Introduction

Shrinking lung syndrome (SLS) is a rare complication mainly associated with SLE, however it was also reported in patients with other connective tissue diseases (CTDs), including Sjögren syndrome, systemic sclerosis, rheumatoid arthritis and undifferentiated connective tissue disease ⁽¹⁾. It is characterized by its low prevalence, estimated between 0.5% and 1.1% in the general lupus population ^{(2, 3)}. However, a study by Deeb et al., ⁽⁴⁾ involved 1439 SLE patients and reported a prevalence of 1.5%. A much higher incidence was reported by Gheita et al.,⁽⁵⁾, as SLS was present in 8 patients (17.02%) out of 47 SLE patients complaining of dyspnea. SLS was considered in those with exertional dyspnea, restrictive pulmonary function tests (PFTs) and elevated copula of the diaphragm. Casey et al., ⁽⁶⁾ recorded 10 (4.44%) cases with SLS out of 225 SLE patients. It may complicate SLE at any time over its course, ranging from as early as 1 month to 35 years after disease onset. Although it is much more frequent in advanced stages of the disease, rarely, SLS may be the presenting manifestation of SLE ^{( 7, 8, 9)}.

This complication is more common in SLE patients of female sex, with a female-to-male ratio of 17:1. The major symptom of SLS is progressive exertional dyspnea of variable severity, accompanied by pleuritic chest pain in three quarters of patients. This complication usually occurs in patients without previous or concomitant major organ involvement other than SLS, and, in more than half of the patients, in inactive stages of the disease, according to SELENA-SLEDAI scores ⁽¹⁰⁾.

Case presentation

We are presenting a case of a 25-years-old SLE female patient presented with erythematous photosensitive skin rash, oral ulcers, polyarthritis, anemia, lymphopenia, Positive antinuclear and anti-double stranded DNA antibodies. She was diagnosed with SLE and treated with corticosteroids, hydroxyl-chloroquine and azathioprine, but she was not compliant on her treatment. 2 years after lupus diagnosis, she presented to our rheumatology clinic with progressive shortness of breath of 4 months duration. At time of admission the patient was vitally stable, dyspneic at rest, with decreased air entry at lung bases, malar rash, oral ulcers and polyarthritis of hand and wrist joints bilaterally. Her laboratory work showed: normocytic, normochromic anemia, normal white cell count (5.8), normal platelets, elevated erythrocyte sedimentation rate (40 mm/hr), normal liver and renal function, normal CPK, positive antinuclear antibody (ANA) titer of 1 : 80 (homogenous), and a highly positive double-stranded DNA titer (> 200), mild albuminuria in simple urine, normal C3 and C4 levels and negative antiphospholipid antibodies. Chest radiography (CXR) showed elevated copula of diaphragm and markedly decreased lung volumes (Fig. 1a), however high-resolution chest computed tomography (HRCT) showed normal parenchyma. She was found to have restricted PFTs (forced expiratory volume 1(FEV1) 39%, forced vital capacity (FVC) 40%; total lung capacity (TLC) 40%) and normal carbon monoxide diffusion capacity (DLCO) denoting extra-pulmonary cause (table 1). When repeating PFT in supine position there was further decrease in FVC by 25%. According to these findings, she was diagnosed as SLS which was confirmed by decreased diaphragmatic excursion by M-mode ultrasound. Treatment was started with prednisolone 60mg/day, azathioprine (100 mg/day) and hydroxychloroquine (200 mg twice daily) for 2 weeks. Unfortunately, her dyspnea progressed and PFT showed deterioration (FEV1 31%, FVC 30%; TLC 30%) (table 1). So, the next decision was to start Rituximab 1 gm twice, 15 days apart which showed dramatic improvement in dyspnea after 1 week of the first cycle. Steroid was gradually tapered with improvement of pulmonary symptoms, function test and CXR showed less elevation of the diaphragm (Fig. 1b).

Discussion

An important diagnostic delay is observed in the clinical practice, indicating that SLS is still an under-recognized pulmonary complication of SLE. Patients should be considered to have an

SLS if they have: a compatible clinical picture (progressive exertional dyspnea of variable severity with or without pleuritic chest pain); lung volume reduction and restrictive ventilatory defect in PFT; and no evidence of parenchymal lung disease or vascular pathology on imaging (chest x-ray and thoracic high-resolution computed tomography [HRCT]) findings ⁽¹⁾.

Despite its rarity, SLS should be considered in the differential diagnosis of lupus patients with dyspnea and/or pleuritic chest pain. In many ways, it represents a diagnosis of exclusion. In this sense, the recommended first-line procedures for diagnosis should include chest x-ray and thoracic HRCT, along with pulmonary and diaphragmatic function tests. The most distinctive findings of this entity were elevated unilateral or bilateral hemi diaphragms with reduced lung volumes, a restrictive ventilatory defect in PFT with reduced TLC and DLCO in absence of parenchymal lung disease or vascular pathology on imaging techniques ⁽¹¹⁾.

Historically, Gibson et al.,,⁽¹²⁾ measured trans-diaphragmatic pressure in those patients with SLS and found extra pulmonary volume restriction and inability of the diaphragm to generate normal pressure. The weakness of inspiratory and expiratory muscles could contribute to the cause of this syndrome. Controversially, other authors have found normal diaphragmatic strength in 12 patients with SLS, suggesting that a primary disorder of this muscle is an unlikely explanation. Phrenic neuropathy, pleural inflammation, adhesions and pain may also play a role in the pathogenesis of SLS ⁽⁸⁾.

The evaluation of diaphragm dome motion by M-mode ultrasonography or dynamic contrast-enhanced lung MRI might be a useful second-line tool to reinforce clinical suspicion in cases of diagnostic difficulty. On the contrary, the diagnostic usefulness of the electromyography seems poor ^{(11, 13)}.

There are no standardized guidelines for the treatment of SLS in SLE. According to the available experience, the majority of patients should be initially treated with medium or high doses of glucocorticoids ⁽¹⁰⁾.

An immunosuppressive agent in conjunction with steroids should be used if the patient fails to improve, and it is advisable from the beginning of the treatment in patients with severe clinical and functional decline, but there

are no randomized controlled trials to provide data concerning their efficacy. The most widely used drugs were azathioprine and cyclophosphamide, with variable success ⁽¹⁰⁾. Further, RTX was used in severe or refractory SLS (9 patients), with effectiveness and good safety profile in all cases ^{(14, 15)}. Based on this preliminary experience, RTX might emerge as the first-choice immunosuppressant, particu-larly in patients with severe or refractory disease, although larger-cohort studies must be performed in this field to confirm the efficacy of RTX in SLS. Theophylline and beta-agonists, alone or in combination with glucocorticoids, have also been suggested with the intent to increase diaphragmatic strength, but evidence of beneficial effects is lacking ⁽¹⁵⁾. Recently, one case report showed good response to belimumab ⁽¹⁶⁾.

Information about the duration of applied treatment, particularly with respect to glucocorticoid regimen and tapering, was not specified in the revised articles. In addition, the dose and duration of corticosteroids required for controlling SLS have never been tested in a randomized trial design. So it must be individualized based on the clinical response and evolution of pulmonary and diaphragmatic function tests, but taking also into account the recommendations for a more rational prescription of glucocorticoids ^{(17, 18)}.

The overall response to treatment is positive. The great majority of patients had significant clinical improvement and stabilization, or mild to moderate improvement on PFT. Despite the persistence of a chronic restrictive defect in most of these patients, none required chronic home oxygen therapy, and death because of respiratory failure or associated complications was extremely rare, indicating a low-grade defect ⁽¹¹⁾.