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 Table of Contents  
Year : 2015  |  Volume : 7  |  Issue : 9  |  Page : 379-383

Sarcoidosis and antiphospholipid syndrome: A systematic review of cases

1 Department of Internal Medicine, Reading Health System, Pennsylvania, USA
2 Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
3 Department of Internal Medicine, Rapid City Regional Hospital, Rapid City, South Dakota, USA
4 Department of Oral Medicine, College of Dental Sciences, Kathmandu, Nepal
5 Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA

Date of Web Publication29-Sep-2015

Correspondence Address:
Ranjan Pathak
Reading Health System, 6th Avenue and Spruce Street, West Reading, Pennsylvania - 19611
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1947-2714.166213

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Association between sarcoidosis and antiphospholipid syndrome (APS) is rare with few reported cases. We sought to systematically review the published cases of APS with sarcoidosis to better characterize the demographics, clinical characteristics, treatment, and the outcome of this association. Systematic electronic search for case report, case series, and related articles published until May 2014 was carried out and relevant data were extracted and analyzed. Four cases of APS with sarcoidosis were identified exclusively in females. These cases were seen in the sixth decade of life. Pulmonary embolism and central retinal artery occlusion were the presenting thrombotic events. All the patients were treated with lifelong anticoagulation with warfarin. During the median follow-up period of 5.5 months, additional thrombotic events were not observed. Although rare, sarcoidosis may be associated with APS. Further reporting of the cases will help to better establish this association, elucidate pathogenesis, and define clinical characteristics and outcomes.

Keywords: Antiphospholipid syndrome, association, sarcoidosis, systematic review

How to cite this article:
Pathak R, Khanal R, Aryal MR, Giri S, Karmacharya P, Pathak B, Acharya U, Bhatt VR. Sarcoidosis and antiphospholipid syndrome: A systematic review of cases. North Am J Med Sci 2015;7:379-83

How to cite this URL:
Pathak R, Khanal R, Aryal MR, Giri S, Karmacharya P, Pathak B, Acharya U, Bhatt VR. Sarcoidosis and antiphospholipid syndrome: A systematic review of cases. North Am J Med Sci [serial online] 2015 [cited 2023 Mar 22];7:379-83. Available from: https://www.najms.org/text.asp?2015/7/9/379/166213

  Introduction Top

Sarcoidosis is a systemic inflammatory disorder of unknown cause that is characterized by the granulomatous inflammation of various organs. [1] Antiphospholipid syndrome (APS) is an autoimmune condition defined by persistently positive antiphospholipid antibodies as well as recurrent arterial or venous thromboses and pregnancy complications. [2] Diagnosis of APS is made according to the revised Sapporo criteria, [3] which requires at least one clinical (vascular thrombosis or pregnancy morbidity) and one laboratory criteria (presence of lupus anticoagulant, presence of immunoglobulin G [IgG], and/or immunoglobulin [IgM] anticardiolipin antibody [>40 U/ml, or >99 th percentile], and/or presence of IgG and/or IgM anti-beta 2 glycoprotein antibody [>99 th percentile]). All antibodies must be demonstrated on two or more occasions separated by at least 12 weeks. Both APS and sarcoidosis have been known to occur with autoimmune conditions [4],[5] with genetic factors playing equally important roles. [6],[7] Even though studies have found an association between antiphospholipid antibodies and sarcoidosis, [8] cases with concurrent sarcoidosis and APS are rare. In order to expand the current understanding of this association, we carried out a systematic review of all the published cases.

  Search Strategy and Data Collection Top

We searched Medline (via PubMed) and Embase for case reports, case series, and related articles on the association between sarcoidosis and APS from inception to March 15, 2014. We used the search terms "antiphospholipid syndrome," "sarcoidosis," "pulmonary sarcoidosis," and "lung sarcoidosis" in addition to the medical subject heading terms "sarcoidosis" and "antiphospholipid syndrome." The search was limited to human subjects. We also performed hand search to identify additional publications. Eligibility criteria included the following requirements:

  1. Concurrent sarcoidosis (confirmed by biopsy) [9] and APS and
  2. The diagnosis of APS was confirmed according to the revised Sapporo criteria.

We excluded three cases with sarcoidosis, where APS was thought to be secondary to other causes such as systemic lupus erythematosus, [10] treatment with tumor necrosis factor inhibitor, or interferon alpha [Figure 1]. [11],[12] With this approach, we identified four eligible cases in English language. We studied their demographic variables, clinical presentation, treatment, and outcomes.
Figure 1: Systematic literature search and study selection process

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  Results Top

Demographic data and clinical presentation

All four cases included in the study met the revised Sapporo criteria and there were no obvious alternative causes for APS. Of the four cases of sarcoidosis with APS, all of them were females. The age ranged from 29 to 72 years, with a median (interquartile range) of 58 (50-62), and a mean of 54 years. Presenting thrombotic event varied from central retinal artery occlusion (n = 1) to pulmonary embolism (n = 1). Stroke was the most common arterial thrombosis (n = 2). A history of fetal loss was present in two cases. The duration of sarcoidosis was more than eight years in two cases and was not mentioned in the rest. APS was observed in early (n = 2) as well as late (n = 1) stages of sarcoidosis. Only one case had extra-thoracic involvement (ocular and skin sarcoidosis) [Table 1].
Table 1: Demographic characteristics, clinical presentation, diagnostic evaluation, treatment, and follow-up of identified patients with sarcoidosis and APS

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Laboratory investigation

Positive titers of anticardiolipin antibodies and anti-beta 2-glycoprotein antibodies were present in four and two cases, respectively. Lupus anticoagulant activity was positive in two cases and negative in the other two. Angiotensin converting enzyme (ACE) level was elevated in all the reported cases (n = 3, mean ACE level 95 U/L). Erythrocyte sedimentation rate was elevated in one reported case (50 mm/h).

Treatment and prognosis

Three cases with APS were treated with heparin acutely, followed by lifelong warfarin. Details of the treatment were not provided in one of the case. None of the cases reported further thrombotic events while on anticoagulation on follow-up (median duration 5.5 months).

  Discussion Top

Only four definite cases of APS and sarcoidosis have been reported in the literature. Both APS and sarcoidosis share immune dysregulation and autoimmunity, [4],[5] which might explain their co-occurrence.

In our study, an association of APS and sarcoidosis was exclusive to females, which is consistent with the female predominance of APS in general. [13],[14] The mean age of patients with APS in sarcoidosis was higher than the average age of patients with APS alone (54 years vs. 42 years [13] ). Although sarcoidosis is more common in the younger age group (20-40), [15] a second peak has been observed at about age 50, especially in women. [16] The higher mean age of APS in sarcoidosis may be due to the propensity of APS to develop in older sarcoidosis patients.

Common presenting thrombotic events were pulmonary embolism and central retinal artery occlusion. Interestingly, deep venous thrombosis, the most common thrombotic complication of APS in a large European cohort, [13] was not seen in the any of these patients. Stroke was the most common arterial thrombosis, which is consistent with the results of the European study. [13] Catastrophic APS, which is associated with more than 50% mortality, [4] has been found to be associated with various autoimmune disorders. [17] However, none of the patients in our review had the features of catastrophic APS.

As only one patient in our study had extra-thoracic involvement, we were unable to clearly elucidate the relationship between the levels of antiphospholipid antibody and the extent of extra-thoracic involvement, as previously suggested by Ina et al. [8] Ina et al. had also demonstrated a significant correlation between antiphospholipid antibody level and chest X-ray abnormality, thus linking antiphospholipid antibody as a prognostic marker for sarcoidosis. In our study, we observed APS with both the early and late stages of sarcoidosis. However, due to small number of cases, we could not study if APS can also help prognosticate sarcoidosis.

Three cases in our study were initially treated with heparin and then with lifelong warfarin to decrease the risk of future thrombotic events. After the first thrombotic event, lifelong warfarin is recommended to achieve an international normalized ratio ranging from 2.0 to 3.0. [18] The treatment of thrombotic complications of APS is generally the same regardless of whether it is primary APS or secondary APS. [4] Studies have previously looked at the efficacy of hydroxychloroquine in preventing thrombosis in systemic lupus erythematosus patients, but data remain elusive. [19] By extension of this analogy, it is uncertain if future thrombotic events can be prevented in patients with APS and sarcoidosis with the treatment of underlying sarcoidosis. Further studies are needed to shed more light in this regard.

Patients who survive the initial thrombotic event remain at risk for recurrent events which may be as high as 7%, even with anticoagulation. [20] The risk of developing recurrent thrombotic events increases with the presence of anti-beta 2-glycoprotein antibodies, autoimmune hemolysis, or the involvement of more than one vascular bed. [21] Although two of the cases had positive anti-beta 2-glycoprotein antibodies, none of our patients were reported to have recurrent episodes of thrombotic events.

Small sample size precluded the use of statistical tests to determine the relationship between antiphospholipid antibody levels and the stage/extent of disease.

  Conclusion Top

Although rare, APS associated with sarcoidosis may tend to occur in older age group than APS alone and may occur exclusively in females. It commonly presents with venous thrombotic events such as pulmonary embolism. Further reporting of cases will help to better define this association, determine if APS is a prognostic marker of sarcoidosis, and provide details on whether treating the underlying sarcoidosis may reduce the thrombotic risk in this subset of APS.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Fahim A, Mann JS. Pulmonary sarcoidosis: Diagnostic and treatment update. Expert Rev Respir Med 2014;8: 493-501.  Back to cited text no. 1
Comarmond C, Cacoub P. Antiphospholipid syndrome: From pathogenesis to novel immunomodulatory therapies. Autoimmun Rev 2013;12:752-7.  Back to cited text no. 2
Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: Report of an international workshop. Arthritis Rheum 1999;42:1309-11.  Back to cited text no. 3
Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet 2010;376:1498-509.  Back to cited text no. 4
Sharma OP. Sarcoidosis and other autoimmune disorders. Curr Opin Pulm Med 2002;8:452-6.  Back to cited text no. 5
Biggioggero M, Meroni PL. The geoepidemiology of the antiphospholipid antibody syndrome. Autoimmun Rev 2010;9:A299-304.  Back to cited text no. 6
Morgenthau AS, Iannuzzi MC. Recent advances in sarcoidosis. Chest 2011;139:174-82.  Back to cited text no. 7
Ina Y, Takada K, Yamamoto M, Sato T, Ito S, Sato S. Antiphospholipid antibodies. A prognostic factor in sarcoidosis? Chest 1994;105:1179-83.  Back to cited text no. 8
Heinle R, Chang C. Diagnostic criteria for sarcoidosis. Autoimmun Rev 2014;13:383-7.  Back to cited text no. 9
Wesemann DR, Costenbader KH, Coblyn JS. Co-existing sarcoidosis, systemic lupus erythematosus and the antiphospholipid antibody syndrome: Case reports and discussion from the Brigham and Women's Hospital Lupus Center. Lupus 2009;18:202-5.  Back to cited text no. 10
Shinohara MM, Davis C, Olerud J. Concurrent antiphospholipid syndrome and cutaneous [corrected] sarcoidosis due to interferon alfa and ribavirin treatment for hepatitis C. J Drugs Dermatol 2009;8:870-2.  Back to cited text no. 11
Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med 2001;135:27-31.  Back to cited text no. 12
Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019-27.  Back to cited text no. 13
Bertero MT, Bazzan M, Carignola R, Montaruli B, Silvestro E, Sciascia S, et al. Antiphospholipid syndrome in northwest Italy (APS Piedmont Cohort): Demographic features, risk factors, clinical and laboratory profile. Lupus 2012;21:806-9.  Back to cited text no. 14
O'Regan A, Berman JS. Sarcoidosis. Ann Intern Med 2012;156:ITC5-1-16.  Back to cited text no. 15
Hillerdal G, Nöu E, Osterman K, Schmekel B. Sarcoidosis: Epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis 1984;130:29-32.  Back to cited text no. 16
Nayer A, Ortega LM. Catastrophic antiphospholipid syndrome: A clinical review. J Nephropathol 2014;3:9-17.  Back to cited text no. 17
Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, Brey R, Crowther M, Derksen R, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: Report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 2011;20: 206-18.  Back to cited text no. 18
Barbhaiya M, Erkan D. Primary thrombosis prophylaxis in antiphospholipid antibody-positive patients: Where do we stand? Curr Rheumatol Rep 2011;13:59-69.  Back to cited text no. 19
Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003;349:1133-8.  Back to cited text no. 20
Tektonidou MG, Ioannidis JP, Boki KA, Vlachoyiannopoulos PG, Moutsopoulos HM. Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome. QJM 2000;93:523-30.  Back to cited text no. 21


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