Biomarkers Linking SLE-Associated Pulmonary Arterial Hypertension

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The findings identified 2 antibodies as risk factors for SLE-associated PAH: the anti-RNP antibody and the anti-Sm antibody.
The findings identified 2 antibodies as risk factors for SLE-associated PAH: the anti-RNP antibody and the anti-Sm antibody.

Although the risk for death associated with systemic lupus erythematosus (SLE) has improved substantially in the last 50 years as diagnostic and treatment strategies have advanced, it remains significantly higher among patients with SLE-associated pulmonary arterial hypertension (PAH) compared with the general SLE population (pooled 5-year survival: 68% vs 94.8%, respectively).1 PAH has been found to independently predict mortality risk in patients with SLE (hazard ratio [HR], 3.10; 95% CI, 1.10-8.69; P =.032), which may be improved through prompt detection and treatment.2

"However, early recognition is difficult because PAH is often silent and patients may not exhibit specific cardiopulmonary symptoms until they are already in the advanced stages," wrote the authors of a recent systematic review and meta-analysis published in Lupus.3 "In addition, the development of PAH and its severity does not correlate with SLE disease activity or the duration of SLE, which often causes it to be missed by clinicians."

These factors underscore the need for reliable biomarkers for early detection or prediction of PAH. SLE-associated PAH showed a moderate response to immunosuppressive therapy in previous research, suggesting the condition could be a result of pulmonary vasculitis, which may have associated clinical biomarkers such as antibodies.4,5 Other findings demonstrate a link between several antibodies and PAH in SLE, although such results have been mixed overall.

For the new meta-analysis, researchers at Peking Union Medical College and Chinese Academy of Medical Science aimed to clarify potential serological biomarkers for SLE-associated PAH by comparing patients with SLE with and without PAH. They searched several databases for relevant studies with publication dates ranging from 1967 to 2016, and they obtained additional, unpublished information through correspondence with the study authors.

After excluding studies with duplicate data and those that did not meet all inclusion criteria, the final analysis consisted of 12 observational studies, most of which focused on Asian patients. No significant differences were observed based on sex, pulmonary artery systolic pressure (PASP), or average age.

The findings identified 2 antibodies as risk factors for SLE-associated PAH: the anti-RNP antibody (pooled odds ratio [OR], 3.68; 95% CI, 2.04-6.63; P <.0001) and the anti-Sm antibody (pooled OR, 1.71; 95% CI, 1.06-2.76, P =.03). The analysis further revealed heterogeneity of anti-RNP and anti-Sm antibodies (I2=81% and 57%, respectively), which could be a result of the use of different diagnostic criteria for SLE, varying approaches to confirming PAH, and the range of etiologies from which PAH may arise. The heterogeneity was not found to be related to publication bias, small sample size, or variations in study type or quality, ethnic backgrounds, or disease duration and severity.

Anti-dsDNA, anti-SSA, and anti-SSB antibodies failed to reach statistical significance as potential biomarkers. Although there were too few studies to allow for meta-analysis of additional markers, other research suggests serum uric acid, interleukin 6, and anti-endothelin receptor type A antibodies may also be indicators of PAH in patients with SLE.6,7

In a 2015 study, for example, anti-endothelin receptor type A antibodies more commonly occurred in patients with SLE with PAH compared with those without PAH (41.5% vs 17.1%).8 Those researchers also noted that those antibody titers were significantly correlated with the pulmonary artery systolic pressure.

The main findings of the current meta-analysis are consistent with the clinical observations of Michael D. Lockshin, MD, a rheumatologist at the Hospital for Special Surgery in New York City and the director of the Barbara Volcker Center for Women and Rheumatic Disease at the Hospital for Special Surgery. "According to the paper, and my experience, anti-RNP antibody is the best predictor, though only a few patients with this antibody develop pulmonary artery hypertension," he told Infectious Disease Advisor. In his experience, other predictors include severe, long-standing Raynaud's phenomenon; absence of kidney disease; and possibly Asian heritage.

According to Dr Lockshin, it is advisable to monitor patients, especially those who have the noted characteristics, using transthoracic echocardiograms with a special focus on pulmonary artery pressure every 2-3 years. "The test is painless and easy to perform. Suspicious findings will lead to a somewhat more invasive test, a trans-esophageal echocardiogram, which consists of swallowing a small device to examine the heart from the esophagus' side," he explained. If PAH is detected, the appropriate treatment strategy will depend on each patient's specific characteristics and severity of hypertension.

More studies focused on predictors, treatment, and mechanisms of PAH are warranted. "Other than recognizing those patients at highest risk, we don't have a good way to predict exactly who will develop pulmonary hypertension, so there is a need to identify even better predictors so that we can prevent this complication," said Dr Lockshin.

Future research should also explore ways to repair advanced disease other than by heart-lung transplant. "Finally, we don't know why Raynaud's, anti-RNP antibody, and Asian race are markers. If we knew, we might know more about the why and how of the complication, so that is one more thing to research."

References

  1. Qian J, Wang Y, Huang C, et al. Survival and prognostic factors of systemic lupus erythematosus-associated pulmonary arterial hypertension: a PRISMA-compliant systematic review and meta-analysis. Autoimmun Rev. 2016;15:250-257. doi: 10.1016/j.autrev.2015.11.012
  2. Min HK, Lee JH, Jung SM, et al. Pulmonary hypertension in systemic lupus erythematosus: an independent predictor of patient survival. Korean J Intern Med. 2015; 30:232-241. doi: 10.3904/kjim.2015.30.2.232
  3. Wang J, Qian J, Wang Y, et al. Serological biomarkers as risk factors of SLE-associated pulmonary arterial hypertension: a systematic review and meta-analysis [published online April 14, 2017]. Lupus. doi: 10.1177/0961203317702255
  4. Tanaka E, Harigai M, Tanaka M, Kawaguchi Y, Kamatani N.. Pulmonary hypertension in systemic lupus erythematosus: evaluation of clinical characteristics and response to immunosuppressive treatment. J Rheumatol. 2002;29:282-287.
  5. Huang C, Zhang S, Tian Z, Li M, Zeng X. Could pulmonary arterial hypertension be an active index of systemic lupus erythematosus? A successful case of SLE–PAH cured by methylprednisolone pulse therapy. Lupus. 2014;23:1533-1536. doi: 10.1177/0961203314552461
  6. Dimitroulas T, Giannakoulas G, Dimitroula H, et al. Significance of serum uric acid in pulmonary hypertension due to systemic sclerosis: a pilot study. Rheumatol Int. 2011;31:263-267. doi: 10.1007/s00296-010-1557-4
  7. Steiner MK, Syrkina OL, Kolliputi N, et al. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res. 2009;104:236-244. doi: 10.1161/CIRCRESAHA.108.182014
  8. Guo L, Li M, Chen Y, et al. Anti-endothelin receptor type A autoantibodies in systemic lupus erythematosus-associated pulmonary arterial hypertension. Arthritis Rheumatol. 2015;67:2394-2402. doi: 10.1002/art.39212
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