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7©Pavli P, Gioti O, Spyridopoulos TN,
G, Tsourous G, Elezoglou A, Kaziani K, Fanouriakis A.
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CASE SERIES
Acute Abdominal Situations as Presenting or Flaring Manifestations of Systemic Lupus Erythematosus: A Case Series
Polina Pavli1, Ourania Gioti2, Themistoklis N. Spyridopoulos3, George Katsikas4, George Tsourous5, Antonia Elezoglou2, Katerina Kaziani1, Antonis Fanouriakis2
1Third Department of Internal Medicine, Evaggelismos General Hospital, Athens, Greece, 2Department of Rheumatology, "Asklepieion" General Hospital, Athens, Greece, 32nd Unit of Diagnostic and Interventional Radiology, National and Kapodistrian University of Athens, Medical School, Evgenidion Hospital, Athens, Greece, 4Department of Rheumatology, Evaggelismos General Hospital, Athens, Greece, 5Department of Internal Medicine, "Mediterraneo" Hospital, Athens, Greece
ABSTRACT
Systemic lupus erythematosus (SLE)is a multisystem autoimmune disease, characterized by clinical heterogeneity, ranging from mild to severe, life-threatening manifestations. Although gastrointestinal (GI) symptoms are frequently encountered during disease course (mainly associated with complications of medication or infection), primary GI involvement due to SLE is rare. Among variable presentations, lupus abdominal serositis (defined as peritonitis if accompanied by symptoms and signs of acute abdomen) and lupus enteritis/mesenteric vasculitis are causes of SLE-related acute abdominal pain. They occur, although not always, in the context of high disease activity and prompt diagnosis and treatment is necessary due to their potential severe complications. However, the diagnosis of these manifestations remains challenging even for experts, especially in cases of "organ-dominant" lupus flares. Exclusion of these rare manifestations from classification criteria increases the likelihood of misdiagnosis and highlights the inherent limitations of classification criteria when the latter are used for diagnosis. Urgent abdominal computed tomography can lead to a prompt diagnosis of these lupus manifestations, especially characteristic for lupus mesenteric vasculitis. Herein, we describe four cases of patients with lupus flare, presenting with acute abdominal manifestations and highlight the potential complexity of diagnostic approach in such situations.
Mediterr J Rheumatol 2022;33(3):339-45 https://doi.org/10.31138/mjr.33.3.339
Article Submitted: 16 May 2021; Revised Form: 16 Nov 2021; Article Accepted: 30 Nov 2021; Available Online: 30 Sep 2022
Keywords: systemic lupus erythematosus, lupus peritonitis, lupus enteritis, mesenteric vasculitis, gastrointestinal involvement
Corresponding Author:
Antonis Fanouriakis, MD Department of Rheumatology, "Asklepieion" General Hospital Voula 16673, Athens, Greece Tel.: +30 213 216 3195 E-mail: afanour@med.uoa.gr
MAIN POINTS
1) Although rare, primary SLE gastrointestinal involvement, including lupus peritonitis and lupus enteritis/ mesenteric vasculitis, should be suspected in SLE patients presenting with abdominal pain.
2) The threshold for an abdominal CT
should be low, as typical imaging findings (such as target sign and comb sign) are suggestive for the diagnosis.
3) Early diagnosis and treatment of these entities is crucial, in order to avoid severe complications (eg, ischemia or perforation).
Cite this article as: Pavli P, Gioti O, Spyridopoulos TN, Katsikas G, Tsourous G, Elezoglou A, Kaziani K, Fanouriakis A. Acute Abdominal Sit- 339 uations as Presenting or Flaring Manifestations of Systemic Lupus Erythematosus: A Case Series. Mediterr J Rheumatol 2022;33(3):339-45.
INTRODUCTION
Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder with a wide range of clinical presentations involving almost all organs. Gastrointestinal (GI) symptoms are not uncommon in SLE and are usually related to adverse events of treatment or infectious causes. More rarely, acute abdominal situations may represent GI involvement of the disease per se.1-3 The British Isles Lupus Assessment Group (BILAG) has provided different definitions for presentations of acute abdominal pain due to SLE, based on clinical and imaging findings.4 Abdominal serositis occurs mainly in patients with active disease and usually responses adequately to glucocorticoids.5 Abdominal serositis presenting as acute abdomen with rebound tenderness/guarding constitutes lupus peritonitis. Finally, lupus mesenteric vasculitis (also known as lupus enteritis), is a rare, yet most serious cause of acute abdominal pain in SLE patients, potentially leading to bowel necrosis or perforation.6 Typical computed tomography (CT) findings of target sign (bowel wall thickening with abnormal wall enhancement) and comb sign (engorgement of mesenteric vessels) are important for a prompt diagnosis.
As these disease-related manifestations may result in even life-threatening complications, early diagnosis and treatment is crucial.7 Of note, the rarity of severe abdominal involvement in SLE has excluded these manifestations from all sets of classification criteria.8-10 Importantly, although the aim of classification criteria is the inclusion of patients in clinical trials, they are nevertheless frequently used for diagnostic purposes, especially by physicians with limited experience in lupus. We herein describe four cases of SLE, presenting or flaring as acute abdomen and discuss relevant issues regarding the need for prompt diagnosis, especially when this is the sole manifestation of the disease (Table 1).
CASE DESCRIPTIONS
Case 1
A 30-year-old Caucasian woman with a history of Sjögren's syndrome was referred due to a 20-day history of fever and worsening abdominal pain that appeared two days ago. She had delivered her second child by caesarean section one month before. During pregnancy, she was receiving treatment with low molecular weight heparin and low-dose prednisone for one month for un-
Table 1. Clinical, laboratory features and treatment of patients.
Case 1 Case 2 Case 3 Case 4
Age(years)/Sex 30/F 26/F 40/F 40/F
SLE duration(years) 0 10 0 20
Treatment at flare None 5mg PZ HCQ, MTX None 5mg PZ HCQ
Extra-GI manifestations at flare Fever, arthritis, pleuritis, pericarditis, cytopenias Fever, arthritis, pleuritis, cytopenias Fever, pleuritis None
Abnormal blood tests Hb 6.6g/dl WBC 2530/pl CRP 9.4mg/dl ESR 120mm/hr Hb 10g/dl WBC 3020/pl PLT 127000/pl ALT 439 U/l AST 824 U/l CRP 22 mg/dl ESR 56 mm/hr Hb 11.6g/dl None
Serological activity Yes Yes Yes Yes
Treatment administeredv 1mg/kg PZ HCQ 3gr MP iv 0.6mg/kg PZ Belimumab 3gr MP iv 0.8mg/kg PZ AZA, HCQ 3gr MP iv 1mg/kg PZ CYC iv
Follow-up No relapse No relapse No relapse No relapse
F: female; PZ: prednisone; HCQ: hydroxychloroquine; MTX: methotrexate; GI: gastrointestinal; iv: intravenous; MP: methylprednisolone; AZA: azathioprine; CYC: cyclophosphamide
clear reasons. Sjögren's syndrome had been diagnosed six years ago, based on polyarthritis and positive anti-Ro/ anti-La, and had been treated with glucocorticoids and hydroxychloroquine for a short period. On admission, the patient was febrile and physical examination was remarkable for guarding and rigidity of the lower abdomen, and peripheral enema. Blood tests revealed anaemia and leukopenia (Hb=6,6g/ dl, WBC=2.53x10.000), raised erythrocyte sedimentation rate (ESR=120mm/hr) and C-reactive protein (CRP=9.4mg/dl). Urgent abdominal CT scan showed fluid collections perihepatically and in the lower pelvis (Figure 1A).
Empirical antimicrobial treatment was initially started for a possible postoperative intraabdominal infection, without clinical improvement. A transvaginal ultrasound did not reveal findings consistent with local infection. On the third day of hospitalization, the patient developed arthralgias and thoracic pain. Physical examination revealed symmetrical polyarthritis and clinical signs of pleuritis (diminished breath sounds). New onset Raynaud's phenomenon was also present, along with progressive worsening of leukopenia and lymphopenia. Chest CT revealed right pleural and small pericardial fluid collections. At this point, clinical manifestations were considered as possibly related to a SLE flare (fever, arthritis, polyserositis, cyto-penias) and the patient was started on prednisone (1mg/ kg/daily with gradual tapering) and hydroxychloroquine, while antibiotics were interrupted. Immunological testing showed diffuse hypergammaglobulinemia, positive antinuclear antibodies (ANA> 1: 640), anti-dsDNA >95.0 U/ ml (cut-off: 7 U/ml), positive anti-Ro and anti-La, as well as IgM-anticardiolipin antibodies (52.2, normal values: 0.1-20 MPL). Complement levels were low-normal. Following initiation of immunosuppressive therapy, the patient gradually improved in terms of clinical and laboratory findings. She was discharged in good clinical condition, with a final diagnosis of multiorgan SLE flare,
initially manifesting as abdominal serositis/peritonitis. During follow-up and after having reduced glucocor-ticoids to acceptable daily doses, the patient remains clinically quiescent.
Case 2
A 26-year-old Caucasian woman was admitted to another hospital with fever (up to 39oC) accompanied by rigor, fatigue, headache, and nausea; symptoms had started four days before admission. The patient had been diagnosed with SLE ten years ago, based on arthritis, alopecia, pleuritis and compatible serology (positive ANA and ds-DNA, hypocomplementemia). Her treatment included low-dose prednisone, hydroxychloroquine, and methotrexate.
On admission, the patient was febrile (39.6oC) and in distress, with mild tachycardia (110 beats/minute). Initial physical examination was remarkable only for late inspiratory crackles at both lung bases. Laboratory tests revealed normochromic anaemia and increased inflammatory markers (CRP 22 mg/dl, ESR 56 mm/hr). On the second day of hospitalization, the patient developed progressively worsening epigastric pain with signs of guarding and rebound tenderness. Urgent CT scans showed mild bilateral pleural effusions with areas of ground glass in the lung bases, hepato- and splenomegaly, as well as fluid accumulation in the pericholecystic, perihepatic, perisplenic, and lower pelvic area (Figure 1B,C). Evidence of a hypodense tissue surrounding the celiac artery and portal vein was also suspected. Paracentesis of the ascitic fluid showed lymphocytic pleocytosis (350 cells, 60% lymphocytes), with negative cultures and cytology.
Broad-spectrum antibiotic treatment was administered; nevertheless, on day 3 of hospitalisation, she experienced severe clinical deterioration with hemodynamic instability and hypoxemia. Complete blood count revealed pancytopenia, without evidence of microangiopathic
- r -
Figure 1. Abdominal CT images of patients 1 and 2. (a) Patient 1, axial CECT image: Fluid collection at the lower pelvis (red arrow) and mild fluid collection in the uterine cavity (yellow arrow). (b) Patient 2, axial CECT image: Pericholecystic fluid collection (green arrow); enlarged lymph nodes (red arrows). (c) Patient 2, axial CECT image: Fluid collection in the lower pelvis.
haemolytic anaemia, and profoundly elevated liver enzymes (AST: 824 U/l, ALT: 439 U/l), which were attributed to possible liver hypoperfusion (shock liver). Repeat CT showed deterioration of pleural and peritoneal effusions and pericholecystic enema. The patient was admitted to the Intensive Care Unit and aggressive intravenous fluid resuscitation together with enhanced antibiotics were administered. A thorough work-up for infectious causes, including bacteria and viruses, was negative. Ultrasound of the splenoportal axis and magnetic resonance cholan-giopancreatography were unremarkable. Rheumatologic evaluation at the time detected symmetrical polyarthritis of hands and feet and consulted for a possible SLE flare, presenting with cytopenias, pleuritis and peritonitis. Immunology testing was positive for ANA 1/640, anti-dsDNA (43 U/ml), lowC3 (0.77 gr/lt) and a positive direct Coombs test (++).Three daily intravenous pulses of 1gr methylprednisolone were initiated, followed by 40mg prednisone (0.6 mg/kg), leading to an immediate clinical and laboratory response. Ultimately, the patient was discharged with gradual tapering of gluco-corticoids and subcutaneous belimumab was initiated; methotrexate was discontinued due to the markedly elevated liver function tests. One year later, the patient remains in clinical remission, with persistent serologic activity, but no new flares.
Case 3
A 40-year-old Caucasian woman with a history of leuko-penia and photosensitivity but no formal diagnosis of an autoimmune rheumatic disease, presented with new-onset abdominal pain, nausea, vomiting, accompanied by low grade fever. The symptoms had started 3 days prior to admission, although the patient reported recurrent episodes of abdominal pain in the preceding 5 months,
without having sought medical attention. On admission, the patient was ill-appearing and physical examination revealed metallic bowel sounds, rebound tenderness, and shifting dullness (indicative of ascites). Laboratory tests showed mild, normocytic, normochro-mic anaemia (white blood cells were normal). An abdominal CT scan confirmed the presence of ascites, together with profound, segmental dilatation and wall thickening of the small intestine, concerning mainly the jejunum. Paracentesis of the ascitic fluid showed pleocytosis (170 cells/|jl, 55% lymphocytes), with negative cultures and cytology. Subsequent abdominal CT angiography revealed remarkable jejunal wall thickening with abnormal enhancement (target sign) and wall thickening of the jejunal branches of the superior mesenteric artery. The latter findings were also confirmed by abdominal MRI (Figure 2). Collectively, imaging findings were suggestive of mesenteric vasculitis. A chest CT showed bilateral pleural effusions.
Gastrointestinal endoscopy revealed segmental mucosal oedema of the duodenum and jejunum; biopsies were negative for malignancy. Following sterile blood and as-citic fluid cultures, broad-spectrum antibiotics, initiated empirically on admission, were gradually discontinued. Immunologic testing revealed positive ANA 1/320, anti-dsDNA (40 U/ml) and anti-Ro, and significantly reduced C3/C4 levels; antiphospholipid and anti-neutro-phil cytoplasmic antibodies (ANCAs) were negative. A diagnosis of SLE was suspected following rheumato-logic evaluation, based on both clinical manifestations (mesenteric vasculitis/peritonitis, history of photosen-sitivity and leukopenia) and compatible serology. Three daily intravenous methylprednisolone pulses 1 gr were administered, followed by 50 mg prednisone orally. Azathioprine and hydroxychloroquine were also started.
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Figure 2. Abdominal CT and MR images of patient 3. (a) Axial CTA image; Ascites (red arrows); wall thickening of jejunal arterial branches (yellow arrow); jejunal wall thickening (green arrows). (b) MRI T2 haste coronal image: Jejunal wall thickening (green arrows); ascites (red arrow). (c) MRI T2 haste coronal image: Jejunal wall thickening (green arrow); ascites (red arrows).
The patient experienced a gradual clinical and imaging improvement. Glucocorticoids were ultimately discontinued six months later and over 4-year follow-up the patient remains in glucocorticoid-free sustained remission.
Case 4
A 40-year-old Caucasian woman with a 20-year history of SLE (based on arthritis, rash, positive ANA, anti-dsD-NA, anti-Sm, anti-Ro and hypocomplementemia), was admitted to another hospital due to epigastric pain and vomiting. Prior to admission, she was treated with hydroxychloroquine and low-dose prednisone, and was clinically quiescent, although serologically active. Clinical examination upon admission revealed guarding, rebound tenderness and decreased bowel sounds. Blood tests were unremarkable with normal inflammatory markers; complement levels were low and anti-dsDNA significantly elevated. Urgent abdominal CT revealed ascites and bowel wall thickening with a typical target sign, mainly concerning the jejunum and a smaller part of the ileum. Multiple enlarged lymph nodes were also present, and the findings were confirmed by MR en-teroclysis (Figure 3). Upper GI endoscopy showed no abnormalities and histological examination of small intestine showed non-specific inflammatory mucosal lesions. A thorough work-up for infectious causes, including Yersinia and cytomegalovirus, was negative. Antibiotics were initially started empirically, but based on patient's medical history and imaging findings, a diagnosis of lupus enteritis/mesenteric vasculitis was suspected, and highdose prednisone (1mg/kg daily) was added. The patient showed a clinical improvement and was transferred to our hospital for further management. On day 2 of hospitalization and following reduction of prednisone dose, the patient experienced recurrence
of abdominal pain and vomiting, together with rebound tenderness in examination. Repeat abdominal CT and CT angiography revealed improvement of findings concerning the small intestine, but a profound dilatation and wall thickening of the transverse colon, sigmoid and rectum, without signs indicative of thrombosis or ischemia. Ascitic fluid analysis showed normal white cell count and culture was negative.
With a presumed lupus flare presenting with lupus enteritis, three pulses of 1gr methylprednisolone were administered, followed by 0.6mg/kg prednisone orally. Intravenous cyclophosphamide was also started, due to the patient's deterioration after initial glucocorticoid tapering. The patient showed an immediate clinical response and subsequent ultrasound revealed improvement of bowel dilatation. Three months later, the patient is asymptomatic, on treatment with monthly pulses of cyclophosphamide and gradual prednisone tapering.
DISCUSSION
GI symptoms are frequently encountered in SLE patients and may vary from minor and non-specific, such as nausea, vomiting, diarrhoea, to more serious like malabsorption, ascites or acute abdomen. Although usually related to medication adverse effects, infections or metabolic disorders, abdominal manifestations may occasionally represent disease-related involvement. A wide spectrum of clinical entities including abdominal serositis/peritonitis, mesenteric vasculitis, intestinal pseudo-obstruction, protein-losing enteropathy, have been described as clinical manifestations of abdominal lupus. GI involvement is usually seen in the context of multisystem disease activity, but infrequently may appear as an isolated or even presenting symptom of the disease. To this end, physicians' awareness for primary
Figure 3. Abdominal CT, MR enteroclysis images of patient 4. (a) Axial CT image; jejunal wall thickening, target sign (red arrows); wall thickening of the ileum (yellow arrows). (b) MR enteroclysis image; wall thickening of jejunum and ileum (red arrows). (c) Lateral CT image; wall thickening of sigmoid and rectum (red arrows); ascites (yellow arrow).
acute lupus abdominal situations is crucial, because if remain unrecognised, they can lead to severe morbidity.2 Although pleuritis and pericarditis are cardinal findings in SLE, ascites as a clinical manifestation of lupus serositis is rare and usually mild, with exudative characteristics (SAAG<1.1) and a lymphocytic predominance. However, cases of massive painless ascites as a prominent and occasionally initial manifestation of lupus serositis have been reported. 11,12When accompanied by abdominal pain and clinical signs of peritoneal irritation, the condition is usually termed lupus peritonitis (BILAG-2004 glossary). The latter may appear as acute surgical abdomen frequently leading to misdiagnosis.3 Pathophysiologically, peritoneal microvessel inflammations considered the most probable underlying mechanism. Immune-complex deposition and complement activation have been described in the peritoneal microvasculature, together with granular depositions of IgG and complement along the mesothelial layer and blood vessels in SLE patients with serositis.13
The terms lupus enteritis and mesenteric vasculitis are often used interchangeably, and present with non-specific symptoms, such as abdominal pain, vomiting, diarrhoea and fever.6 They usually -although not always-manifest in the context of generalized disease activity.2 Pathophysiologically, both inflammatory and thrombotic pathogenetic mechanisms have been proposed. The former is a classic leucocytoclastic vasculitis due to immune-complex deposition in vessel walls and complement activation. The thrombotic form is caused by vascular thrombosis due to circulating antiphospholipid antibodies (aPLs), a finding not confirmed in patients 3 and 4 of our series.14,15Since different bowel wall layers are not equally sensitive to diminished blood supply, variable clinical symptoms may be present, depending on the layer predominantly involved. Ischemia of mucosal blood vessels leads to ulceration, diarrhoea, and haemorrhage, while deeper involvement of the bowel wall can be manifested as pseudo-obstruction, perforation and ultimately peritonitis.14
Computed tomography is the gold standard for the diagnosis of mesenteric vasculitis, showing focal or diffuse bowel wall thickening with abnormal wall enhancement (target sign), characteristic dilated bowel loops, mes-enteric vessel stenosis and engorgement (comb sign) and increased attenuation of the mesenteric fat; these findings were evident in cases 3 and 4 of our series. 16Furthermore, ultrasonography is an underestimated tool, that can be helpful in diagnosis and follow-up of mesenteric vasculitis, showing bowel oedema, whereas the "thumb-print" sign is a radiographic finding indicative of ischemic changes, caused by irregular bowel fold thickening. Endoscopy may reveal signs of either ischemia or ulcers that look like "punch out" mucosal areas. Although lupus enteritis/mesenteric vasculitis are
not typically diagnosed by histological biopsy due to the location of affected vessels that are usually inaccessible, histology is nevertheless important to rule out competing diagnoses.14
There are limited data guiding therapeutic approach to these rare lupus manifestations, as controlled studies are lacking. Moderate to high glucocorticoid doses (usually following intravenous pulses), are considered as first-line therapy, leading to rapid response in most patients. In severe or refractory cases (like patients 2-4 in our series), or in relapses, immunosuppressive agents should be considered.5,17,18 The choice of drug is based on severity of manifestation or concurrent disease activity from other organ-systems(renal, neuropsychiatry).6 Case 4 demonstrates the necessity of cyclophosphamide in a severe lupus abdominal flare refractory to glucocorticoids, whereas in case 2 belimumab was preferred because of extra-gastrointestinal (musculoskeletal) and persistent serological activity.
Patients 3 and 4 in our case series highlight the challenging scenario of "organ-dominant" lupus. Both patients presented with a major lupus abdominal manifestation, lacking other significant clinical findings; in patient 3, particularly, this was the presenting manifestation leading to SLE diagnosis (although history of photosensitivity and leukopenia were "alarming" findings).These patients represent a true diagnostic challenge, which becomes greater if a diagnosis of SLE does not pre-exist. Classification criteria are not helpful in this regard, because abdominal serositis and mesenteric vasculitis (owing to their rarity) are not included in any set of criteria (serositis is defined as pericardial or pleural inflammation). These situations highlight the inherent limitation of classification criteria, which by default aim for a high specificity and inevitably have to exclude rare manifestations of diseases.19Lacking diagnostic criteria, the diagnosis of SLE will continue to rely on expert physician judgment, however physicians with less experience in the disease should also keep a high index of suspicion in patients presenting with even solitary organ-threatening manifestations. In conclusion, we describe four patients with acute abdominal manifestations as presenting or predominant symptoms of a lupus flare. Rather than being distinct entities, lupus abdominal manifestations could be considered as a clinical continuum with variable grade of severity, sharing same pathophysiological mechanisms and bearing overlapping symptoms and imaging findings.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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