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Pleuritis and Pericarditis in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis

      Background

      Pleural and pericardial involvements are well recognized in eosinophilic granulomatosis with polyangiitis (EGPA) but considered rare manifestations of the other forms of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV).

      Research Question

      What are the frequency and clinical characteristics of pleuritis and pericarditis in AAV?

      Study Design

      and Methods: Using an institutional database of 1,830 patients with AAV, we analyzed clinical notes and diagnosis codes for key words related to pleuritis and pericarditis. Chart review to confirm these findings was performed.

      Results

      Eighty-eight of 1,058 patients (8.3%) with granulomatosis with polyangiitis (GPA), 27 of 267 (10.1%) with microscopic polyangiitis (MPA), and 35 of 201 (17.4%) with EGPA had a manifestation of pleuritis and/or pericarditis attributable to vasculitis. There was a higher frequency of pericarditis in EGPA compared with that in the other AAVs (P < .01). There was no difference in the frequency of pleuritis in GPA, MPA, or EGPA. In the 156 patients with AAV with pleuritis and/or pericarditis, this was a presenting feature in 127 (81.4%). Overall, it was a presenting feature in 6.9% of all patients with AAV, including 6.5% with GPA, 8.6% with MPA, and 15.9% with EGPA.

      Interpretation

      Pleuritis and pericarditis occur across all the AAVs and, when present, are commonly presenting features of these diseases. Patients with EGPA have a higher proportion of pericardial involvement compared with pleural involvement, whereas this distribution is more equal in patients with GPA and MPA. Pleuritis and pericarditis are underrecognized features of AAV. All forms of AAV should be considered in the differential diagnosis when evaluating a patient with pleuritis or pericarditis.

      Key Words

      Abbreviations:

      AAV (ANCA-associated vasculitis), ANCA (antineutrophil cytoplasmic antibody), BVAS/WG (Birmingham Vasculitis Activity Score for Wegener granulomatosis), EGPA (eosinophilic granulomatosis with polyangiitis), GPA (granulomatosis with polyangiitis), MPA (microscopic polyangiitis)
      Study Question: What are the frequency and clinical characteristics of pleuritis and pericarditis in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV)?
      Results: Pleuritis and pericarditis occur across all the AAVs and, when present, are commonly presenting features of these diseases. Patients with eosinophilic granulomatosis with polyangiitis have a higher proportion of pericardial involvement compared with pleural involvement, whereas this distribution is more equal in patients with granulomatosis with polyangiitis and microscopic polyangiitis.
      Interpretation: All forms of AAV should be considered in the differential diagnosis when evaluating a patient with pleuritis or pericarditis.
      Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) syndromes include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). They are rare small-vessel vasculitides involving multiple organs.
      • Jennette J.C.
      • Falk R.J.
      • Bacon P.A.
      • et al.
      2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.
      Without treatment, the clinical course of AAV can be fatal, but effective immunosuppressive therapy can induce remission in most patients with AAV.
      • Stone J.H.
      • Merkel P.A.
      • Spiera R.
      • et al.
      Rituximab versus cyclophosphamide for ANCA-associated vasculitis.
      ,
      • Unizony S.
      • Villarreal M.
      • Miloslavsky E.M.
      • et al.
      Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type.
      Depending on how quickly therapy can be initiated, patients may experience clinically significant organ damage from the disease. The variability in clinical manifestations of the AAV syndromes makes the diagnosis difficult. Familiarity with the possible manifestations of these disease processes can aid in a timely diagnosis and identification of relapse so that treatment can be started as early as possible to minimize end-organ damage.
      Pleural and pericardial involvement is well recognized in EGPA.
      • Guillevin L.
      • Cohen P.
      • Gayraud M.
      • Lhote F.
      • Jarrousse B.
      • Casassus P.
      Churg-Strauss syndrome: clinical study and long-term follow-up of 96 patients.
      ,
      • Sable-Fourtassou R.
      • Cohen P.
      • Mahr A.
      • et al.
      Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome.
      In contrast, pleuritis and pericarditis are considered rare manifestations of GPA and MPA. Multiple case reports of pleuritis or pericarditis occurring in MPA and GPA have emerged,
      • Dewan R.
      • Trejo Bittar H.E.
      • Lacomis J.
      • Ocak I.
      Granulomatosis with polyangiitis presenting with coronary artery and pericardial involvement.
      • Diot E.
      • Lavigne C.
      • Renjard L.
      • et al.
      Wegener's disease mimicking acute infectious pleurisy [in French].
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      • Henriksen P.A.
      • Amft E.N.
      Granulomatosis with polyangiitis and constrictive pericarditis: a case report.
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      • Ohnishi H.
      • Fujii M.
      • Yumura M.
      • Yoshimura S.
      • Kinami S.
      Microscopic polyangiitis presented with biopsy-confirmed pleuritis.
      • Koyama S.
      • Murakami K.
      • Sakakibara T.
      • et al.
      Massive pleural effusion and bronchopleural fistula in Wegener's granulomatosis.
      • Miyawaki M.
      • Oda S.
      • Hirata K.
      • et al.
      Granulomatosis with polyangiitis can cause periaortitis and pericarditis.
      suggesting these manifestations may not be uncommon in GPA and MPA. Data on the presence of these manifestations across all AAV phenotypes is limited because previous studies were based on a small number of subjects.
      • Agard C.
      • Mouthon L.
      • Mahr A.
      • Guillevin L.
      Microscopic polyangiitis and polyarteritis nodosa: how and when do they start?.
      • Guillevin L.
      • Durand-Gasselin B.
      • Cevallos R.
      • et al.
      Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients.
      • Hoffman G.S.
      • Kerr G.S.
      • Leavitt R.Y.
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      • Oliveira G.H.
      • Seward J.B.
      • Tsang T.S.
      • Specks U.
      Echocardiographic findings in patients with Wegener granulomatosis.
      The current study aims to determine the frequency and clinical characteristics of pleuritis and pericarditis in a large cohort of patients with AAV.

      Materials and Methods

       Study Population

      A database of patients with AAV evaluated at a single referral institution from January 1996 to November 2015 was created. Two complementary search strategies were applied: a prospectively collected clinical database of patients with AAV who were consecutively evaluated and a search of the electronic medical record by using terms and diagnosis codes related to AAV. The Mayo Clinic Life Sciences System and Data Discovery and Query Builder was used to identify patients from January 1996 through November 2015 who had query terms and International Classification of Diseases, Ninth Revision codes related to AAV. A total of 1,953 potential patients with AAV were identified through a search of the electronic medical record for terms related to AAV, as well as from a prospectively collected clinical database. Of these, 32 patients were excluded owing to a lack of consent for research, and 91 were eliminated after chart review because the diagnosis was not consistent with the Chapel Hill Consensus Conference 2012 definition of GPA, MPA, or EGPA.
      • Jennette J.C.
      • Falk R.J.
      • Bacon P.A.
      • et al.
      2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.
      A total of 1,830 patients with confirmed AAV seen between January 1996 and November 2015 were included in the institutional database. This database of patients with AAV was then searched to identify clinical notes and diagnosis codes with the following key words: pleuritis, pleurisy, pleural, effusion, pericarditis, thoracentesis, and pericardiocentesis. Direct chart review to confirm these findings was performed. This study was approved by the institutional review board (17-006608). Need for informed consent was waived. Each patient included in the study had consented for their medical record to be used for research.

       Definitions

      Pleuritis was defined as identification of pathologic inflammation at pleural biopsy or a pleural effusion seen at chest radiography or CT scanning of the chest. Pericarditis was defined as pericardial inflammation diagnosed by a physician on the basis of consistent clinical features or a pericardial effusion identified at echocardiography or CT scanning of the chest. Other potential causes of pleuritis and pericarditis, including heart failure, malignancy, and infection, were sought; if found, these patients were excluded. Presenting feature was defined as being present at the time of, or before, diagnosis. Clinically relevant was defined as causing symptoms and/or requiring treatment. Severe disease was defined as disease that threatens the function of an organ, leading to potentially irreversible organ damage or life-threatening complications. Disease manifestations that would qualify a patient as having severe disease include scleritis, nervous system involvement, alveolar hemorrhage, GI involvement, heart involvement, and glomerulonephritis.
      • Jennette J.C.
      • Falk R.J.
      • Andrassy K.
      • et al.
      Nomenclature of systemic vasculitides: proposal of an international consensus conference.
      The Birmingham Vasculitis Activity Score for Wegener granulomatosis (BVAS/WG) instrument was used to quantify disease activity at the time of pleuritis and/or pericarditis presentation.
      • Stone J.H.
      • Hoffman G.S.
      • Merkel P.A.
      • et al.
      A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score—International Network for the Study of the Systemic Vasculitides (INSSYS).
      Unspecified AAV indicated a diagnosis of AAV established by serologic, clinical, and/or renal or skin biopsy support without further characterization because of limited follow-up.

       Statistical Analysis

      Categorical variables are reported as percentages. Continuous variables are reported as mean with SD if normally distributed and median with interquartile range if not normally distributed. χ2 and Kruskal-Wallis tests were used for comparisons between groups. A P value less than .05 was considered statistically significant. To represent the degree of difference and determine which group or groups accounted for the statistical significance, we reported 95% CIs for proportions where applicable. Analyses were performed using JMP, version 14 (SAS Institute). To explore the associations of pleuritis and pericarditis with disease phenotypes further, we also performed multiple correspondence analysis and hierarchical clustering on principal components. Analyses were performed in R (R project for Statistical Computing) by using the FactoMineR and Factoshiny software packages (e-Appendix 1).

      Results

       Demographic Characteristics

      Of the 1,830 patients with AAV in the database, 156 (8.5%) were identified through search of the medical records as having a manifestation of pleuritis and/or pericarditis attributable to vasculitis (Fig 1). Demographic characteristics of this cohort were consistent with previously reported demographic characteristics of patients with AAV, including the association of ANCA type with disease phenotype (Table 1, e-Fig 1, e-Tables 1, 2).
      • Stone J.H.
      • Merkel P.A.
      • Spiera R.
      • et al.
      Rituximab versus cyclophosphamide for ANCA-associated vasculitis.
      • Unizony S.
      • Villarreal M.
      • Miloslavsky E.M.
      • et al.
      Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type.
      • Guillevin L.
      • Cohen P.
      • Gayraud M.
      • Lhote F.
      • Jarrousse B.
      • Casassus P.
      Churg-Strauss syndrome: clinical study and long-term follow-up of 96 patients.
      ,
      • Guillevin L.
      • Durand-Gasselin B.
      • Cevallos R.
      • et al.
      Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients.
      ,
      • Hoffman G.S.
      • Kerr G.S.
      • Leavitt R.Y.
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      ,
      • Samson M.
      • Puechal X.
      • Devilliers H.
      • et al.
      Long-term outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) enrolled in two prospective trials.
      ,
      • Walsh M.
      • Merkel P.A.
      • Peh C.A.
      • et al.
      Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis.
      The median follow-up after pleuritis or pericarditis manifestations was 5 years. Thirty-one patients (19.9%) had less than 1 year of follow-up after pleuritis or pericarditis manifestations. Two of these patients died of pleuritis or pericarditis manifestation within the year, with neither death attributable to pleuritis, pericarditis, or AAV. Follow-up data were not available in the remaining 29 patients. All patients with unspecified AAV had > 1 year of follow-up, contributing to the lack of further delineation of their disease. In the remaining 125 patients, the median follow-up was 6 years (interquartile range, 3.0-11.0).
      Figure thumbnail gr1
      Figure 1Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis cohort development and identification of patients with pleuritis and/or pericarditis. AAV = ANCA-associated vasculitis; EGPA = eosinophilic granulomatosis with polyangiitis; GPA = granulomatosis with polyangiitis; MPA = microscopic polyangiitis.
      Table 1Demographic Characteristics of Patients With ANCA-Associated Vasculitis With a Manifestation of Pleuritis and/or Pericarditis
      CharacteristicTotal (N = 156)GPA(n = 88)MPA (n = 27)EGPA (n = 35)Unspecified AAV (n = 6)
      Demographic
       Age at pleuritis or pericarditis diagnosis, mean (SD), y54.5 (16.5)55.7 (15.0)62 (15.4)46.4 (16.6)51.7 (23.6)
       Age at AAV diagnosis, mean (SD), y54.5 (16.6)55.1 (15.2)63.9 (14.2)46.5 (16.8)51.5 (23.9)
       Female, No. (%)73 (46.8)35 (39.8)12 (44.4)24 (68.6)2 (33.3)
       Ethnicity, No. (%)
      White141 (90.4)82 (93.2)25 (92.6)29 (82.9)5 (83.3)
      Black1 (0.6)0 (0.0)0 (0.0)1 (2.9)0 (0.0)
      Asian Indian1 (0.6)1 (1.1)0 (0.0)0 (0.0)0 (0.0)
      Native American2 (1.3)1 (1.1)1 (3.7)0 (0.0)0 (0.0)
      Mexican1 (0.6)0 (0.0)0 (0.0)1 (2.9)0 (0.0)
      Chose not to disclose10 (6.4)4 (4.5)1 (3.7)4 (11.4)1 (16.7)
      ANCA serology, No. (%)
       PR3-ANCA61 (39.1)58 (65.9)1 (3.7)0 (0.0)2 (33.3)
       MPO-ANCA50 (32.1)17 (19.3)25 (92.6)5 (14.3)3 (50.0)
       ANCA negative30 (19.2)3 (3.4)0 (0.0)27 (77.1)0 (0.0)
       Positive IF with negative PR3- and MPO-ANCA testing3 (1.9)2 (2.3)0 (0.0)1 (2.9)0 (0.0)
       Positive IF without concurrent PR3- and MPO-ANCA testing9 (5.8)6 (6.8)1 (3.7)1 (2.9)1 (16.7)
       ANCA status unknown
      ANCA status was unknown because patients received diagnosis at an outside institution without record of ANCA positivity.
      3 (1.9)2 (2.3)0 (0.0)1 (2.9)0 (0.0)
      Severe AAV at diagnosis, No. (%)101 (64.7)48 (54.5)22 (81.5)25 (71.4)6 (100.0)
      BVAS/WG score at pleuritis or pericarditis onset, median (IQR)4.5 (2.0-6.8)3.0 (1.0-4.0)4.0 (2.0-5.0)4.0 (2.0-5.0)5.5 (2.5-7.5)
      Duration of follow-up from pleuritis and/or pericarditis diagnosis, median (IQR), y5.0 (1.0-9.0)5.0 (2.0-9.3)3.0 (0.5-9.0)4.0 (1.0-7.5)0.0 (0.0-0.0)
      Duration of follow-up from AAV diagnosis, median (IQR), y4.0 (1.0-10.0)6.0 (2.8-12.0)2.0 (0.0-4.5)4.0 (1.0-8.0)0.0 (0.0-0.0)
      Percentages may not total 100% because of rounding. AAV = ANCA-associated vasculitis; ANCA = antineutrophil cytoplasmic autoantibody; BVAS/WG = Birmingham Vasculitis Activity Score for Wegner granulomatosis; EGPA = eosinophilic granulomatosis with polyangiitis; GPA = granulomatosis with polyangiitis; IF = immunofluorescence; IQR = interquartile range; MPA = microscopic polyangiitis; MPO = myeloperoxidase; PR3 = proteinase 3.
      a ANCA status was unknown because patients received diagnosis at an outside institution without record of ANCA positivity.

       Disease Characteristics

      There was no significant difference in median BVAS/WG score at pleuritis and/or pericarditis presentation between the different AAV syndromes (P = .14). Five patients had an incidental pericardial effusion identified at imaging without evidence of other disease activity and, therefore, had a BVAS/WG score of 0. Nine patients who had a previous diagnosis of AAV had a BVAS/WG score of 1, with pericarditis or pleurisy as their sole manifestation of relapse. The most common concurrent organ involvement at the time of pleuritis was general manifestations (49.4% [42 of 85]). Renal involvement was present in 45.9% (39 of 85) of patients with pleuritis. Of the 85 patients with pleuritis, 36 (42.4%) had no other concurrent pulmonary manifestations of AAV. The remaining patients had pulmonary nodules (24.7% [21 of 85]), pulmonary infiltrates (18.8% [16 of 85]), diffuse alveolar hemorrhage (9.4% [eight of 85]), or pulmonary nodules with diffuse alveolar hemorrhage (4.7% [four of 85]).
      Pericarditis frequently occurred concomitantly with general manifestations (29.8% [28 of 94]) and with pulmonary (45.7% [43 of 94]) and nervous system (23.4% [22 of 94]) involvement. One patient had concurrent myocarditis and one patient had heart block at the time of pericarditis manifestation. Concurrent renal involvement occurred in 23.4% (22 of 94) of patients with pericarditis and consisted of hematuria (5.3% [five of 94]) and acute kidney injury (18.1% [17 of 94]). When pleuritis and pericarditis occurred together, multisystem organ involvement was common.
      Pleuritis and/or pericarditis were more likely to occur in patients with EGPA compared with those with GPA or unspecified AAV. This difference was attributable to a higher frequency of pericarditis in EGPA compared with the other AAV subtypes (Table 2). Pleuritis was least likely to occur in patients with unspecified AAV. There were no other differences between groups in the frequency of pleuritis (Table 2). Patients with EGPA had a higher proportion of pericardial involvement compared with pleural involvement. The proportion of pericarditis and pleuritis was more equally distributed in patients with GPA and MPA. The relationships between pleuritis and/or pericarditis presentation and main clinicopathologic diagnosis (GPA, MPA, and EGPA) were also confirmed with the multiple correspondence analysis and hierarchical clustering on principal components analyses performed (e-Figs 1-3, e-Tables 1, 2).
      Table 2Characteristics of Pleuritis and Pericarditis in ANCA-Associated Vasculitis
      CharacteristicAAV (n = 1,830)GPA (n = 1,058)MPA (n = 267)EGPA (n = 201)Unspecified AAV (n = 304)P Value
      Pleuritis and/or pericarditis manifestation, No. (%; 95% CI)156 (8.5)88 (8.3; 6.8-10.1)27 (10.1; 7.0-14.3)35 (17.4; 12.8-23.3)6 (2.0; 0.9-4.2)< .01
       Any pleuritis, No. (%; 95% CI)85 (4.6)52 (4.9; 3.8-6.4)17 (6.4; 4.0-10.0)13 (6.5; 3.8-10.7)3 (1.0; 0.3-2.9).01
       Pleuritis only, No. (%; 95% CI)62 (3.4)42 (4.0; 3.0-5.3)13 (4.9; 2.9-8.2)6 (3.0; 1.4-6.4)1 (0.3; 0.1-1.8).01
      Incidental at imaging No. (%)18 (1.0)11 (1.0)4 (1.5)2 (1.0)1 (0.3)
      Identified at biopsy with symptoms, No. (%)3 (0.2)3 (0.3)0 (0.0)0 (0.0)0 (0.0)
      Clinical symptoms confirmed by imaging, No. (%)41 (2.2)28 (2.6)9 (3.4)4 (2.0)0 (0.0)
       Any pericarditis No. (%; 95% CI)94 (5.1)46 (4.3; 3.2-5.8)14 (5.2; 3.1-8.6)29 (14.4; 10.2-20.0)5 (1.6; 0.7-3.8)< .01
       Pericarditis only No. (%; 95% CI)71 (3.9)36 (3.4; 2.5-4.7)10 (3.7; 2.0-6.8)22 (10.9; 7.3-16.0)3 (1.0; 0.3-2.9)< .01
      Incidental at imaging, No. (%)24 (1.3)11 (1.0)4 (1.5)9 (4.5)0 (0.0)
      Clinically diagnosed inflammation, No. (%)47 (2.6)25 (2.4)6 (2.2)13 (6.5)3 (1.0)
       Pleuritis and pericarditis No. (%; 95% CI)23 (1.3)10 (0.9; 0.5-1.7)4 (1.5; 0.6-3.8)7 (3.5; 1.7-7.0)2 (0.7; 0.2-2.4).02
      Both incidental at imaging, No. (%)3 (0.2)2 (0.2)0 (0.0)1 (0.5)0 (0.0)
      Pleuritis clinically relevant only, No. (%)6 (0.3)2 (0.2)0 (0.0)3 (1.5)1 (0.3)
      Pericarditis clinically relevant only, No. (%)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)
      Both clinically relevant, No. (%)14 (0.8)6 (0.6)4 (1.5)3 (1.5)1 (0.3)
      Pleuritis and/or pericarditis presenting feature of AAV, No. (%; 95% CI)127 (6.9)69 (6.5; 5.2-8.2)23 (8.6; 5.8-12.6)32 (15.9; 11.5-21.6)3 (1.0; 0.3-2.9)< .01
       Pleuritis or pericarditis preceded AAV diagnosis69 (3.8)37 (3.5; 2.5-4.8)15 (5.6; 3.4-9.1)15 (7.5; 4.6-11.9)2 (0.7; 0.2-2.4)
       Pleuritis or pericarditis within 1 mo of AAV diagnosis58 (3.2)32 (3.0; 2.2-4.2)8 (3.0; 1.5-5.8)17 (8.5; 5.3-13.1)1 (0.3; 0.1-1.8)
      Time from pleuritis or pericarditis to AAVdiagnosis, median (IQR), mo8.0 (2.0-23.5)8.5 (2.8-17.5)23.0 (4.5-67.5)4.0 (2.0-8.5)5.5 (4.3-7.4).11
      Pleuritis and/or pericarditis after AAV diagnosis established, No. (%; 95% CI)29 (1.6)19 (1.8; 1.2-2.8)4 (1.5; 0.6-3.8)3 (1.5; 0.5-4.3)3 (1.0; 0.3-2.9).77
      Time from AAV to pleuritis or pericarditis diagnosis, median (IQR), mo31.0 (12.0-84.0)53.0 (26.5-120.0)16.5 (10.3-27.3)27.0 (14.5-40.0)5.0 (3.0-14.5).03
      AAV = ANCA-associated vasculitis; ANCA = antineutrophil cytoplasmic autoantibody; EGPA = eosinophilic granulomatosis with polyangiitis; GPA = granulomatosis with polyangiitis; IQR = interquartile range; MPA = microscopic polyangiitis.
      Pleuritis and/or pericarditis were clinically relevant in most cases (71.2% [111 of 156]). When pleuritis and/or pericarditis were present in AAV, they frequently were presenting features of the disease. Pleuritis and/or pericarditis were more likely to be a presenting feature in EGPA than in GPA and unspecified AAV (Table 2). Pleuritis and/or pericarditis occurred greater than 1 month before AAV diagnosis in 69 patients, with a median time to diagnosis of 8 months (Table 2). Most (87.4% [111 of 127]) of the patients in whom pleuritis and/or pericarditis was a presenting feature had a single episode of pleuritis and/or pericarditis before the AAV diagnosis. Seven patients had two episodes, two patients had three episodes, and five patients had four or more episodes of pleuritis and/or pericarditis before the AAV diagnosis. There were 13 patients in whom pleuritis or pericarditis manifestations were present in isolation before AAV diagnosis. Other symptoms later developed that prompted the AAV diagnosis. The clinical course for these patients is described in Table 3.
      Table 3Patients With ANCA-Associated Vasculitis With Initial Manifestation of Pleuritis and/or Pericarditis
      Demographic Characteristic at Pleuritis and/or Pericarditis PresentationPleuritis or Pericarditis ManifestationDiagnosis and SerologyTime From Manifestation to AAV Diagnosis, dHow AAV Diagnosis EstablishedTreatment of Pleuritis and/or Pericarditis Before AAV DiagnosisTreatment of AAVClinical Course After AAV Treatment Initiated
      81-year-old womanPleuritisGPA, PR3-ANCA306Recurrent pleural effusion for 1 y, then inflammatory arthritis, constitutional symptoms, rash, subglottic stenosis, and DAH, prompting AAV diagnosisThoracentesisGCs, RTXNo AAV or pleuritis relapse
      62-year-old manRecurrent pericarditis and pleuritisGPA, MPO-ANCA1,745Recurrent pericarditis prompted further investigation that revealed elevated creatinine levels. AAV diagnosis was established with renal biopsy.GCsGCs, RTXNo AAV or pleuritis or pericarditis relapse

      Long-term use of RTX because of CLL
      46-year-old manPericarditisGPA negative1,809Pericarditis, then 2 y later he experienced a seizure. Brain imaging demonstrated a mass lesion and lung nodules. VATS lung biopsy was consistent with GPA.PericardiocentesisGCs, RTXLimited follow-up after diagnosis
      48-year-old manPericarditisGPA, PR3-ANCA3,011Two episodes of pericarditis, then 8 y after initial pericarditis he developed joint pain, prompting evaluation that revealed microscopic hematuria. AAV diagnosis was established with renal biopsy.PericardiocentesisGCs, RTXNo AAV or pericarditis relapse
      63-year-old manPericarditisGPA, PR3-ANCA1,350Pericarditis, then years later he developed constitutional symptoms, arthralgias, and mononeuritis multiplex, prompting investigation and AAV diagnosis.UnknownGCs, RTXNo AAV or pericarditis relapse
      46-year-old womanPericarditisGPA, MPO-ANCA5,144Pericarditis, then years later she developed polyarthritis, microscopic hematuria, panniculitis, blepharitis, sinusitis, and pulmonary nodules. VATS lung biopsy was consistent with GPA.Indomethacin, GCs, MTXGCs, RTX, CYCNo AAV or pericarditis relapse
      77-year-old manPleuritisMPA, MPO-ANCA868Recurrent pleural effusions were followed by meningoencephalitis 7 mo later. Two years after that, he experienced acute kidney injury. AAV diagnosis was established with renal biopsy.Thoracentesis, intrapleural catheterGCs, RTXNo AAV or pleuritis relapse
      78-year-old womanPleuritisMPA, MPO-ANCA142Persistent pleural effusion, then she developed acute renal failure. AAV diagnosis was established with renal biopsy.ThoracentesisGCs, CYCNo AAV or pericarditis relapse
      71-year-old womanPericarditisMPA, MPO-ANCA699Pericarditis episode, then years later she developed swelling and erythema of ears that led to evaluation that demonstrated elevated creatinine levels. AAV diagnosis was established with renal biopsy.IndomethacinGCs, CYCOne AAV relapse

      No relapse of pericarditis
      34-year-old manPericarditisMPA, MPO-ANCA2,411Episode of pericarditis, then many years he later developed renal failure. AAV diagnosis was established with renal biopsy.IndomethacinGCs, RTXNo AAV or pericarditis relapse
      31-year-old womanPleuritisMPA, MPO-ANCA5,813Pleuritic chest pain, then 5 y later she developed a rash. Ten years after initial rash, epistaxis and recurrent rash developed, leading to AAV diagnosis.MeperidineGCs, AZANo AAV or pleuritic relapse
      57-year-old manPericarditisUnspecified, MPO-ANCA245Two episodes of pericarditis were followed by joint pains and epistaxis that prompted evaluation that revealed elevated creatinine levels. AAV diagnosis was established with renal biopsy.UnknownGCs, CYCLimited follow-up
      31-year-old manPericarditisMPA, MPO-ANCA2,404Pericarditis, then 5 y later he developed iritis. One year after iritis, joint pains and constitutional symptoms developed that prompted evaluation that revealed hematuria. AAV diagnosis was established with renal biopsy.NoneGCs, RTXOne AAV relapse

      No pericarditis relapse
      AAV = ANCA-associated vasculitis; ANCA = antineutrophil cytoplasmic autoantibody; AZA = azathioprine; CLL = chronic lymphocytic leukemia; CYC = cyclophosphamide; DAH = diffuse alveolar hemorrhage; GC = glucocorticoid; GPA = granulomatosis with polyangiitis; MPA = microscopic polyangiitis; MPO = myeloperoxidase; MTX = methotrexate; PR3 = proteinase 3; RTX = rituximab; VATS = video-assisted thoracoscopic surgery.
      Pleuritis and/or pericarditis occurred after the diagnosis of AAV in 29 patients, with a median time to pleuritis and/or pericarditis manifestation of 31 months. In these patients, pleuritis and/or pericarditis occurred later in patients with GPA compared with those with MPA or unspecified AAV (Table 2). There were no other significant differences between groups.

       Treatment and Prognosis

      Treatment of pleuritis included immunosuppressive therapy (43.5% [37 of 85]), a combination of symptom and immunosuppressive therapy (28.2% [24 of 85]), or symptom management only (21.2% [18 of 85]). Of the patients with pleuritis, 43.5% (37 of 85) underwent thoracentesis, and 7.1% (six of 85) underwent pleural biopsy. Pleural fluid analysis was documented in 31 patients, and most of it was exudative (77.4% [24 of 31]). The cell count was available for 12 of the 43 procedures and was most frequently lymphocyte predominant (41.7% [five of 12]) or monocyte or macrophage predominant (41.7% [five of 12]). Treatment of pericarditis included immunosuppressive therapy (52.1% [49 of 94]), a combination of symptom and immunosuppressive therapy (14.9% [14 of 94]), or symptom management only (18.1% [17 of 94]). Procedural management of pericarditis occurred in 13.8% (13 of 94) of patients with pericarditis. Those who received no treatment for pleuritis or pericarditis either had no other signs of active disease (three patients) or had the pleuritis or pericarditis manifestation before the diagnosis of AAV (six patients). Most patients who underwent only symptom management of pleuritis or pericarditis had the manifestation before the diagnosis of AAV (82.9% [29 of 35]).
      Of the patients who had pleuritis and/or pericarditis as a presenting feature and had 1 or more years of follow-up after their initial pleuritis and/or pericarditis manifestation (105 patients), most (92.4% [97 of 105]) did not have a recurrence of pleuritis or pericarditis after treatment of AAV was initiated. Six patients had one recurrence and the other two patients had chronic relapsing pericarditis. All 14 patients who had multiple episodes of pleuritis or pericarditis before their diagnosis were treated with symptom management only or symptom management with a short course of prednisone therapy. Only two of these 14 patients had a recurrence after AAV treatment was initiated. A combination of glucocorticoids and cyclophosphamide was the most common induction regimen for patients with GPA (52.3% [46 of 88]), MPA (55.6% [15 of 27]), and unspecified AAV (66.7% [four of six]) in this cohort. The most common therapy for EGPA was glucocorticoids alone (45.7% [16 of 35]). Twenty patients had the first manifestation of pleuritis and/or pericarditis after AAV diagnosis and had 1 or more years of follow-up. Most (85.0% [17 of 20]) of these patients had a single episode of pleuritis or pericarditis throughout the disease course.

      Discussion

      The current study demonstrated a lower frequency of pleuritis and pericarditis among patients with AAV compared with that seen in previous studies. In the current study, 14.4% of patients with EGPA had a manifestation of pericarditis and 3% had pleuritis. Pleural and pericardial involvement in EGPA
      • Guillevin L.
      • Cohen P.
      • Gayraud M.
      • Lhote F.
      • Jarrousse B.
      • Casassus P.
      Churg-Strauss syndrome: clinical study and long-term follow-up of 96 patients.
      ,
      • Sable-Fourtassou R.
      • Cohen P.
      • Mahr A.
      • et al.
      Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome.
      has been documented, with up to 22%, 22.9%, and 25% of patients with EGPA reported to have pleural effusions, pericardial effusions, and pericarditis, respectively.
      • Guillevin L.
      • Cohen P.
      • Gayraud M.
      • Lhote F.
      • Jarrousse B.
      • Casassus P.
      Churg-Strauss syndrome: clinical study and long-term follow-up of 96 patients.
      ,
      • Sable-Fourtassou R.
      • Cohen P.
      • Mahr A.
      • et al.
      Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome.
      The current study showed a higher prevalence of pericarditis in EGPA than in the other vasculitis subtypes, whereas pleuritis was similar between groups. This is consistent with other studies in which pericarditis is reported in 3.4% to 17.7% of patients with GPA
      • Hoffman G.S.
      • Kerr G.S.
      • Leavitt R.Y.
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      ,
      • Oliveira G.H.
      • Seward J.B.
      • Tsang T.S.
      • Specks U.
      Echocardiographic findings in patients with Wegener granulomatosis.
      ,
      • Ahn S.S.
      • Park E.S.
      • Jung S.M.
      • Song J.J.
      • Park Y.B.
      • Lee S.W.
      Echocardiographic features in patients with ANCA-associated vasculitis within 3 months before and after diagnosis.
      ,
      • Zycinska K.
      • Borowiec A.
      • Zielonka T.M.
      • et al.
      Echocardiographic assessment in patients with granulomatosis with polyangiitis.
      and 6% to 22.5% of patients with MPA.
      • Agard C.
      • Mouthon L.
      • Mahr A.
      • Guillevin L.
      Microscopic polyangiitis and polyarteritis nodosa: how and when do they start?.
      ,
      • Guillevin L.
      • Durand-Gasselin B.
      • Cevallos R.
      • et al.
      Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients.
      ,
      • Ahn S.S.
      • Park E.S.
      • Jung S.M.
      • Song J.J.
      • Park Y.B.
      • Lee S.W.
      Echocardiographic features in patients with ANCA-associated vasculitis within 3 months before and after diagnosis.
      Pleuritis has been found in 5% to 20% of patients with GPA and MPA.
      • Zycinska K.
      • Borowiec A.
      • Zielonka T.M.
      • et al.
      Echocardiographic assessment in patients with granulomatosis with polyangiitis.
      ,
      • Mohammad A.J.
      • Mortensen K.H.
      • Babar J.
      • et al.
      Pulmonary involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: the influence of ANCA subtype.
      In the current study, we found pleuritis in 4.9% of patients with GPA and 6.4% of patients with MPA.
      When present, pleuritis and/or pericarditis were a presenting feature of AAV in most cases (81.4%). When unrecognized as a manifestation of AAV, pleuritis and pericarditis frequently were treated in terms of symptoms and led to recurrences or further organ involvement of AAV. This morbidity potentially may be avoided if AAV is considered in the differential diagnosis of pleuritis and pericarditis and treated with immunosuppression. After treatment of AAV with immunosuppression was initiated, pleuritis and pericarditis rarely recurred.
      The lower frequency of pleuritis and pericarditis in this study may be partially attributable to the large cohort of patients with AAV and, therefore, a large denominator. This was a retrospective study with limitations of documentation that may omit pertinent manifestations, including pleuritis or pericarditis. Complete follow-up data were not available in all patients. Chest imaging and echocardiograms were not completed in all patients with AAV in the present study; hence, subclinical manifestations may not have been detected, resulting in lower frequencies of pleuritis and pericarditis in this cohort compared with that in other studies in which imaging was completed in all patients with AAV.
      • Oliveira G.H.
      • Seward J.B.
      • Tsang T.S.
      • Specks U.
      Echocardiographic findings in patients with Wegener granulomatosis.
      ,
      • Zycinska K.
      • Borowiec A.
      • Zielonka T.M.
      • et al.
      Echocardiographic assessment in patients with granulomatosis with polyangiitis.
      Strengths of this study include this being, to our knowledge, the largest known cohort of patients with AAV. Use of the database allowed identification of manifestations of pleuritis or pericarditis before and after the diagnosis of AAV, permitting the determination of the temporal relationship of this manifestation within the overall disease course of individual patients. Use of the database also allowed characterization of the clinical course of pleuritis and pericarditis in AAV and the effect of treatment on these manifestations. Most pleuritis and pericarditis manifestations in the current study were clinically relevant and discovered owing to symptoms. In previous studies, most pleuritis and pericarditis manifestations were found incidentally at screening imaging.
      • Ahn S.S.
      • Park E.S.
      • Jung S.M.
      • Song J.J.
      • Park Y.B.
      • Lee S.W.
      Echocardiographic features in patients with ANCA-associated vasculitis within 3 months before and after diagnosis.
      • Zycinska K.
      • Borowiec A.
      • Zielonka T.M.
      • et al.
      Echocardiographic assessment in patients with granulomatosis with polyangiitis.
      • Mohammad A.J.
      • Mortensen K.H.
      • Babar J.
      • et al.
      Pulmonary involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: the influence of ANCA subtype.
      The frequencies reported in the current study likely represent a more accurate estimation of the clinically relevant manifestations of pleuritis and pericarditis in the population with AAV.

      Interpretation

      Pleuritis and pericarditis are detected in all forms of AAV. Patients with EGPA have a higher proportion of pericardial involvement compared with pleural involvement, whereas this distribution is more equal in patients with GPA and MPA. All forms of AAV should be considered in the differential diagnosis when evaluating a patient with pleuritis or pericarditis of unknown cause. These manifestations can occasionally be the sole presenting manifestations of such systemic diseases, and alone they are not enough to affiliate the patient presentation correctly with a specific clinicopathologic entity. Recognition of this disease manifestation may result in decreased morbidity, with earlier AAV identification and treatment.

      Acknowledgments

      Author contributions: G. E. T. takes responsibility for the integrity of the data and the accuracy of the data analysis. G. E. T. completed data organization and analysis and writing of manuscript. M. H. B. completed data organization. G. E. T., M. C. M., B. J. B., and U. S. analyzed the data. M. H. B., M. C. M., M. B., R. C. C., A. M., M. J. K., K. J. W., and U. S. contributed substantially to the study design, data interpretation and writing of the manuscript. All authors were involved with editing the manuscript and approved the final version.
      Financial/nonfinancial disclosures: None declared.
      Additional information: The e-Appendix, e-Figures, and e-Tables can be found in the Supplemental Materials section of the online article.

      Supplementary Data

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