Hemorrhagic complications associated with PR3-ANCA crescentic glomerulonephritis

Abstract

Hemorrhagic complications of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis are life-threatening conditions. Of these, alveolar hemorrhage is the most common and well-described hemorrhagic complication and is a prominent component of the pulmonary-renal syndrome. The clinical presentation of alveolar hemorrhage is highly variable ranging from mild to serious disease that may require respiratory support. Less attention has been directed at hemorrhagic complications that have been reported in other organs and which may be as severe or more severe with regard to morbidity and mortality. For example, among the most serious non-pulmonary complications are those related to cerebral and gastrointestinal hemorrhage. Cerebral hemorrhage is the clearly the most critical issue with a persistent high mortality rate. The prognosis of gastrointestinal hemorrhage, once an ominous complication has improved with medical and surgical intervention. Not to be dismissed are the consequences of hemorrhagic issues related to skin, soft tissue or muscle involvement. Muscle hematomas, while rare, also accompanied by significant morbidity.

• Alveolar hemorrhage
• anti-neutrophil cytoplasmic autoantibody
• crescentic glomerulonephritis
• gastrointestinal bleeding
• rectus muscle hematoma

Introduction

Anti-neutrophil cytoplasmic autoantibody (ANCA) disease comprises a group of autoimmune disorders including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilia granulomatosis with polyangiitis (EGPA),1 characterized by necrotizing small-vessel vasculitis with autoantibodies directed against neutrophil cytoplasmic constituents, in particular proteinase 3 (PR3) and myeloperoxidase (MPO). Focal necrotizing change is a common pathologic feature in the affected vessels.2 Crescentic glomerulonephritis is a very common pathologic condition that can potentially progress to permanent renal dysfunction. Other complications such as pulmonary hemorrhage occur frequently,3 whereas cerebral, gastrointestinal and other hemorrhagic complications are much less common but may be associated with significant morbidity and even mortality.

Detailed characteristics of patients with ANCA disease and associated hemorrhagic complications have been limited to a few individual case reports and case series. We conducted a systematic review to ascertain the epidemiology, clinical features, short-term and long-term outcomes of patients with hemorrhagic complications of ANCA disease and present the results against a background of an exceptional case of GPA manifesting as PR3-ANCA positive crescentic glomerulonephritis with near fatal alveolar hemorrhage and complicated by gastrointestinal bleeding and rectus muscle hematoma.

Case report

A previously healthy 67-year-old female was admitted to the China–Japan Friendship Hospital with constitutional symptoms of 5 weeks duration and a 3-d history of blood-tinged sputum. On admission, she was febrile with the most prominent physical findings consisting of obvious edema of her lower limbs with inspiratory crackles over her middle and lower right lung fields. Subsequent radiographic studies showed large areas of ground glass opacity consistent with alveolar hemorrhage were seen on chest films (Figure 1A) and confirmed with thoracic CT scan (Figure 1B). Her serum creatinine concentration (Scr) was 283 μmol/L (3.2 mg/dL). Urinalysis showed the presence of microscopic hematuria and moderate proteinuria. Indirect immunofluorescence revealed cytoplasmic ANCA (c-ANCA) at a titer of 1:100 with anti-PR3 ANCA specificity by ELISA (340 U/L). She was diagnosed with an ANCA-related disease. Treatment with antibiotics and plasmapheresis was instituted. The clinical course is shown in Figure 2. After the second plasmapheresis, she suddenly complained of abdominal pain and swelling in the right rectus muscle region accompanied by hypotension. Her hemoglobin (Hb) level dropped from 8.9 to 4.2 g/dL in the subsequent hours. Abdominal CT showed an extensive, irregular low-density mass in the right muscle (Figure 1C and D). On hospital day 5, she was started on methylprednisolone pulse therapy, 500 mg/d given intravenously for 3 d. This was followed by oral prednisolone (1 mg/kg/d) and intravenous cyclophosphamide (0.5 g/m²). This resulted in the cessation of hemoptysis resolution of the abnormal radiographic findings. However, she developed tinnitus and bloody nasal discharge and diagnosed as frontal sinuses by the CT scan. During this time, her Scr continued to increase and a third plasmapheresis was performed. On day 10, massive hematochezia occurred, with a drop in Hb from 8.3 to 5.2 g/dL. Endoscopy showed two duodenal ulcers approximately 2 cm in diameter (Figure 1E and F). Biopsies of these lesions showed inflammatory cells and fibrosis to the laminapropia. She received another MP pulse (500 mg/d × 3) along with transfusions and supportive therapy and gradually improved.

Figure 1. Chest X-ray (A) and CT (B) revealed large areas of ground glass opacity in the middle and lower lung fields. Abdominal CT (C and D) showed an extensive, irregular low-density mass in the right rectus muscle (white arrow). Gastrointestinal (GI) endoscopy demonstrated two duodenal ulcers around 2 cm diameter. Some of the mucosa between the ulcers is reddish and edematous. The border of the ulcer is unclear and covered with white coating (E). Another ulcer is square and clears (F). Renal biopsy showed two large fibrocellular crescent (black arrow) and a small cellular crescent (black thin arrow) in the renal glomeruli (G and H). Protein cast were presented with lymphomonocyte interstitial infiltration around glomeruli (H). Periodic acid-Schiff stain, 200×.

Figure 2. Clinical course of the patient. Scr, serum creatinine; Hb, hemoglobin; UGIH, upper gastrointestinal hemorrhage; PE, plasma exchange; MP, methylprednisolone.

Tissue obtained on percutaneous renal biopsy showed fibrocellular crescentic glomerulonephritis (Figure 1G and H) consistent with a diagnosis of GPA. A third MP pulse (500 mg/d × 3) was given. Cyclophosphamide was continued monthly for total of six doses, followed by azathioprine (2 mg/kg/d). On day 25, the patient was discharged with improving Hb and Scr. During the 18-month follow-up, her Hb and PR3-ANCA were normal. The Scr had decreased to 96 μmol/L (1.1 mg/dL). Her drug therapy consisted of prednisone 10 mg on alternate days, and azathioprine 100 mg per day.

Discussion

The various forms of vasculitis are generally categorized by the size of the affected blood vessel. ANCA-associated vasculitis is one of several entities marked by inflammatory infiltrates of small vessels that occur in response to autoantibody deposition. Hemorrhagic complications occur most often with involvement of the renal and pulmonary vasculature. However, other tissues and organs may be affected as a result of increased permeability of vascular walls due to inflammation or occlusive disease consequent on thrombus formation.4 At times, other complicating features such as the co-existence of severe hypertension or the consequences and/or side effects of treatment protocols are implicated in the etiology of the hemorrhage. The present case highlights the interaction of these factors in that the patient had life-threatening pulmonary hemorrhage as a result of the systemic vasculitis, gastrointestinal bleeding with inflammation and fibrosis of the laminapropia of the small intestine and a large muscle hematoma perhaps related to heparin therapy.

Alveolar hemorrhage is an important pulmonary manifestation of ANCA disease, with presentations ranging from mild to serious disease often requiring respiratory support. Indeed, severe, diffuse alveolar hemorrhage is the most common vasculitic cause of early death.5 Alveolar hemorrhage can occur in the context of various systemic disorders or present as an isolated event.6 The prevalence of alveolar hemorrhage in ANCA disease ranges from 10% to 45%.7–11 A systematic review of a total of nine studies performed between 1985 and 2012 described the clinical features of alveolar hemorrhage.12 The individual studies varied from 5 to 80 patients in size with a total of 207 patients. Hemoptysis and dyspnea were common but non-specific features. Although chest radiography is usually abnormal, high-resolution computerized tomographic scanning is a more sensitive diagnostic tool. Fiberoptic bronchoscopy and bronchoalveolar lavage are useful when a superimposed pulmonary infection is suspected.12 Severe alveolar hemorrhage requiring ventilation occurs in 5% of patients with ANCA disease.8 Despite increased understanding of pathogenesis and newer therapeutic options, patients with ANCA disease accompanied by severe alveolar hemorrhage have a 5-year patient survival of 75%.13 However, this number is reduced to 50% at 2 years if ventilation had been required.14 In a retrospective study, Hruskova et al. reported on a cohort of 53 patients and found that severe alveolar hemorrhage was more commonly associated with PR3-ANCA (vs. MPO-ANCA) and strongly correlated with renal vasculitis.15 Mortality was higher in those requiring dialysis at entry and in patients aged >65 years, and tend to be higher in those requiring intubation.

Cerebrovascular involvement in ANCA disease is rare, occurring in from 0 to 3.6% of all cases.16–18 Curiously, GPA patients with CNS involvement may have a high rate of ANCA negativity.19 Table 1 summarizes the clinical manifestations of intra-cerebral hemorrhage in patients with ANCA disease. The hemorrhagic neurological complications are thought to be secondary to weakening of blood vessel walls due to an inflammatory vasculitis, resulting in vessel rupture and subsequent bleeding.18^,20 It is difficult to identify the pathogenesis of every case in the absence of an examination of vascular tissue obtained by biopsy or at the time of autopsy. By themselves, cerebral imaging methods may not be able to the specific findings of vasculitis that include irregularity of arterial walls or obstruction of arteries.21 The clinical course of patients with cerebral hemorrhage is rapid progressive and the prognosis is poor. Less symptomatic lesions may respond to immunosuppressive therapy,22 while more extensive and life-threatening lesions require emergency surgery in view of the associated high-mortality rate.23–28 Thus, prompt diagnosis and treatment with immunosuppressive therapy and/or surgical intervention are essential. In addition to the vessel wall thickening due to the vasculitis itself, rupture of cerebral aneurysms, or complication of hypertension need to be considered.29–31

Table 1. The clinical manifestations of intra-cerebral hemorrhage in patients with ANCA disease.

No.	Sex/Age	ANCA pattern	Diagnosis	CNS involvement	Treatment	Outcome	Reference
1	F/10	MPO-ANCA	MPA	Hemorrhagic focus in the right parietal lobe	Seven cycles of plasmapheresis, steroid and cyclophosphamide therapy	The neurological settled but dialysis-dependent	Tan23
2	F/62	MPO-ANCA	MPA	Hemorrhage in the right frontal lobe, a second Hemorrhage was also noticed in the left frontal lobe	Steroid and cyclophosphamide therapy	Death	Akkara Veetil24
3	M/48	MPO-ANCA	MPA	Massive right-sided parieto-temporo-occipital Hematoma with cerebral hernia and intraventricular hemorrhage	Surgical evacuation of the hematoma, steroid and cyclophosphamide therapy	Full recovery other than a persistent bilateral foot drop	Sassi25
4	M/43	MPO-ANCA	MPA	Massive intra-cerebral hemorrhage	Methylprednisolone and cyclophosphamide	Death	Han26
5	M/56	p-ANCA	MPA	Massive cerebral hemorrhage	Steroid therapy alone	Death	Ito27
6	F/44	MPO-ANCA	MPA	Subarachnoid hemorrhage, a saccular-like aneurysm from the right distal posterior inferior cerebellar artery	Two operations, steroid, and cyclophosphamide therapy	Full recovery (modified Rankin scale score 1)	Kimura28
7	M/46	PR3-ANCA	GPA	Right thalamic hemorrhage	Steroid, and cyclophosphamide therapy	Recovery	Takaoka22

Notes: ANCA, anti-neutrophil cytoplasmic autoantibody; CNS, central nervous system; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PR3, proteinase 3.

Gastrointestinal involvement is not rare with focal necrotizing arteriolitis having been detected by necropsy in 24% of the 56 GPA cases for whom data are available.32 However, reports of significant clinical manifestations of gastrointestinal hemorrhage are rare. Since 1962, five cases with severe intestinal involvement were detected by emergency surgery due to perforation.33–37 Two cases with MPA were reported to have duodenal ulcers.38^,39 Pagnoux et al. presented 62 patients with medium- and small-sized vasculitis accompanied by gastrointestinal involvement. There was one patient with EGPA and two additional patients with MPA who developed bowel perforations and received surgery.40 The detailed available information of those patients with gastrointestinal hemorrhage is listed in Table 2. It has been emphasized that vasculitis-related gastroduodenal ulcerations typically have an extensive and profound pattern.41 The cause of ulcer formation in GPA is generally considered to be related to the vasculitis itself. Severe, occlusive damage often leads to ischemia that may result in ulceration and perforation whereas non-occlusive vascular disease may lead to vascular leakage resulting in edema and hemorrhage. Those patients often present with diarrhea or symptoms of bleeding.42 The prognosis has dramatically improved, probably owing to better management of the more severely ill patients, with prompt surgical intervention when indicated, and the combined use of steroids and immunosuppressant.40 Intestinal perforation has been reported where pathologic analysis of a surgically resected portion of the small intestine showed chronic suppurative inflammation in all layers of the ileal wall and mesentery.43

Table 2. The clinical manifestations of gastrointestinal hemorrhage in patients with ANCA disease.

No.	Sex/Age	ANCA pattern	Diagnosis	GI involvement	Histology	Outcome	Reference
1	M/46	NK	GPA	Small bowel, colon	Ulceration	Death	Geraghty33
2	M/50	NK	GPA	Distal ileum	Ulceration	Good (after surgery, follow 6 mo)	McNabb34
3	M/24	cANCA	GPA	Colon	Vasculitis	Good (after surgery, follow 3 mo)	Storesund35
4	F/55	cANCA	GPA	Small bowel, colon	Vasculitis	Good (after surgery, follow 2 mo)	Storesund35
5	M/44	NK	GPA	Small bowel	Vasculitis	Good (after surgery, follow 4 mo)	Deniz36
6	M/57	MPO-ANCA	MPA	Duodenal	Vasculitis	Death	Wakura37
7	M/54	MPO-ANCA	MPA	Ileum	Vasculitis	Good	Inaguma38
8	M/19	NK	EGPA	Appendix	Vasculitis	GI relapse (after surgery 24 mo), then good (120 mo)	Pagnoux40
9	F/39	NK	MPA	Small intestine, large bowel	Vasculitis	Multiple relapses, and cerebral vasculitis (after surgery 132 mo), ongoing regression (140 mo)	Pagnoux40
10	F/43	NK	MPA	Small intestine, appendix	Vasculitis	Good (after surgery, follow 6 mo)	Pagnoux40

Notes: ANCA, anti-neutrophil cytoplasmic autoantibody; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; EGPA, eosinophilia granulomatosis with polyangiitis; MPO, myeloperoxidase; M, male; F, female; NK, not known.

Although intra-muscular hematoma has been reported in 2% of patients with Henoch-Schönlein purpura,44 reports of muscle hemorrhage in ANCA disease are rare with only two cases reported.45^,46 One case with MPA was found to have femoral hemorrhage and another autopsy case of PR3-ANCA disease was complicated with rectus muscle hematoma. Commonly, GPA affects small vessels (capillaries, venules, or arterioles). However, since the report of aneurysm formation and free-vessel rupture of medium and large vessels in a patient with ANCA disease, the possibility that medium-sized vessels might be ruptured cannot be ruled out.47 In our case, due to the absence of thrombocytopenia, disseminated intravascular coagulation, and trauma in the present case, GPA was considered to be the cause of the femoral hemorrhage. Although heparin was administered (5000 µ for plasmapheresis), the last dose was given 3 h before the occurrence of rectus hemorrhage. None-the-less, because heparin may accumulate in plasma due to the renal insufficiency and because its T1/2 is 1.5 h, the possibility that heparin contributed to the development of hemorrhage cannot be ruled out.

In conclusion, hemorrhagic complications of ANCA disease other than alveolar hemorrhage are uncommon but may be associated with significant morbidity and mortality. The patient in this report presented with rapidly progressive renal insufficiency, pulmonary hemorrhage, rectus muscle hematoma and duodenal ulcer in succession. It should be noted that multi-organ hemorrhages are serious complications and prompt diagnosis and treatment are required.

Acknowledgments

We are very grateful to National Natural Science Foundation of China and Youth Science and Technology Excellence Project of China-Japan Friendship Hospital for the financial assistance.

Declaration of interest

Financial assistance was provided by National Natural Science Foundation of China [grant number 81200535] and Youth Science and Technology Excellence Project of China-Japan Friendship Hospital [Grant number: 2014-QNYC-A-01]. The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.