction bronchiectasis (characteristic of stage IV sarcoidosis). Less characteristic patterns include cavitation, nodular and alveolar opacities, and the recently described patterns of sarcoid galaxy and sarcoid cluster, as well as rare patterns (ground-glass opacities, linear opacities and cystic destruction). The authors will further review the evidence regarding imaging and functional correlations at baseline (including various features associated with airflow limitation) and during evolution (imaging as predictor of outcome), and the impact of imaging evaluation on clinical management. Examples are provided of how chest CT can guide diagnostic interventions [10] and may allow the diagnosis of most complications that carry significant morbidity in pulmonary sarcoidosis.

18F fluorodeoxyglucose positron emission tomography (PET) scanning identifies areas with active metabolic (inflammatory) activity [11], which can be targeted by biopsies [12], and suggests the presence of disease in organs that are difficult to access and with potential morbidity, especially the brain and the heart. PET scanning has progressively replaced gallium-67 scanning in most centres. However, it is expensive, nonspecific and associated with significant radiation; therefore, it can’t be routinely recommended in patients with sarcoidosis. In the article by J. Grutters, the authors synthesise the available evidence and suggest situations where PET scanning is useful, especially in the diagnosis of cardiac sarcoidosis, provided that images are acquired specifically to address this question and in close collaboration with knowledgeable specialists in nuclear imaging.

Among all organs (all of which can be involved by sarcoidosis), the heart is the one associated with the most difficult challenge in diagnosis and management. U. Costabel will review the accumulating evidence that cardiac sarcoidosis is more common than previously evaluated, although often not causing any clinical manifestation [13], and occasionally occurring in the absence of apparent disease elsewhere in the body. Potentially life-threatening, heart involvement by sarcoidosis may be found in up to 25% of patients during post mortem in the USA [14], and can affect any part of the heart especially the conducting system (causing complete heart block) and the myocardium (with granulomas and fibrosis causing heart failure, syncope or sudden death due to ventricular arrhythmias) [1]. The relative strengths and weaknesses of available investigations will be discussed, with the most commonly used tests being PET scanning (the results of which can be affected by anti-inflammatory drugs) and delayed enhancement magnetic resonance imaging (which is not widely available). U. Costabel will address the question of whether cardiac sarcoidosis detected by systematic imaging techniques in asymptomatic patients requires treatment. Indications for electrocardiogram, echocardiography, cardiac electric monitoring and advance electrophysiologic studies will also be discussed, as well as involvement of other non-thoracic organs relevant for chest physicians.

Another issue of particular interest is that of chronic fatigue, a disabling symptom causing impaired quality of life and reported in up to 50–80% of sarcoidosis patients [15], as reviewed by Drent et al. [16] in this issue of the ERJ. Usually multifactorial and enhanced by comorbidities (including anaemia, depression, anxiety, hypothyroidism, altered sleep patterns, etc.), and possibly by complications of corticosteroid therapy, fatigue-associated sarcoidosis may persist despite the treatment of possible causes, and is not correlated with clinical parameters of disease activity. This suggests that other pathogenic factors may take place, providing targets for specific therapy once identified.

Two articles in the series are devoted to the therapy and management of patients with sarcoidosis, with a focus on severe complications of the disease. R. Baughman will discuss the standard treatment for pulmonary sarcoidosis, especially corticosteroids (which represent the standard therapy) and steroid-sparing agents such as methotrexate, azathioprine and leflunomide [17]. Important practical considerations concern the indications for therapy and measures used to assess the response. The authors will further review the potential role of newer biological agents (infliximab and adalimumab) that are being evaluated in patients with sarcoidosis especially those with extra-pulmonary refractory involvement, although the role of these agents in the management of patients with pulmonary sarcoidosis is currently marginal [18].

Although a minority of sarcoidosis patients progress to advanced stages of their disease, complications at this stage are challenging. In a recent issue of the ERJ, Schlobin and Nathan [19] comprehensively reviewed the evidence regarding pulmonary hypertension associated with sarcoidosis. Seven case series and one clinical trial [20–27] using therapy specific for pulmonary arterial hypertension collectively suggest a possible benefit of these agents in specific patients with sarcoidosis-associated pulmonary hypertension, although this requires further study. Schlobin and Nathan [19] also discussed the specificities of lung transplantation in the setting of sarcoidosis, with the main particularities being the multi-organ involvement, the risk of infection (fungal infections developing in cavities) and surgical difficulties due to bulky hilar adenopathy and perihilar fibrosis, pleural thickening or pulmonary hypertension.

More fundamental issues are addressed in the final three articles of the series, namely genetics, immunopathogenesis and biomarker development; topics that are immediately relevant for clinicians. Familial clustering of sarcoidosis may be found in 5–10% of patients, and represents, together with genome-wide scanning for susceptibility genes [28], one of the best ways to progress in the understanding of this disease of elusive aetiology. In 2005, dentification of butyrophilin-like-2 as a main genetic determinant of sarcoidosis was reported [29]. This was a landmark discovery that has stimulated further research in sarcoidosis genetics, yielding new susceptibility gene variants [28, 30] and even susceptibility loci shared by sarcoidosis and another granulomatous disorder [31]. Recent progress in the immunopathogenesis of this condition notably includes the probable role of regulatory T-cell lymphocytes and natural killer T-cells in granuloma formation, and the role of the shift from T-helper 1 to T-helper 2 lymphocytes in fibrogenesis. Finally, P. Rottoli will review the state-of-the-art regarding biomarker development in sarcoidosis and the search for simple tests that are useful for diagnosis and assessing disease activity.

Source: European Respiratory Journal