Pulmonary manifestations in late versus early systemic lupus erythematosus: A systematic review and meta-analysis

https://doi.org/10.1016/j.semarthrit.2018.01.010Get rights and content

Abstract

Objectives

Phenotypes differ between late- and early-onset systemic lupus erythematosus (SLE). Prior studies suggested that there may be more pulmonary disease among late-onset patients. Our objective was to perform a systematic review and meta-analysis to evaluate the differences in pulmonary manifestations in late- versus early-onset SLE.

Methods

We searched the literature using PubMed, CINAHL, Web of Science, Cochrane Library, and EMBASE. We excluded studies that did not include American College of Rheumatology SLE classification criteria, an early-onset SLE comparison group, or those that defined late-onset SLE as <50 years of age. We rated study quality using the Newcastle–Ottawa Quality Scale. We used Forest plots to compare odds ratios (95% confidence intervals) of pulmonary manifestations by age. Study heterogeneity was assessed using I2.

Results

Thirty-nine studies, representing 10,963 early-onset and 1656 late-onset patients with SLE, met eligibility criteria. The odds of developing several pulmonary manifestations were higher in the late-onset group. Interstitial lung disease (ILD) was nearly three times more common (OR = 2.56 (1.27, 5.16)). Pleuritis (OR = 1.53 (1.19, 1.96)) and serositis (OR = 1.31 (1.05, 1.65)) were also more common in the late-onset group. The mean Newcastle–Ottawa Quality Scale score for study quality was moderate (6.3 ± 0.7, scale 0–9).

Conclusions

Pulmonary manifestations of SLE were more common in late-onset SLE patients compared to their younger peers, in particular ILD and serositis. Age-related changes of the immune system, tobacco exposure, race, and possible overlap with Sjögren’s syndrome should be examined in future studies.

Introduction

Systemic lupus erythematosus (SLE) is a pleomorphic autoimmune disease that often begins in early life. Presentation ranges from rashes and arthralgia to life-threatening lung and kidney involvement. Late-onset SLE is a distinct classification that begins in patients ≥50 years old. Prior meta-analyses report significant differences in the clinical manifestations between late- and early-onset SLE patients, including fewer cutaneous manifestations and more sicca symptoms [1], [2]. A recent meta-analysis demonstrated increased pulmonary manifestations in adult-onset lupus patients compared to childhood-onset patients, suggesting a higher risk with increasing age [3]. Late-onset lupus patients were not included in this study, however. Other studies have suggested increased pulmonary involvement in late-onset patients as well [4], but conclusions have been limited by sample size. In the multiethnic prospective LUMINA cohort (n = 626), age was an independent risk factor for development of pulmonary damage in patients with SLE [5].

Moreover, in non-lupus populations, lung fibrosis increases with advanced age, raising our interest in examining these relationships in lupus [6]. Pulmonary involvement is common in SLE, and pulmonary features are the presenting symptom in 5% of patients [7]. The most common pulmonary manifestation, pleuritis, occurs in up to 50% of all lupus patients. Chronic interstitial lung disease (ILD) occurs in up to 13% of lupus patients, typically later in the disease course [8]. Other pulmonary manifestations of SLE including acute pneumonitis, diffuse alveolar hemorrhage, pulmonary hypertension, shrinking lung syndrome, and pulmonary embolism are less common and often difficult to classify independently from antiphospholipid antibody syndrome or medication complications [8]. Although some studies have suggested more pulmonary disease in the late-onset group [4], [9], we found no large dedicated meta-analysis that quantified the relative odds of lung involvement in late- versus early-onset SLE. Such information could have important implications for the diagnosis, screening, and prognosis in older adults with SLE.

We aimed to conduct a systematic review and meta-analysis to compare the odds of pulmonary involvement, including serositis, pleuritis, ILD, pulmonary embolism (PE), and pulmonary hypertension in late- versus early-onset lupus patients.

Section snippets

Literature search inclusion criteria

We performed a systematic review of the literature to identify articles comparing clinical manifestations of patients with late- versus early-onset lupus as described in our previous work [2]. We included the studies used in our prior meta-analysis that had data on pulmonary manifestations. Additionally we performed an electronic search of the literature in PubMed, CINAHL, and EMBASE using keyword subject headings “late-onset systemic lupus erythematosus” then “systemic lupus erythematosus,”

Results

The PubMed, CINAHL, and EMBASE literature search for our meta-analysis yielded 1568 potential articles of which 97 articles merited full-text review for application of exclusion criteria. Ultimately, we included 39 studies in this meta-analysis, encompassing 35 cohort and 4 case–control studies (see Fig. 1).

See Table 1 listing the 39 studies included in the systematic review and meta-analysis [4], [9], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]

Discussion

Results of our meta-analysis indicate that late-onset SLE patients are more likely than early-onset patients to develop pulmonary manifestations. Older-onset SLE patients had a nearly three-fold increased odds of ILD, similar to age trends in idiopathic ILD. Overall, findings were consistent with prior SLE cohort studies [4], [9], [21] and a prior 1989 meta-analysis [1] which included 170 late-onset cases compared with our 1645 late-onset cases. It is known that idiopathic ILD is strongly

Conclusions

Our pooled analysis demonstrates increased odds of pulmonary manifestations, especially ILD, in late-onset SLE patients compared to their younger peers. Factors that likely contribute to this discovery are increased age, tobacco exposure, immune senescence, and the potential role of an SLE-SS overlap disease phenotype in older patients. Clinicians should recognize that late-onset patients are more likely to have ILD, and screen for the condition when appropriate. Future studies should

Acknowledgments

Authors would like to thank Sara Fitz, MD for help with original study selection, and Natalie Wietfeldt, Zaher Karp, Aimée Wattiaux, and Amanda Perez for help with manuscript preparation.

References (54)

  • J. Boddaert

    Late-onset systemic lupus erythematosus: a personal series of 47 patients and pooled analysis of 714 cases in the literature

    Medicine

    (2004)
  • Wells GA, et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses....
  • M.D. Alonso

    Late-onset systemic lupus erythematosus in Northwestern Spain: differences with early-onset systemic lupus erythematosus and literature review

    Lupus

    (2012)
  • J. Antolin

    Systemic lupus erythematosus: clinical manifestations and immunological parameters in 194 patients. Subgroup classification of SLE

    Clin Rheumatol

    (1995)
  • S. Appenzeller et al.

    Greater accrual damage in late-onset systemic lupus erythematosus: a long-term follow-up study

    Lupus

    (2008)
  • S. Cartella

    Evaluation of mortality, disease activity, treatment, clinical and immunological features of adult and late onset systemic Lupus erythematosus

    Autoimmunity

    (2013)
  • R. Cervera

    Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients

    Medicine

    (1993)
  • J. Choi

    Comparison of clinical and serological differences among juvenile- adult- and late-onset systemic lupus erythematosus in Korean patients

    Lupus

    (2015)
  • G.S. Cooper

    Differences by race, sex and age in the clinical and immunologic features of recently diagnosed systemic lupus erythematosus patients in the southeastern United States

    Lupus

    (2002)
  • L.T. Costallat et al.

    Systemic lupus erythematosus: clinical and laboratory aspects related to age at disease onset

    Clin Exp Rheumatol

    (1994)
  • M. das Chagas Medeiros

    Clinical and immunological aspects and outcome of a Brazilian cohort of 414 patients with systemic lupus erythematosus (SLE): comparison between childhood-onset, adult-onset, and late-onset SLE

    Lupus

    (2015)
  • J. Dimant

    Systemic lupus erythematosus in the older age group: computer analysis

    J Am Geriatr Soc

    (1979)
  • I. Domenech

    Systemic lupus erythematosus in 50 year olds

    Postgrad Med J

    (1992)
  • J.B. Feng

    Gender and age influence on clinical and laboratory features in Chinese patients with systemic lupus erythematosus: 1,790 cases

    Rheumatol Int

    (2010)
  • J. Font

    Systemic lupus erythematosus: a clinical and immunological study of 300 patients

    Med Clin (Barc)

    (1993)
  • J. Gomez

    Systemic lupus erythematosus in Asturias, Spain: clinical and serologic features

    Medicine

    (2006)
  • H. Hashimoto

    Differences in clinical and immunological findings of systemic lupus erythematosus related to age

    J Rheumatol

    (1987)
  • Cited by (34)

    • Systemic Lupus Erythematosus

      2022, Clinical Immunology: Principles and Practice, Sixth Edition
    • Lung involvement in SLE

      2022, Handbook of Systemic Autoimmune Diseases
      Citation Excerpt :

      Results of a recent systematic review of the literature and meta-analysis indicated that late-onset SLE patients, defined as ≥50 years of age, are more likely than early-onset patients to develop pulmonary manifestations. In fact, older-onset SLE patients had a nearly threefold increased odds of ILD, similar to age trends in idiopathic ILD [13]. From the clinical point of view, SLE patients with ILD may present with chest pain, nonproductive cough, and dyspnea resulting in decreased exercise tolerance.

    View all citing articles on Scopus

    Funding: Bartels received K23 time support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number AR062381 during this project. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Bartels currently receives unrelated institutional grant funding from Independent Grants for Learning and Change (Pfizer). All other authors have no direct financial, consultant, or institutional conflict of interest pertaining to this manuscript.

    View full text