Case Report: A Polyarteritis Nodosa Conundrum

Figure 4: Positive Feedback Loop

A positive feedback loop is a theory proposed to explain the pathophysiology of shrinking lung syndrome.

PAN can affect virtually any organ, but tends to spare the lungs.¹ However, rheuma­­tologists should recognize dyspnea and possible pulmonary pathology complicating this medium-vessel vasculitis. We describe shrinking lung syndrome and PTS as two pulmonary manifestations potentially associated with PAN.

Shrinking lung syndrome is a rare cause of dyspnea characterized by a progressive decline in lung volumes without evidence of pleural or interstitial lung disease. In SLS, chest radiography reveals decreased lung volumes with an elevated hemi­diaphragm, pulmonary function testing is consistent with a restrictive pattern, and the workup for dyspnea excludes major parenchymal or pleural disease on CT imaging.⁶ All of the above characteristics were present in our patient’s case, leading to a diagnosis of SLS as the etiology of his dyspnea.

SLS has been described in the literature mainly in the context of SLE.⁶ The prevalence of SLS in patients with SLE is <1%, where it tends to be a late pulmonary manifestation.⁷ Duron et al. evaluated 15 cases of SLS in SLE and found all cases occurred in women with a median age of 27 years at onset.⁸ Table 2  shares a small sampling of case reports of SLS cases in a variety of autoimmune diseases.^7,9,10 A 2017 case series and literature review by Smyth et al. found 89 cases of SLS reported in the literature.¹¹

Table 2: Shrinking Lung Syndrome Case Reports

PTS is an idiopathic brachialathy with an abrupt onset of symptoms. Multiple conditions have been associated with the development of PTS, including stressful exercise, infection, immunizations, surgery, pregnancy and rheumatic diseases, such as SLE, PAN, giant cell arteritis and connective-tissue disease (see Table 3).^12,13

Table 3: Parsonage-Turner Syndrome Case Reports

Nerve involvement in PTS tends to be unilateral, but can be bilateral and may involve nerves outside the brachial plexus, such as the phrenic nerve. When the phrenic nerve is involved, patients may experience dyspnea and have evidence of diaphragmatic elevation on chest X-ray.¹⁴ Our patient’s low lung volumes could, therefore, have been due to SLS or PTS resulting in phrenic nerve dysfunction.

Pathogenesis of PAN

The pathogenesis of PAN is not well understood, but the disease can be either idiopathic or triggered. Triggered causes of PAN include infections with parvo­virus, hepatitis B, hepatitis C and human immunodeficiency viruses, as well as hairy-cell leukemia.¹ PAN was initially thought to be an immune complex-mediated disease due to the injury pattern of blood vessels, but complement consumption is rare.³

PAN differs from other systemic necro­tizing vasculitides in that anti-neutrophil cytoplasmic antibodies are typically absent and histopathologic features of granulomatous inflammation exclude a diagnosis of PAN.^1,4 The histopathologic finding characteristic for PAN is focal, segmental, pan-mural necrotizing inflammation of medium-sized or small arteries, predominantly at branch points and bifurcations of these vessels.⁵ Early, active lesions biopsied from symptomatic sites may reveal fibrinoid necrosis, as was noted in our patient’s skin biopsy.¹ However, because PAN generally presents with successive flares, multiple histologic stages may present simultaneously.⁴

The pathophysiology of PTS and SLS is poorly understood. Shrinking lung syndrome presents with pleuritic chest pain in nearly 75% of cases. The pleuritic pain and inflammation are thought to trigger reflex inhibition of diaphragmatic activation. This inhibition leads to chronic lung hypoinflation, which ultimately leads to decreased lung compliance.

It is not fully understood why lung compliance worsens, but tissue remodeling and changes in surfactant are suspected contributing factors. Decreased lung compliance propagates lung hypo­inflation, which initiates a positive feedback loop (see Figure 4, above). The etiology of SLS is likely multi-factorial, and the aforementioned theory accounts for only a portion of SLS cases.

Approximately 25% of patients with SLS do not present with pleuritic chest pain (as was true with our patient).¹⁵ Other proposed theories for the pathophysiology of SLS include pleural adhesions leading to diaphragmatic dysfunction, surfactant deficiency causing increased surface tension and subsequent micro-atelectasis, and the development of an inspiratory and expiratory myopathy or phrenic neuropathy.¹¹ Our patient may have had some level of phrenic neuropathy caused by PAN.

Nerve ischemia from either an inflammatory or mechanical etiology is thought to result in the symptoms of PTS. In PTS associated with vasculitic conditions, a vascular etiology contributing to the develop­ment of PTS is postulated.¹⁴ There is limited understanding about why the brachial plexus is involved.

Treatment of Idiopathic PAN

Treatment of idiopathic PAN usually begins with corticosteroid therapy at a dose of 1 mg/kg/day.¹ The Five-Factor Score (FFS) is a prognostic index used to determine if immunosuppressive therapy, in addition to corticosteroid therapy, is warranted. Each of the following manifestations receives one point on the FFS: renal insufficiency (serum creatinine level >1.7 mg/dL), gastrointestinal involvement, cardiac involvement and age >65 years. If a patient has a score of 1 or higher, the recommended treatment is a combination of cyclophosphamide and prednisone to achieve remission. Patients may be switched to a steroid-sparing agent, such as azathioprine or methotrexate, once remission is achieved.¹

Relapses occur in up to 20% of idiopathic PAN cases.⁵ The five-year mortality rate is 12% for PAN patients with an FFS of 0, 26% for patients with an FFS of 1, and 46% for patients with an FFS ≥2.⁵ In our case, the patient’s abdominal pain was not attributed to his diagnosis of PAN because it was self-limited (i.e., resolving before his initial hospital admission) and his CT angiography was unremarkable. His FFS was therefore 0, which led to the initial decision to treat his cutaneous lesions with prednisone alone.

Treatment of SLS targets the underlying disease process and involves immuno­suppressive therapy.⁶ In contrast, the management of symptoms associated with PTS primarily involves physical therapy, and recovery may take several years.¹⁴ Our patient predominantly presented with cutaneous manifestations of PAN and did not have any of the poor prognostic factors. However, his recalcitrant symptoms of dyspnea and right arm pain attributed to SLS and/or PTS illustrate that some vasculitic manifestations may be refractory to corticosteroid and immunosuppressive therapy.

Conclusion

We describe a rare case of idiopathic polyarteritis nodosa with primarily cutaneous disease. Cutaneous PAN is associated with a lower mortality, although lesions may be refractory to treatment and tend to be recurrent.¹

In our patient, with predominantly cutaneous manifestations of PAN and a Five-Factor Score of 0, the historical factors, along with the diagnosis of shrinking lung syndrome and PTS, led to the combination of corticosteroid and immunosuppressive therapy.

In spite of our patient’s dismal outcome, we emphasize that early recognition of shrinking lung syndrome and PTS as possible complications in PAN may warrant early, aggressive therapy to improve outcomes.

Hannah Krebsbach, MD, is a first-year rheumatology fellow at Indiana University School of Medicine, Indianapolis. She completed her internal medicine residency at Tulane University, New Orleans, and medical school at Indiana University School of Medicine, Indianapolis.

Ileannette M. Robledo Vega, MD, is a staff rheumatologist at Crescent City Physicians Inc., New Orleans.

Nirupa Patel, MD, is an associate professor of clinical medicine—gratis in the Section of Rheumatology at the Louisiana State University Health Sciences Center, New Orleans.

Nkechinyere Emejuaiwe, MD, MPH, is a staff rheumatologist at the Cincinnati VA Medical Center, with an adjunct faculty appointment at the University of Cincinnati.