Pulmonary Arterial Hypertension in Adult-Onset Still’s Disease: A Rare but Severe Complication

Introduction

Adult-onset Still’s disease (AOSD) is a rare, multisystem, inflammatory disorder characterized by a triad of high fevers, arthralgia, and evanescent skin rash [1]. Other manifestations can include sore throat, splenomegaly, lymphadenopathy, elevated transaminases, neutrophilic leukocytosis, and hyperferritinemia [2]. AOSD is considered a disease of exclusion, with diagnostic criteria including a clinical triad of cyclic fevers above 39°C, an evanescent salmon-pink erythematous rash, and polyarthritis of the hands, knees, and ankles [2]. Diagnostic criteria also include laboratory evaluation showing increased C-reactive protein (CSR), erythrocyte sedimentation rate (ESR), leukocytosis, elevated transaminases, hyperferritinemia, and increased serum interleukin-18 [2]. Although the etiology of this condition remains obscure, recent advances in molecular genetics have suggested that there may be both molecular and genetic factors at play in development of the disease [2]. For many patients with AOSD, treatment includes at least 1 disease-modifying antirheumatic drug (DMARD) such as methotrexate plus nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids [1]. In patients with disease refractory to DMARD and corticosteroid therapy, the interleukin-1 (IL-1) inhibitor canakinumab is approved for use in the United States [1].

The clinical presentation of AOSD is highly variable and has a broad spectrum of manifestations, including pulmonary disease. Pulmonary complications of AOSD most commonly include pleural effusions and transient pulmonary infiltrates [3]. One especially rare pulmonary complication of AOSD is pulmonary arterial hypertension (PAH), which can manifest as dyspnea, fatigue, and chest pain [4]. PAH has been associated with numerous rheumatologic diseases, such as systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease but only rarely has it been found to be associated with AOSD [5]. A systemic review of literature performed by Narvaez et al reported an overall prevalence of PAH complicating AOSD of 4.8% during a 33-year period [5]. Here, we report a case of a 49-year-old woman with known AOSD who was found to have PAH. Our case report aims to increase awareness of AOSD as a possible cause of PAH, which can possibly lead to more rapid identification of the complication and treatment in order to improve patient outcomes.

Case Report

A 49-year-old woman with a past medical history of treated adult-onset Still’s disease presented to the Emergency Department with a chief concern of 1 week of fever, dyspnea, and pleuritic chest pain. She was initially diagnosed with this condition 5 years prior and was taking daily leflunomide for management. She stated the current symptoms were different than her usual Still’s disease flare-ups, which typically manifested as high-grade fever, sore throat, arthralgias, and a rash of her lower extremities. Potentially relevant medical history included COVID-19 infection 3 weeks prior, from which she recovered without complications. The differential diagnosis, in this case, included long-COVID syndrome, post-viral pericarditis or myocarditis, and coronary artery disease.

Initial evaluation included an electrocardiogram (EKG), revealing tachycardia with a heart rate of 118 and no ST elevation, and a negative chest X-ray. Relevant preliminary laboratory evaluation included serial troponins that peaked at 0.27 ng/mL, a brain natriuretic peptide (BNP) level of 386 pg/mL, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) of 76 mm/hr and 43 mg/L (normal range of <9.9 mg/L), a ferritin of 2002 mg/mL (normal range of 15–200 ng/mL), and a D-dimer of 14,014 ng/mL (normal range of <0.5 µg/mL). (Table 1) A cytokine panel revealed elevations in tumor necrosis factor (TNF) at 24.1 pg/mL (normal: <10.0 pg/mL), interleukin-18 (IL-18) at >11000.0 pg/mL (normal: <468 pg/mL), interleukin-6 (IL-6) at 5.7 pg/mL (normal: <5.0 pg/mL), inter-leukin-1 beta (IL-1β) at 39.4 pg/mL (normal: <20.0 pg/mL), and interleukin-2 receptor alpha (IL-2Rα) at 1146 pg/mL (normal: <959 pg/mL). Further immunologic and infectious work-up revealed a negative anti-nuclear antibody (ANA), and negative rheumatoid factor, anticardiolipin IgA, IgG, IgM, blood cultures, HIV (human immunodeficiency virus), and COVID-19. Based on the patient’s described previous Still’s disease flare-ups, which included the classic triad of high-grade fever, arthralgias, and rash of her lower extremities, as well as her laboratory findings of elevated ESR, CRP, hyperferritinemia more than 5 times above normal range, and high serum IL-18, we confirmed that she did have AOSD per the clinical practice guidelines established by Mimura et al in 2018.

While in the Emergency Department, she underwent tomography angiography (CTA) of the chest to rule out pulmonary embolism and showed persistent progressive multifocal lymphadenopathy, and new gravity-dependent pleural effusions bilaterally. An echocardiography was completed and revealed a left ventricular ejection fraction of 60–64%, mild tricuspid valve regurgitation, and right ventricular systolic pressure of 48 mmHg, with mild pulmonary hypertension. Further testing by coronary calcium score and cardiac stress test was unrevealing.

The patient then underwent right-heart catheterization, which revealed an elevated pulmonary artery pressure (PAP) and mean PAP at 43/18 mmHg and 27 mmHg, respectively. Nitric oxide at 40 ppm testing showed a decrease in PAP to 38/16 mmHg with a corresponding decrease in mean PAP to 25 mmHg. Her wedge pressure was normal. These findings were consistent with mild pulmonary arterial hypertension. She was stabilized and discharged to a pulmonologist for further management of heart failure with preserved ejection fraction (HFpEF), and group 1 pulmonary arterial hypertension secondary to Still’s disease. She was found to have clinically significant precapillary vasculopathy, evidenced by New York Heart Association (NYHA) class 2, American College of Cardiology/American Heart Association (ACC/AHA) stage C symptoms, desaturation with exertion, and moderately reduced diffusion capacity of the lung for carbon monoxide (DLCO). Her Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) score was 3, indicating that she was at low risk of progression.

She was started on 20 mg of tadalafil daily. After 6 months of treatment, she described improving symptoms consistent with NYHA Class 1 (ACC/AHA stage B) with no limitation of ordinary physical activity. A repeat echocardiography revealed unchanged ejection fraction and cavity size, and an improvement in her right ventricular systolic pressure from 48 mmHg to 21 mmHg.

Discussion

This case report demonstrates that PAH can be a rare but important complication of AOSD that, if identified and treated early, can lead to better patient outcomes, such as with our patient. AOSD is a systemic inflammatory disorder characterized by recurrent fevers, joint pain, and a salmon-colored rash [1]. Due to its rarity and variable clinical presentation and many nonspecific symptoms, AOSD is considered a diagnosis of exclusion [1]. The Yamaguchi Criteria are the most sensitive of the 7 diagnostic criteria for AOSD in the literature [6]. Mimura et al recently developed a set of clinical practice guidelines (CPG) for AOSD, which included 26 clinical questions and recommendations to assist physicians in the diagnosis and management of this disease [2]. These guidelines noted that possible clinical manifestations of AOSD can include a spiking fever of 39°C or higher once or twice a day, with an evanescent salmon-pink erythematous rash, and polyarthritis of the hands, knees, and ankles are all possible clinical manifestations of AOSD [2]. Laboratory evaluation showing increased CRP, ESR, leukocytosis >10 000/uL, elevated transaminases, hyperferritinemia more than 5 times the upper limit of normal, and increased serum IL-18 levels could also be indicative findings of AOSD [2]. Our patient manifested several of these clinical and laboratory findings, thus likely confirming her previous diagnosis of AOSD.

The etiology of AOSD is believed to be related to genetic and environmental factors, but evidence supporting the role of genetic factors is mixed [7]. AOSD has an annual incidence estimated to be between 0.16 and 0.62 cases per 100 000 individuals worldwide, with equal distribution between sexes and race [4,8]. The clinical presentation of AOSD can range from mild to severe, typically presenting in 3 clinical phenotypes: systemic, chronic articular, and intermittent. The systemic form is characterized by daily spiking fevers, arthralgia, skin rash, lymphadenopathy, and hepatosplenomegaly. These symptoms often progress within weeks to months and can fluctuate in intensity [9]. The chronic articular phenotype presents as persistent arthritis that can eventually lead to joint destruction if left untreated [10]. The intermittent phenotype is characterized by recurrent episodes of high-spiking fevers and systemic symptoms that often resolve between episodes [11].

The progression of AOSD can be unpredictable, with disease activity often fluctuating over time [1]. Some patients may experience a single disease episode followed by complete remission, while others have persistent active disease or recurrent flares interspersed with periods of remission [1]. Factors influencing disease course and progression remain largely unknown. Additionally, the disease can potentially evolve from one phenotype to another over time [9]. There is a small subset of patients who may develop serious systemic complications, such as macrophage activation syndrome (MAS), disseminated intravascular coagulation (DIC), or pulmonary arterial hypertension (PAH), which can significantly impact prognosis [12]. AOSD patients can also experience significant functional impairment and reduced quality of life, particularly in the presence of chronic articular disease. Treatment strategies aimed at reducing inflammation and preventing joint damage are critical in managing AOSD and improving patient outcomes [12]. Most AOSD patients are treated with at least 1 DMARD, most commonly methotrexate [1]. However, cyclosporine A, azathioprine, leflunomide, and hydroxychloroquine have also been used and shown to be beneficial in AOSD patients [1]. The IL-1 inhibitor canakinumab is the only biologic currently approved in the United States for the treatment of AOSD, however, rilonacept, tumor necrosis factor-α (TNF-α) blockers, and tocilizumab can be used off-label [1]. In most patients on TNF-α blockers, partial response has been achieved [1]. For patients on an IL-1 inhibitor, full clinical remission has been achieved [1].

Pulmonary arterial hypertension (PAH) is a rare but potentially life-threatening complication of AOSD, with a prevalence of 4.8% during a 33-year study [5]. It has also been noted that the complication seems to occur more commonly in female patients such as ours and could appear at any point over the course of the disease [5]. While it is possible that our patient’s PAH could have been due to other causes, her normal wedge pressure excluded clinically significant left ventricular disease. Her echocardiogram also showed a preserved left ventricular ejection fraction, no significant valvular abnormality, and no congenital heart disease. She also did not endorse a history of sleeping disorders or chronic liver disease and her infectious work-up was negative. Her CTA was negative for any pulmonary embolism and did not show any disease of the lung parenchyma. Therefore, it was concluded that her PAH was likely secondary to her existing diagnosis of AOSD.

The pathophysiology of PAH in AOSD is not entirely understood, but it is believed to be related to the overproduction of cytokines such interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-18 (IL-18) and tumor necrosis factor-alpha (TNF-α) [13]. These cytokines can cause endothelial dysfunction, leading to progressive vasoconstriction and vascular remodeling of pulmonary arteries that ultimately result in the development of PAH [14]. PAH alone is found in 15–50 persons per million within the United States and Europe and can be idiopathic, heritable, caused by drugs or toxins, or associated with other conditions such as connective tissue disease, or congenital heart disease [15].

The clinical presentation of PAH in AOSD can vary, but patients often present with dyspnea, fatigue, and chest pain [4]. Clinical signs of right heart failure and syncope have been associated with the poorest outcome for patients with PAH due to AOSD [5]. Acute-phase reactants have been elevated at the time of PAH diagnosis in a majority of patients [5]. It has been suggested that, like in idiopathic PAH, endothelial proliferation is a hallmark of PAH associated with rheumatic disease [16]. Smooth-muscle cell proliferation has also been reported [16]. In this case, the patient’s PAH was categorized as Group 1, PAH associated with connective tissue disorders. Laboratory findings in patients with PAH and AOSD may include elevated levels of cardiac biomarkers such as troponin and brain natriuretic peptide (BNP). Troponin levels may be elevated due to right ventricular strain, while BNP levels may be elevated due to ventricular wall stress. Imaging studies such as echocardiography and right heart catheterization (RHC) are used to confirm the diagnosis of PAH. The echocardiogram may show evidence of right ventricular hypertrophy or dilation, while RHC can measure pulmonary artery pressure and determine the pulmonary vascular resistance. PAH is defined as an elevated mean pulmonary artery pressure ≥20 mmHg at rest [15]. In some cases, additional imaging such as CT scans may be used to assess the extent of pulmonary involvement.

Our review of literature found a few previously reported cases of PAH in AOSD [5,13,17,18]. In each of these cases, PAH was diagnosed within an age range of 18–43 years. Our patient was 49 years old at the time of diagnosis, thus making her the oldest reported case of PAH associated with AOSD to our knowledge. All patients received the diagnosis of AOSD based on the Yamaguchi Criteria [5,6,13,17,18]. The diagnosis of PAH was established via right-heart catheter in all but 2 patients [13,18]. One patient was diagnosed with PAH based on echocardiographic findings showing pulmonary artery pressure of 65 mmHg [18]. The second was unable to have a right-heart catheterization performed due to a severely dilated pulmonary artery and was given a diagnosis of probable PAH based on clinical and imaging findings [13]. Notably, our patient’s echocardiographic findings indicated only mild tricuspid valve regurgitation, which sets her apart from several other cases in which the status of the tricuspid valve was either severe or not reported [5]. One patient also presented with bilateral pleural effusions, but unlike our patient, she required temporary insertion of chest tubes in order to manage the pleural effusions [13].

In the case series and systematic review by Narvaez et al, PAH was established by echocardiogram and subsequent RHC in 12 (60%) of the patients with AOSD. One patient was treated with a phosphodiesterase 5 (PDE5) inhibitor and showed improved right ventricular systolic pressure (63–65 mmHg to 30 mmHg) after 33 months of treatment [5]. Our patient was successfully diagnosed and treated following a similar methodology. A separate case report noted that the patient with severe PAH due to AOSD was included in a clinical trial and received ambrisentan and tadalafil plus anakinra and corticosteroids [17], but died 1 month later in the Intensive Care Unit (ICU) due to septic shock associated with Staphylococcus epidermidis infection [17].

The differential diagnosis of our patient included long-COVID syndrome. However, based on the differences in presentation and inflammatory markers, PAH was more likely associated with underlying AOSD rather than the recent un-complicated COVID-19 infection. Thromboembolic events were strongly associated with COVID-19-induced PAH, which was not present in this case [19]. A COVID-19 cytokine storm features high levels of IL-6, while the inflammatory state present in AOSD features significantly higher levels of IL-18 and ferritin [20]. The patient in this case had very high IL-18 and ferritin levels and only slightly elevated IL-6 levels, which correlates with the findings in the literature. It is possible that AOSD coupled with a hyperinflammatory state after recovering from COVID-19 could have led to an increased risk of developing PAH, but this has not been studied. The prognosis of PAH in AOSD can be assessed using the REVEAL score, which takes into account factors such as age, functional class, and hemodynamic parameters [21]. Treatment of PAH in AOSD involves the use of pulmonary vasodilators such as prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase inhibitors. Immunosuppressive therapy may also be used to control the underlying inflammatory disorder to stop further disease progression and in the acute setting of the disease given the high pro-inflammatory component of this condition. In AOSD cases of greater severity, the addition of other immunosuppressive agents such as anti-interleukin- 1, anti-interleukin -6, anti -IL 1b, and TNF-α inhibitors has been shown to improve outcomes in AOSD-PAH.

Our case report has several limitations. This report describes only a single case of PAH due to AOSD, which limits the generalizability of our findings. We also cannot completely exclude the possibility that PAH was due to another cause. In addition, the clinical practice guidelines we used to confirm our patient’s previous diagnosis of AOSD offer only weak recommendations in terms of clinical and laboratory features that can be used to establish the diagnosis. Despite its limitations, it is important to recognize PAH as a rare, potentially life-threatening complication of AOSD.

Conclusions

Pulmonary complications of AOSD, such as pulmonary arterial hypertension (PAH), are rare but potentially life-threatening. Our case report highlights the importance of considering PAH in patients with AOSD who present with dyspnea, fatigue, and chest pain. Increased physician awareness of this possible complication of AOSD can potentially lead to early identification and treatment, which would improve patient outcomes. The pathophysiology of PAH in AOSD is believed to be related to the overproduction of cytokines, which can cause endothelial dysfunction, progressive vasoconstriction, and vascular remodeling of pulmonary arteries. Treatment of PAH in AOSD involves the use of pulmonary vasodilators, immunosuppressive therapy, and regular monitoring using the REVEAL score to assess the prognosis. Further research is needed to understand the pathophysiology of PAH in AOSD and to develop more effective treatment strategies.