Introduction. The most common types of vasculitis that involve the gastrointestinal tract (GIV) are immune complex-mediated in systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), mixed connective tissue disease (MCTD), and IgA vasculitis (IgAV). GI manifestations are rarely the leading symptom of systemic vasculitis. Only 1 – 5% of rheumatoid arthritis (RA) patients develop symptoms of gastrointestinal tract vasculitis (GIV), while up to 40% of them have GI symptoms. GIV is a rare but life-threatening complication in patients with SLE with a prevalence of up to 2.5%. The leading symptoms in patients with GIV include abdominal pain, nausea, vomiting, diarrhoea, small bowel obstruction, and profuse GI bleeding. The objective of this study was to describe the incidence and clinical manifestations of GIV in patients with various systemic autoimmune (AI) diseases who were treated at Split University Hospital Centre over a 10-year period.
Materials and methods. A retrospective study was conducted by analysing medical records of patients diagnosed with GIV and treated for SLE, SS, MCTD, vasculitis syndrome, IgAV, and RA between January 2009 and December 2018. Only patients with anamnestic data in relation to abdominal pain or endoscopic and/or radiographic findings of GIV were included in the study.
Results. Out of a total number of 12 patients with a confirmed diagnosis of GIV, 9 were male. Eight of them had vasculitis with gastrointestinal involvement (GIV) in IgAV, 2 patients had GIV in SLE, 1 patient had microscopic polyangiitis (MPA), and one patient had primary SS. In 6 cases, GIV was diagnosed by an MSCT of the abdomen, in one case it was diagnosed by a PET-CT scan, in another case it was diagnosed through histopathological findings, and in 4 cases it was diagnosed through endoscopic findings. The leading symptom in 4 patients was abdominal pain with nausea and vomiting, 2 had profuse GI bleeding, 1 had fatigue without GI symptoms, and the remaining patients’ clinical features included acute abdomen with visible radiographic thickening of the bowel wall with oedema and stratification with ascites. GIV was the cause of death of one patient with SLE. Others had a good or moderate response to treatment with glucocorticoids and immunosuppressants.
Conclusion. In conclusion, GIV is a rare manifestation of systemic AI diseases, but the clinical features can be very severe and lead to a fatal outcome, especially if it is not diagnosed at an early stage and treated with aggressive immunosuppressive therapy.
Key words: Vasculitis; Gastrointestinal; Mesenteric; IgA vasculitis; Autoimmune diseases
INTRODUCTION
Systemic autoimmune (AI) diseases can cause various gastrointestinal (GI) disorders, some of which may be the first symptom of the disease and some a consequence of underlying disease treatment (1). Rare but potentially fatal GI manifestations of AI diseases, which require timely and rapid care, are vasculitides of the GI tract (gastrointestinal vasculitis, GIV). Vasculitis is an inflammation of the walls of blood vessels with or without necrosis and granuloma. The diagnosis of different forms of GIV is based on a combination of clinical features and available tests (endoscopy, computed tomography (CT), magnetic resonance imaging (MRI), histopathology diagnosis). It is crucial to make a correct diagnosis given the different approaches to treatment, but also the prognosis that varies greatly depending on the type of disorder (2). GI blood vessels can be affected in various types of vasculitis affecting large, medium and small blood vessels and those of variable size according to the 2012 Revised International Chapel Hill classification (Table 1) (3). The GI tract (GIT) may be the primary site of involvement of several systemic vasculitides: Henoch–Schönlein purpura (IgA vasculitis, IgAV), polyarteritis nodosa (PAN), eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), Behçet’s disease, systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), systemic sclerosis (SSc). The most common types of vasculitides that involve the GIT tract are: SLE, MCTD and IgAV (2). GIV is almost just as often induced by drugs and GI infections (due to glucocorticoid [GC]-induced immunosuppression) (4). The pathophysiological mechanism of most gastrointestinal vasculitides (GIVs) is immune-mediated by the deposition of autoantibody and antigen complexes or antibody complexes, as well as the direct action of antibodies. In some cases, a cell-mediated allograft rejection reaction occurs (1, 4). In case of some diseases, such as Takayasu’s arteritis (TAK) or polyarteritis nodosa (PAN), the pathophysiological mechanism is still not completely clear (4).
The clinical course as well as pathological changes in GIV are highly variable and depend on the type of vascular lesions (localised or diffuse) of the GI tract. Accordingly, GIT lesions in vasculitis include ulcers, submucosal oedema, haemorrhage, paralytic ileus, mesenteric ischaemia, bowel obstruction, and perforation (5-7). Clinical manifestations range from abdominal pain (sometimes cramping), which usually gets worse after eating, to obvious signs of intestinal ischaemia or bowel perforation with diffuse and constant abdominal pain, slow peristalsis, guarding and distension, and signs of peritoneal irritation. GI bleeding, often occult, hematochezia, and less frequently melena or rectorrhagia, are common occurrences. Non-specific symptoms such as nausea, vomiting or diarrhoea may also occur. Furthermore, pancreatitis, cholecystitis or appendicitis may rarely occur (8).
GIT involvement in large-vessel vasculitis is not a common occurrence. Takayasu’s arteritis is a type of vasculitis that commonly affects the celiac plexus and hepatic or mesenteric arteries, with clinically significant consequences in about 16% of patients, while only 4% of patients develop mesenteric ischaemia (4, 9). Half of patients with polyarteritis nodosa (PAN) develop GIV, which can manifest as acute abdominal pain, GI bleeding, infarction, peritonitis, cholecystitis, appendicitis, and perforation (4). Up to 60% of patients with Kawasaki disease may have GI symptoms (abdominal pain, vomiting), but these symptoms are severe in only 4.6% of patients (10).
When it comes to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), GIT involvement is more common in eosinophilic granulomatosis with polyangiitis (EGPA) (35 – 50%) in comparison with microscopic polyangiitis (MPA) (5 – 30%) or granulomatosis with polyangiitis (GPA) (5 – 10%). The leading GI symptoms in patients with EGPA are abdominal pain, bloody diarrhoea (30 – 58%), vomiting, ileus, anorexia, GI bleeding (29%), and odynophagia. Patients with GPA have similar symptoms, with possible intestinal perforation and/or ischaemia and granulomatous hepatitis or pancreatitis. Symptoms of GIV in patients with MPA range from abdominal pain, nausea, vomiting, and diarrhoea to, rarely, ischaemic colon ulcers, peritonitis, and bowel perforation (2, 4).
GI symptoms in IgAV are varied and very common (50 – 85% of patients) and they include: diarrhoea, vomiting, abdominal pain, obstruction, perforation, distension, intussusception, haematemesis, melena, and hematochezia. The inferior part of the duodenum is predominantly affected. In approximately 14% of cases, GIV is the first manifestation of IgAV (11, 12). There are two types of GIV in Behçet’s disease that can develop in 3 – 50% of patients. If small blood vessels are affected, inflammation of the intestinal mucosa with ulcerations occurs, and if large-vessel vasculitis develops, ischaemia and infarction of the bowel wall can occur (13, 14).
Various GI manifestations may occur in patients with SLE (up to 40%), including lupus peritonitis, non-necrotising pancreatitis, GIV, and complications of the aforementioned conditions. According to current data, lupus mesenteric vasculitis (LMV) occurs in 10% of patients. Its mortality rate is up to 2.5%, and its prevalence is highest in patients who are in active disease period (2, 4). Despite the fact that 10 – 38% of patients with rheumatoid arthritis (RA) have different GI symptoms, only 1% of them develop GIV (15). In patients with primary Sjögren’s syndrome (SjS), involvement of the entire GIT is possible. Common symptoms include epigastric pain, dyspepsia and nausea. Other GI manifestations include jejunitis, sigmoiditis, and inflammatory bowel disease (16). Some of the GI presentations of vasculitis include the following: large-vessel vasculitis can cause extensive bowel infarctions as well as infarctions of other organs, while small-vessel vasculitis mostly affects intramural arteries causing focal, segmental ischaemia and ulcerations (8). Despite the increased survival rate of patients with GIV due to advanced treatments (various immunosuppressive therapies and surgical interventions), GI manifestations of AI diseases continue to pose a medical challenge, both in their timely recognition and early care.
The objective of this study was to describe the incidence and clinical manifestations of GIV in patients with various systemic autoimmune (AI) diseases who were treated at the Split University Hospital Centre over a ten-year period.
SUBJECTS AND METHODS
This retrospective cohort study was conducted at the Division of Rheumatology and Clinical Immunology of the Split University Hospital Centre. The patients’ medical records were downloaded from the electronic database of the Division of Rheumatology and Clinical Immunology, covering the period from 1 January 2009 to 31 December 2018. Research criteria included anamnestic data on abdominal pain or endoscopic and/or radiographic findings of intestinal vasculitis. GI involvement is defined as GI manifestations present at the time of diagnosis of vasculitis, after other causes of GI symptoms have been ruled out. The aforementioned GI manifestations include: abdominal pain, nausea or vomiting, diarrhoea, bowel obstruction, intussusception, intestinal bleeding, ulceration and perforation, pancreatitis, and bowel infarction. Based on a detailed review of medical records, GIV symptoms were documented in 12 patients. The following diagnostic methods were used in making the diagnosis: multi-slice computed tomography (MSCT), positron emission tomography-computed tomography (PET-CT), endoscopy of the upper gastrointestinal tract, colonoscopy, MR enterography, and histopathology of the GIT mucosa (Table 3). Patients were treated for SLE, SjS, MCTD, IgAV and vasculitis.
In terms of descriptive statistics methods for statistical analysis, an arithmetic mean with standard deviation or a median with interquartile range for continuous variables were used, as well as frequency (percentages) for categorical variables. The analysis was performed using the MedCalc computer programmes (MedCalc Software, Ostend, Belgium).
RESULTS
The diagnosis of gastrointestinal vasculitis was confirmed in 12 patients, of whom 9 were men (75%). The median age at diagnosis of GIV was 45.2 ± 23.3 years. The results of our research are summarised in Table 2. Eight patients (67%) had GIV in IgAV. Other patients with vasculitis also had underlying conditions such as SLE (2 patients), MPA (1 patient), and primary SS (1 patient). The leading symptom in four patients was abdominal pain with nausea and vomiting, 2 patients had profuse GI bleeding, one patient had fatigue without GI symptoms, and the remaining patients’ clinical features included acute abdomen with visible radiographic thickening of the bowel wall with oedema and stratification with ascites. Diagnostic methods are listed in Table 3. In six (50%) cases, vasculitis was detected by an MSCT of the abdomen (three patients with IgAV, two patients with SLE, one patient with SS), in one case it was detected by a PET-CT scan, in one case through histopathological findings, and in four cases through endoscopic findings. CT of the abdomen showed thickening and stratification of the bowel wall, followed by inflammation of the wall of the jejunum, ileum, caecum and ascending colon and sigmoid colon, and dilated bowel loops (Figure 1). In one patient, CT showed congestion and mesenteric oedema (Figure 1). Endoscopy of the upper GIT was performed in 10 (83%) patients, and abnormalities were detected in all of them. The abnormalities were mostly related to hyperemia and mucosal erosions (Figure 1). In one patient with IgAV, MR enterography was subsequently performed through which jejunal loops with bowel wall thickening along with a misty mesentery sign with swollen lymph nodes were detected (Figure 1). Finally, GI biopsies were performed in three patients, and a pathological finding was detected in two of them. Inflammatory infiltrate of the lamina propria of the ileum was detected in a patient with IgAV, and in a patient with SLE who died as a result of GIV, gangrene of the small intestine with acute peritonitis (mucosal necrosis of the jejunum with accumulation of mixed inflammatory infiltrate and blood in lamina propria and bleeding through the rest of the wall with thrombotic microangiopathy and fibrinoid necrosis of the blood vessels) was detected (Figure 1).
All patients were treated with glucocorticoids (GCs) (methylprednisolone administered intravenously or a dose of 0.5 – 1 mg/kg of prednisone administered orally) with gradual dose reduction. An initial dose of methylprednisolone of 80 mg was administered to eight patients (five patients with IgAV, two patients with SLE, and one patient with SS). In the remaining four patients, treatment was initiated with a dose of prednisone of 60 mg, administered orally (three patients with IgAV and one patient with MPA). In four patients with IgAV, azathioprine (AZA) at a dose of 150 mg/day was introduced, and in one patient chloroquine (250 mg/day) was introduced. Other patients with IgAV had an excellent response to treatment with moderate doses of GCs. In patients with SLE, in addition to GC therapy, cyclophosphamide therapy was administered (CYC) at a dose of 500 mg/m2 of body surface area, and in one patient intravenous immunoglobulins therapy was administered (IVIG) at a dose of 0.4 mg/kg. CYC and IVIG therapy was administered to patients with SS as well, at the same doses as in patients with SLE. A satisfactory response to treatment was achieved in three patients; however, one patient with SLE died as a result of mesenteric vasculitis (after repeated surgical interventions – bowel resection). A patient with MPA who was treated with all of the aforementioned drugs had a satisfactory response to treatment (Table 2).
DISCUSSION
The treatment of patients with GIV in systemic AI diseases still poses a serious challenge because GI system involvement is a rare but very serious complication of the underlying disease that can significantly affect its possible outcomes. Given that clinical symptoms are very diverse and non-specific, and that abdominal pain may be the first, early symptom of bowel perforation, rheumatologists should always approach patients who report newly occurring GI complications with caution (1). To the best of our knowledge, no controlled randomised clinical trials have been conducted on this topic. All data were obtained from a series of case reports, retrospective studies, and a systematic literature review. If GIV presents with clinical features of acute abdomen or GI bleeding, the recommendation for treatment is the use of GCs as the first-line therapy with some of the following immunosuppressants: cyclophosphamide (CYC), methotrexate (MTX), azathioprine (AZA), intravenous immunoglobulins (IVIG), rituximab (RTX), chloroquine (1, 2, 4). The results of our study showed that GIV most often occurs in IgAV and has the best response to therapy, which is consistent with most data to date (11, 12). Remission was achieved in most patients and GIT involvement was not associated with an adverse outcome and relapse of IgAV, which is inconsistent with the results of another study in which GI involvement at the time of diagnosis, along with joint involvement, was associated with more frequent relapses. The reason for this is the impartiality in the selection of subjects in this study (children and adults, cutaneous, renal and joint manifestations of the disease, different treatment protocols) (17). In our study, the subjects were individuals ≥ 18 years of age with predominantly cutaneous and GI symptoms who had a good response to treatment, i.e., who have achieved remission. With regard to GIV in SLE, lupus mesenteric vasculitis (LMV) is known to occur in up to 10% of patients, with the highest prevalence being in patients in active disease period. Typical manifestations of lupus enteritis include focal or diffuse thickening of the bowel wall, bowel dilatation, and ascites, which provide visible radiographic signs such as the “target sign” and “comb sign”: increased bowel wall volume, thickening and multiplication of mesenteric blood vessels, and high adipose tissue density. First-line therapy includes administration of high doses of GCs, administered intravenously, and in refractory cases CYC therapy is administered as well. In patients with obvious signs of peritonitis and highly suspected intestinal perforation or ischaemia, surgical treatment should not be delayed (18). In one of our patients, all the aforementioned treatment methods were used with IVIG, but there was a fatal outcome, while in other patients a good response to treatment was achieved. According to data found in literature, the prognosis of LMV varies and depends on the extent of ischaemia, and better outcomes can be achieved with early administration of high doses of GCs, CYC, or RTX (19). In patients with primary SS, systemic vasculitis extremely rarely affects the GIT, and it may be linked to associated cryoglobulinemia. If ischaemia or bowel infarction are present, the condition is life-threatening. If GC therapy or immunosuppressants prove to be inefficient, surgical intervention is required (20). GIT is rarely affected in MPA; however, it is a very serious manifestation of the disease with possible severe consequences. Although there are no clear treatment recommendations, intravenous GCs with immunosuppressants (CYC or RTX) are administered in most cases (21). Survival rates differ in various studies, but recent data suggest that mortality is the same in patients with MPA regardless of GI tract involvement (21–23).
Patients with GIV who were treated in our university hospital centre had a good response to treatment and the outcome was fatal in only one patient. We believe that the reason for the favourable outcomes is the timely diagnosis and rapid therapeutic intervention, but longer follow-ups with more subjects are required in order to find out whether the survival rate has really improved over the last few years. Since these are rare disorders, successful treatment of these patients requires a range of diagnostic and laboratory procedures, as well as good cooperation between experts in a multidisciplinary team (rheumatologists, gastroenterologists, radiologists, pathologists and surgeons). Diagnosis is made based on clinical suspicion and imaging methods because there is no specific test for the detection of GIV in systemic AI diseases.
Our study is limited due to retrospective nature of data collection, which is why there are certain shortcomings. In addition to that, other limitations include the relatively small number of patients and the fact that this study was conducted in a single hospital centre. Despite the descriptive analysis, with all the inherent bias associated with this type of research, we have tried to gain useful insights in order to improve the identification and treatment of patients with GIV in various AI diseases.
CONCLUSION
GIV is a rare manifestation of systemic AI diseases, but the clinical features can be very severe and lead to a fatal outcome, especially if it is not diagnosed at an early stage and treated with aggressive immunosuppressive therapy. However, additional studies are needed to identify factors that influence the prognosis and treatment outcome of these disorders, as well as clear recommendations and guidelines for the treatment of these patients.
REFERENCES / LITERATURA
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<jrn>2. Ahn E, Luk A, Chetty R, Butany J. Vasculitides of the gastrointestinal tract. Semin Diagn Pathol. 2009;26(2):77–88.PubMedhttps://doi.org/10.1053/j.semdp.2009.06.001</jrn>
Legend / Legenda: ANCA – antineutrophil cytoplasmic antibodies / antineutrofilna citoplazmatska antitijela; GBM – glomerular basement membrane / glomerularna bazalna membrana; CNS / SŽS – central nervous system / središnji živčani sustav; HCV – hepatitis C virus / virus hepatitisa C; HBV – hepatitis B virus / virus hepatitisa B.
Table 2 Summarised results of the variables of interest in patients with gastrointestinal vasculitis
Legend / Legenda: CT – computed tomography; PHD – histopathology diagnosis / patohistološka dijagnostika; MR – magnetic resonance / magnetska rezonancija; IgAV – IgA vasculitis / IgA-vaskulitis; SLE – systemic lupus erythematosus / sistemski eritemski lupus; MPA – microscopic polyangiitis / mikroskopski poliangiitis; SS – Sjögren’s syndrome / Sjögrenov sindrom; GI – gastrointestinal / gastrointestinalno; GC / GK – glucocorticoid / glukokortikoid; AZA – azathioprine / azatioprin; CYC – cyclophosphamide / ciklofosfamid; IVIG – intravenous immunoglobulins / intravenski imunoglobulini; RTX – rituximab / rituksimab.
Table 3. Diagnostics of gastrointestinal vasculitis
Legend / Legenda: CT – computed tomography; MR – magnetic resonance / magnetska rezonanca; PET-CT / PET CT – positron emission tomography with computed tomography / pozitronska emisijska tomografija s kompjutoriziranom tomografijom; FDG – fluorodeoxyglucose / fluorodeoksiglukoza; GIT – gastrointestinal tract / gastrointestinalni trakt.
Legend / Legenda: a) multi-slice CT of GIV in patient with SLE shows oedema and stratification of the bowel wall (target sign) / višeslojni CT GIV-a u bolesnice sa SLE-om prikazuje edemi i raslojavanje stijenke crijeva (target sign); b) multi-slice CT in patient with SS shows free fluid perihepatic space, perisplenic space, paracolic gutter and interstitial space with mesenteric congestion / višeslojni CT u bolesnika sa SS-om prikazuje slobodnu tekućinu perihepatalno, perispenično, parakolično i interstinalno uz kongestiju mezenterija; c) multi-slice CT in patient with IgAV shows dilated small bowel loops with torsion and congestion of the associated mesentery; two transition points collapsed into dilated loops: closed loop / višeslojni CT u bolesnika s IgAV-om prikazuje dilatirane vijuge TC uz torziju istih i kongestiju pripadajućeg mezenetrija; dva prelaska kolabiranih u dilatirane vijuge: „closed loop”; d) small bowel histopathology in patient with SLE (hematoxylin and eosin staining, 20x magnification) shows full-thickness necrosis of the bowel wall, as well as complete necrosis of serosa / PHD tankog crijeva u bolesnice sa SLE-om (bojenje hemalaunom i eozinom, povećanje 20x) prikazuje nekrotičnu stijenku u cijeloj debljini, kao i potpunu nekrozu seroze; e) MR enterography of the GIV in patient with IgAV shows jejunal loops with bowel wall thickening; one of the loops is fixed; misty mesentery sign with swollen lymph nodes / MRI enetrografija GIV-a u bolesnika s IgAV-om prikazuje vijuge jejunuma zadebljane stijenke; jedna od vijuga fiksirana; mezenterij zamućen s uvećanim limfnim čvorovima; f) endoscopy of the upper GIT in patients with IgAV shows hyperemia and mucosal erosion / endoskopija gornjeg dijela GIT-a u bolesnika s IgAV-om prikazuje hiperemiju i eroziju sluznice.
Figure 1. Imaging (different techniques) of gastrointestinal vasculitis in patients with autoimmune diseases