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Acute abdominal complications of systemic lupus erythematosus and polyarteritis nodosa
Acute Abdominal Complications of Systemic Lupus Erythematosus and Polyarteritis Nodosa
THOMAS JOHN MARY
M. ZIZIC,
N. CLASSEN, BETTY
Baltimore,
M.D. M.D.
STEVENS,
M.D.
Maryland
From the Division of Rheumatology, Department of Medicine and the Dep&mem of surgery, Johns Hopkins University School of Medicine, The Good Samaritan Hospital, Baltimore. Maryland. This study was supported in part by grants from The Arthritis Foundation Clinical Research Center and the Johns Hopkins Multipurpose Arthritis Center (2-P00-AM20588). Requests for reprints should be addressed to Dr. Thomas M. Zizic, Division of Rheumatology, The Good 8amaritan Hospital, 5801 Loch Raven Boulevard, Baltiie, Maryland, 21239. Manuscript accepted February 23, 1982.
Fifteen (11 percent) of 140 patients with systemic lupus erythematosus (SLE) and five (31 percent) of 16 patients with poiyarteritis nodosa (PA) developed disease-related signs and symptoms of an acute surgical abdomen. Peripheral vasculitis (p <0.025), nervous system involvement (p <0.05), ischemk necrosk of bone (p
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TABLE I
Demographic Features of SLE Abdominal
TABLE II
14 (93%) 7 (47%)
112 (90%) 66 (53%)
29 (14-53) 31(15-54)
30 (9-70) 32 (9-70)
8.1 6.5
15 (100%)
9.0 6.5
107 (86%)
PATIENTS AND METHODS Patients admitted, on one or more occasions, to the Johns Hopkins Rheumatic Disease Unit at The Good Samaritan Hospital with a definite diagnosis of SLE or PA were selected for review solely on the basis of an acute abdominal crisis,
which was defined as symptoms and signs of peritoneal inflammation suggestive of an acute surgical abdomen. In four patients with SLE and two with PA, surgical consultation was
also obtained because of accompanying gastrointestinal bleeding as well as evidence of peritoneal inflammation. All patients with PA had a multisystem disorder with angiographic and/or histologic evidence of involvement of medium-sized arteries. One hundred twenty-two (87 percent) of the 140 patients with SLE fulfilled the preliminary criteria of the American Rheumatism Association for the classification of SLE [3]. The remaining 18 patients had, in addition to at least two criteria, a multisystem disease with additional features characteristic of SLE (for example, fever, lymphadenopathy, compatible skin or renal biopsy, antinuclear antibodies, hypocomplementemia). A manifestation was considered a feature of SLE only when, after diligent search, no alternative cause was established. It should be noted that all 15 patients with SLE and acute abdominal events fulfilled four or more
of the criteria (mean, 7.3 criteria per patient). The immunofluorescent assay for antinuclear antibodies, by the method of Holborow et al. [4] utilizing mouse liver as substrate and the total hemolytic complement by the method of Mayer [5], were uniformly performed in our own laboratory.
RESULTS Of the 140 patients with SLE admitted to our Rheumatic Disease Unit, 15 (11 percent) developed a diseaserelated abdominal event. Seven additional patients had abdominal surgery for nondisease-related problems. Three patients had a cholecystectomy, two had resections of ruptured divetticuli and abscesses, one each had a perforated peptic ulcer and resection of tuboovarian abscesses. Five (31 percent) of the 16 patients with PA also developtid disease-related acute abdomens.
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Clinical Features of SLE
Nonabdominal
( 15 patients) (125 patients) Females Caucasian Age at onset (years) By symptom By diagnosis Mean follow-up (years) From symptom From diagnosis American Rheumatism Association criteria Four or more
ET AL.
Clinical Features Arthralgias/arthritis Fever Skin rash Pleurisy/pericarditis Alopecia Raynaud’s phenomenon Nephritis Splenomegaly Myocarditis Subcutaneous nodules Cytoid bodies
Abdominal (15 patients) 15 15 13 11 10 6 5 4 3 2 2
(100%) (100%) (87%) (73%) (67%) (40%) (33%) (27%) (20%) (13%) (13%)
Nonabdominal (125 patients) 108 (86%) 83 (66%) 97 (78%) 78 (62%) 47 (38%) 26(21%) 62 (50%) 20 (16%) 9 (7%) 10 (8%) 5 (4%)
Demographic features of patients with SLE with or without an acute abdominal event are nearly identical (Table I). In PA, patients with acute abdominal crises are slightly older, more often Caucasian, and are females at a rate double that of the nonabdominal group. Clinico-Laboratory Features: SLE. The majority of clinical features in patients with SLE are not significantly different in the two groups, although most features, clinical (Table II) and laboratory (Table Ill), are more frequent in those with an abdominal syndrome compared with those without an acute abdomen. Those manifestations that were significantly different in the two groups are listed in Table IV. Peripheral vasculitis (such as recurrent leg ulcers, splinter hemorrhages, and mucous membrane and digital ulcerations), central or peripheral nervous system involvement, thrombocytopenia, and circulating rheumatoid factor (latex titer 7 1: 160) were significantly increased among those with acute abdomens. Furthermore, one complication of SLE, and/or its therapy, ischemic necrosis of bone, is almost three times as frequent in the acute abdominal group, occurring in six (40 percent) compared with 18 (14 percent) of those without abdominal crises (p <0.05). The seven patients with non-SLE-related abdominal surgery, such as cholecystectomy and resection of perforated diverticuli, did not have any manifestations that were significantly different from the remainder of the SLE population. Polyarteritis Nodosa. Prominent manifestations of the abdominal group among those with PA were the presence of a mononeuritis multiplex in four of the five and central nervous system involvement in the fifth (100 percent) (Table V). Only four (36 percent) of the 11 nonabdominal PA patients had nervous system involvement (p <0.05). Thrombocytopenia was present at the onset of abdominal crisis in all five patients, with platelet counts ranging from 56,000 to 116,000 (p
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TABLE Ill
LaboratoryFeatures Anemia Leukopenia Antinuclear antibodies Lupus erythematosus ceils Hypocompiementemia Biologic false-positive reaction Anti-ss-DNA Antids-DNA Anti-RNP Anti-Sm Anti-R0 (SSA) Anti-La (SSB)
Abdomtnai (15 patients) 12 10 15 13 9 2 13/14 2114 5114 l/l4 4114 1114
(80%) (67%) (100%) (87%) (60%) (13%) (93%) (14%) (36%) (7%) (29%) (7%)
Acute Abdominal Syndromes in SLE
TABLE IV
Laboratory Manifestations of SLE Nonabdominal (125 patients) 69 (55%) 58 (46 %) 114(91%) 94 (75%) 71 (57%) 18 (14%) 55163 (87 %) 4163 (6%) 16/63 (25%) 4163 (6%) 13/63 (20%) O/63 (0%)
ET AL.
Ciinico-Laboratory Features Peripheral vascuiitis” Central or peripheral nervous system disease+ ischemic necrosis of bone+ Thrombocytopeniaz Rheumatoid factor (iatex)t
Abrbmtaai (15 patients)
Noeabdomtnsl (125 patients)
8 (57%) 10 (67%)
31 (25%) 42 (34%)
6 (40%) 8 (53%) 12/13 (92%)
18 (14%) 24 (19%) 491109 (45%)
p <0.025. + p <0.05. + p
patients had positive rheumatoid factors by the latex system. Titers earlier in their course were, respectively, negative, negative, 1:80, 1:1280, and 1:1280, increasing in three of four patients at the time of their acute abdomen to 1:80, 1: 1280, 1: 1280, and 1: 10240. One patient who was negative early in the course of his illness was unfortunately not retested at the time of the acute abdominal event. In contrast, only three (27 percent) of the 11 nonabdominal PA patients were positive for rheumatoid factor. Acute Abdominal Syndrome: SLE. In more than two-thirds of patients with systemic lupus erythematosus, the abdominal syndrome was characterized by the insidious onset of intermittent, lower quadrant cramping and abdominal pain that were present for an average of 34 days (range, 11 to 74 days) prior to the crisis. The majority of patients had accompanying anorexia, nausea, and vomiting, with diarrhea and melena in approximately one-third. Fever was universally present, and a significant tachycardia, in 85 percent. In more than three-quarters, there was direct and rebound abdominal tenderness at the time of the acute event. Abdominal distention was present in the majority, but a classic surgical abdomen with abdominal guarding and rigidity occurred in only 31 percent of patients, and late in the course of disease. Approximately two-thirds of patients had hypoactive bowel sounds, but completely absent bowel sounds, also late to develop, were again noted in only 31 percent. Early in the course, abdominal roentgenograms were not very revealing but, subsequently, one-quarter had diffuse small bowel distension with air-fluid levels. One of these and three additional patients, (four of 15) developed intra-abdominal free air. On barium contrast studies, one patient each had a “gasless bowel,” “thumb-printing” thought to be secondary to submucosal hemorrhage, and the colon “cut off sign,” that is, distention of the small bowel and colon up to the splenic flexure.
Eleven (73 percent) of the 15 patients with SLE had exploratory laparotomy for acute abdominal events. Six of these patients had intestinal perforations, five colonic and one in the small intestine. In general, small vessels were involved, resulting in discrete, localized lesions so that even in the one patient with multiple perforations there were skip areas with normal-appearing bowel in between (Figure 1). Three patients had “pre-perforations” in that there was evidence of vasculitis but the bowel wall was still intact. Resolution of the abdominal syndrome in these patients occurred with corticosteroid augmentation. Four years later one of these patients had a second acute abdomen and at exploration was found to have pancreatitis. She died five days later and postmortem examination revealed arteritis in a mesenteric as well as a peripancreatic artery. Thus, of the 11 patients with SLE requiring operative intervention, nine (82 percent) were found to have evCllnlco-Laboratory Features of PA
TABLE V
Feature Fever Central or peripheral nervous system disease’ Arthritis/arthraigia Skin rash Peripheral vascuiitis Myaigia Nephritis Serositis Hepatomegaiy Anemia Leukocytosis Thrombocytosis Thrombocytopenia+ Rheumatoid factor Antinuclear antibody Cryogiobuiins Hypocompiementemia Hepatitis-associated antigen
Abdornieal (5 FstteW
NonsWomirlsi (11 patients)
5 5
7 4
4 4 3 3 3 1 1 3 4 4 5 4 1 1 1 0
5 7 7 7 7 4 3 7 7 7 0 3 0 3 3 2
p <0.05. + p
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Figure 1. Patient F.B. with systemic lupus erythematosus. Small, 1 to 2 cm perforations in segment of left transverse colon. Serosa was normal proximal and distal to perforated site.
Figure 2. Patient D. W. with polyarteritis. Large segment of intestinal ischemia with edematous loops of bowel and early gangrene.
idence of intra-abdominal arteritis. Only two had polyserositis without gross evidence of vasculitis at surgery. Four patients with acute abdominal syndromes promptly responded to corticosteroid augmentation alone while surgery was being considered. Two of these patients subsequently died, one and five years later, both of sepsis. Postmortem examination revealed evidence of healed mesenteric vasculitis in both. Eight (53 percent) of the 15 patients with SLE and acute abdomens died as a result of the abdominal crises. Six of the seven surviving patients represent those most recently seen and aggressively treated. Of our seven survivors, all had the prednisone dosage increased to divided doses ranging from 80 to 150 mg/day. Five of these patients had surgical intervention as well. Polyarteritis Nodosa. With several exceptions, the abdominal syndrome seen in patients with PA is clinically similar to that in SLE. In PA the pain was more often sharp and intense rather than cramping and was present for only an average of 11 days (range, one to 39 days) prior to the abdominal crisis. Additionally, all patients had significant fever, tachycardia, abdominal distension, direct and rebound tenderness. Four of the five had abdominal guarding and rigidity with absent bowel sounds in three and markedly decreased sounds in the fourth. The more classic signs of an acute surgical abdomen in patients with PA reflected more diffuse involvement of larger vessels resulting in ischemia and gangrene of larger segments of bowel than was seen in patients with SLE. At surgery, all five patients were found to have gross evidence of mesenteric arteritis with infarcted bowel and intestinal perforations
(Figure 2). Four patients had large ischemic segments of the small bowel with resulting perforation and the fifth had multiple necrotic segments of both small and large intestine. Four of the five patients died within two to 61 days of the abdominal crisis. One patient survived a transmural jejunal infarction with perforation treated with resection and corticosteroid augmentation. Five months later, he succumbed to cryptococcal meningitis. Interestingly, autopsy results did not reveal further evidence of active mesenteric vasculitis at the time of his death. In contrast, only two (18 percent) of the 11 PA patients without abdominal involvement died.
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COMMENTS Gastrointestinal manifestations of SLE were first emphasized by Osler in 1895 [6]; and abdominal pain has long been recognized as a prominent manifestation of both SLE and PA [7-131. Recently, several excellent reviews have been written on this subject [ 14-161. Hoffman and Katz [ 171 point out that abdominal pain is the most common symptom of lupus-induced gastrointestinal involvement and has many potential causes. Severe gastrointestinal symptoms occurred in 19 (18 percent) of the 105 patients reported by Harvey et al. [ 181, and 10 (19 percent) of the 52 autopsied patients in this series had arteritis involving the gastrointestinal tract [ 181. Subsequent cases of documented mesenteric arteritis in SLE have been numerous [ 1,2,13,16,1 g-271. Similarly, symptoms referable to the gastrointestinal tract occur in more than 50 percent of patients with PA [ 7,12,28,29]. In a recent study by
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Travers et al. [ 121, seven (54 percent) of 13 patients with PA had demonstrable involvement of the mesenteric arteries on angiography. Pive had aneurysms and the remaining two had arteriopathy without aneurysmal formation. Although gastrointestinal involvement can occur in any of the connective tissue diseases, it is of most concern in SLE and PA, not only because of its greater frequency but also in view of the numerous clinical entities that can simulate the abdominal involvement by these two disorders [ 1,2,17]. The differential diagnosis includes not only lesions specifically related to these vasculitides and/or their therapies [ 1,2,10,12-201, but also the entire spectrum of intercurrent problems causing acute abdominal syndromes [30-351. Necrotizing enterocolitis with pneumatosis intestinalis has been reported in SLE and PA [30], as has spontaneous rupture of the liver or the spleen [32-351. Primary or spontaneous peritonitis may occur in patients with SLE [31]. In addition, in SLE, not only inflammatory disease df the mesenteric arteries, but also the sterile serositis of SLE can produce nearly identical clinical pictures. Since it is clear that, in contrast to other rheumatic diseases, SLE and PA more frequently have diseaserelated abdominal crises, it is important to recognize the clinical and laboratory features that relate to mesenteric arteritis and to delineate the clinical aspects of the abdominal syndrome which characterize and help to differentiate it from other intraabdominal disorders. As previously pointed out by ourselves [2,27] and Pollack et al. [26], the diagnosis of an acute surgical abdomen due tq SLE could be made with confidence only when the patient had concomitant disease activity in other organs. The index of suspicion should be particularly high in those patients who have peripheral vasculitis, neurologic involvement, thrombocytopenia, or rheumatoid factor positivity, all of which occur significantly more often in those with abdominal crises. In the PA patients, although it is noteworthy that all five (100 percent) had manifestations of peripheral arteritis and nervous system involvement, more striking was the thrombocytopenia that occurred in all five. Only one (6 percent) of 17 patients reported by Travers et al. [ 121 and none of our 11 PA patients without abdominal involvement had thrombocytopenia. Rheumatoid factor was positive initially in three (60 percent) of the five patients with PA. At the time of the acute abdomen, four patients were retested with conversion to seropositivity in one, increased titer in two, and unchanged high titer in the remaining patient. In contrast, rheumatoid factor seropositivity was found in only three (27 percent) of our 11 PA patients without abdominal involvement. Since our overall prevalence of rheumatoid factor (44 percent) is similar to the 47 percent reported by Travers et al.
AN0 POLYARTERITIS NODOSA-ZIZIC
ET AL.
[ 121, it would be of interest to know the association, if any, with acute abdomens in the latter group. Such a correlation, however, may relate to degree of seropositivity, which was more marked and sustained in our patients. In addition to having a high index of suspicion in those with the previously mentioned disease-related risk factors, the character of the abdominal syndrome is of value in the differential diagnosis. It is particularly important not to delay therapy until all of the classic signs of an acute abdomen develop, since abdominal guarding or rigidity and absent bowel sounds often occur extremely late, if at all. In part, this may be due to steroid masking of abdominal signs, as has been reported in steroid-treated patients with perforated peptic ulcers [36-391. Steroid suppression of tissue inflammation makes it essential to pursue the differential diagnosis of acute or recurrent abdominal pain with more than usual intensity. In both SLE and PA, it is difficult to detect the gastrointestinal involvement with routine radiography. Upper gastrointestinal contrast studies were helpful in only 20 percent and barium enemas, in none. Although abdominal x rays may reveal pneumoperitoneum, this occurs late and is of little value in the nonsurgical management of the patient. It would appear that many of the macroscopic lesions seen at autopsy do not lend themselves to recognition by roentgenography. [25,28]. As in one of our patients in whom mesenteric arteriography localized at the site of gastrointestinal bleeding and subsequent perforation, this procedure may be helpful, which has been emphasized by others [12,40,41]. Management of the acute abdomen in SLE and PA is a challenging therapeutic and surgical problem. Pollack et al. [26] successfully treated five of six patients with SLE and severe abdominal symptoms with corticosteroid augmentation alone, but an additional four required surgical intervention as well [26]. In the series of Matolo and Albo [ 421, it is noted that six of 10 medically treated patients with acute abdominal syndromes or hemorrhage died, whereas all four surgical patients survived. Of our seven survivors, two responded to increased corticosteroids alone and five also required surgical intervention. As previously pointed out by us and others, the progression of clinical symptoms and signs despite augmented medical therapy should be followed promptly by laparotomy [2,13,17,26]. Our experience in abdominal PA remains problematic, since all five of these patients have succumbed despite augmented corticosteroid therapy and surgical intervention in ail and the addition of cyclophosphamide therapy in two. Such grave prognosis is found by others as well. In the series of Travers et al., [ 121, four of the five patients who died had had severe abdominal pain,
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with three deaths being the result of bowel infarction and renal failure. The clinical association of rheumatoid factor in high titer in rheumatoid arthritis patients with vasculitis has been shown by many [43-471. A variety of anti-gamma globulin factors has been implicated in the pathogenesis of rheumatoid vasculitis, including conventional 19s rheumatoid factor [43,48], a low molecular weight (7s) immunoglobulin M (IgM) [49,50], an immunoglobulin G (IgG) with antiglobulin activity [50], and cryoprecipitable antigamma activity [51]. Numerous experimental studies have also implicated IgM rheumatoid factor in vascular damage. Baum et al. [52] demonstrated that rheumatoid factor reacting with antigen-antibody complexes becomes deposited on endothelium when infused in rat mesentery, suggesting that the deposition of rheumatoid factor mediates vasculitis. Recently lzui and Eisenberg [53] have studied the MRL/l mouse strain, which spontaneously develops a
ET AL
lupuslike syndrome, vasculitis, and arthritis associated with high levels of anti-DNA antibodies and rheumatoid factors [ 531, and they report IgG-rheumatoid factor complexed with IgG-anti-DNA in this murine model. These investigators suggest that these rheumatoid factors and antinuclear antibodies, singly or in combination, may be pathogenetic for the inflammatory lesions. Whether or not thrombocytopenia is a feature of this murine syndrome has not been studied. Such would be of interest, however, in view of the observations of Yeatts et al. [54], showing release of vasoactive amines from platelets exposed to insoluble complexes. In view of these experimental observations and the statistically significant association between rheumatoid factors and mesenteric arteritis in our patients, the possibility of a pathogenetic role for certain of the anti-gamma globulin antibodies should be further explored; such studies are in progress.
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THOMAS JOHN MARY
M. ZIZIC,
N. CLASSEN, BETTY
Baltimore,
M.D. M.D.
STEVENS,
M.D.
Maryland
From the Division of Rheumatology, Department of Medicine and the Dep&mem of surgery, Johns Hopkins University School of Medicine, The Good Samaritan Hospital, Baltimore. Maryland. This study was supported in part by grants from The Arthritis Foundation Clinical Research Center and the Johns Hopkins Multipurpose Arthritis Center (2-P00-AM20588). Requests for reprints should be addressed to Dr. Thomas M. Zizic, Division of Rheumatology, The Good 8amaritan Hospital, 5801 Loch Raven Boulevard, Baltiie, Maryland, 21239. Manuscript accepted February 23, 1982.
Fifteen (11 percent) of 140 patients with systemic lupus erythematosus (SLE) and five (31 percent) of 16 patients with poiyarteritis nodosa (PA) developed disease-related signs and symptoms of an acute surgical abdomen. Peripheral vasculitis (p <0.025), nervous system involvement (p <0.05), ischemk necrosk of bone (p
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TABLE I
Demographic Features of SLE Abdominal
TABLE II
14 (93%) 7 (47%)
112 (90%) 66 (53%)
29 (14-53) 31(15-54)
30 (9-70) 32 (9-70)
8.1 6.5
15 (100%)
9.0 6.5
107 (86%)
PATIENTS AND METHODS Patients admitted, on one or more occasions, to the Johns Hopkins Rheumatic Disease Unit at The Good Samaritan Hospital with a definite diagnosis of SLE or PA were selected for review solely on the basis of an acute abdominal crisis,
which was defined as symptoms and signs of peritoneal inflammation suggestive of an acute surgical abdomen. In four patients with SLE and two with PA, surgical consultation was
also obtained because of accompanying gastrointestinal bleeding as well as evidence of peritoneal inflammation. All patients with PA had a multisystem disorder with angiographic and/or histologic evidence of involvement of medium-sized arteries. One hundred twenty-two (87 percent) of the 140 patients with SLE fulfilled the preliminary criteria of the American Rheumatism Association for the classification of SLE [3]. The remaining 18 patients had, in addition to at least two criteria, a multisystem disease with additional features characteristic of SLE (for example, fever, lymphadenopathy, compatible skin or renal biopsy, antinuclear antibodies, hypocomplementemia). A manifestation was considered a feature of SLE only when, after diligent search, no alternative cause was established. It should be noted that all 15 patients with SLE and acute abdominal events fulfilled four or more
of the criteria (mean, 7.3 criteria per patient). The immunofluorescent assay for antinuclear antibodies, by the method of Holborow et al. [4] utilizing mouse liver as substrate and the total hemolytic complement by the method of Mayer [5], were uniformly performed in our own laboratory.
RESULTS Of the 140 patients with SLE admitted to our Rheumatic Disease Unit, 15 (11 percent) developed a diseaserelated abdominal event. Seven additional patients had abdominal surgery for nondisease-related problems. Three patients had a cholecystectomy, two had resections of ruptured divetticuli and abscesses, one each had a perforated peptic ulcer and resection of tuboovarian abscesses. Five (31 percent) of the 16 patients with PA also developtid disease-related acute abdomens.
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Clinical Features of SLE
Nonabdominal
( 15 patients) (125 patients) Females Caucasian Age at onset (years) By symptom By diagnosis Mean follow-up (years) From symptom From diagnosis American Rheumatism Association criteria Four or more
ET AL.
Clinical Features Arthralgias/arthritis Fever Skin rash Pleurisy/pericarditis Alopecia Raynaud’s phenomenon Nephritis Splenomegaly Myocarditis Subcutaneous nodules Cytoid bodies
Abdominal (15 patients) 15 15 13 11 10 6 5 4 3 2 2
(100%) (100%) (87%) (73%) (67%) (40%) (33%) (27%) (20%) (13%) (13%)
Nonabdominal (125 patients) 108 (86%) 83 (66%) 97 (78%) 78 (62%) 47 (38%) 26(21%) 62 (50%) 20 (16%) 9 (7%) 10 (8%) 5 (4%)
Demographic features of patients with SLE with or without an acute abdominal event are nearly identical (Table I). In PA, patients with acute abdominal crises are slightly older, more often Caucasian, and are females at a rate double that of the nonabdominal group. Clinico-Laboratory Features: SLE. The majority of clinical features in patients with SLE are not significantly different in the two groups, although most features, clinical (Table II) and laboratory (Table Ill), are more frequent in those with an abdominal syndrome compared with those without an acute abdomen. Those manifestations that were significantly different in the two groups are listed in Table IV. Peripheral vasculitis (such as recurrent leg ulcers, splinter hemorrhages, and mucous membrane and digital ulcerations), central or peripheral nervous system involvement, thrombocytopenia, and circulating rheumatoid factor (latex titer 7 1: 160) were significantly increased among those with acute abdomens. Furthermore, one complication of SLE, and/or its therapy, ischemic necrosis of bone, is almost three times as frequent in the acute abdominal group, occurring in six (40 percent) compared with 18 (14 percent) of those without abdominal crises (p <0.05). The seven patients with non-SLE-related abdominal surgery, such as cholecystectomy and resection of perforated diverticuli, did not have any manifestations that were significantly different from the remainder of the SLE population. Polyarteritis Nodosa. Prominent manifestations of the abdominal group among those with PA were the presence of a mononeuritis multiplex in four of the five and central nervous system involvement in the fifth (100 percent) (Table V). Only four (36 percent) of the 11 nonabdominal PA patients had nervous system involvement (p <0.05). Thrombocytopenia was present at the onset of abdominal crisis in all five patients, with platelet counts ranging from 56,000 to 116,000 (p
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TABLE Ill
LaboratoryFeatures Anemia Leukopenia Antinuclear antibodies Lupus erythematosus ceils Hypocompiementemia Biologic false-positive reaction Anti-ss-DNA Antids-DNA Anti-RNP Anti-Sm Anti-R0 (SSA) Anti-La (SSB)
Abdomtnai (15 patients) 12 10 15 13 9 2 13/14 2114 5114 l/l4 4114 1114
(80%) (67%) (100%) (87%) (60%) (13%) (93%) (14%) (36%) (7%) (29%) (7%)
Acute Abdominal Syndromes in SLE
TABLE IV
Laboratory Manifestations of SLE Nonabdominal (125 patients) 69 (55%) 58 (46 %) 114(91%) 94 (75%) 71 (57%) 18 (14%) 55163 (87 %) 4163 (6%) 16/63 (25%) 4163 (6%) 13/63 (20%) O/63 (0%)
ET AL.
Ciinico-Laboratory Features Peripheral vascuiitis” Central or peripheral nervous system disease+ ischemic necrosis of bone+ Thrombocytopeniaz Rheumatoid factor (iatex)t
Abrbmtaai (15 patients)
Noeabdomtnsl (125 patients)
8 (57%) 10 (67%)
31 (25%) 42 (34%)
6 (40%) 8 (53%) 12/13 (92%)
18 (14%) 24 (19%) 491109 (45%)
p <0.025. + p <0.05. + p
patients had positive rheumatoid factors by the latex system. Titers earlier in their course were, respectively, negative, negative, 1:80, 1:1280, and 1:1280, increasing in three of four patients at the time of their acute abdomen to 1:80, 1: 1280, 1: 1280, and 1: 10240. One patient who was negative early in the course of his illness was unfortunately not retested at the time of the acute abdominal event. In contrast, only three (27 percent) of the 11 nonabdominal PA patients were positive for rheumatoid factor. Acute Abdominal Syndrome: SLE. In more than two-thirds of patients with systemic lupus erythematosus, the abdominal syndrome was characterized by the insidious onset of intermittent, lower quadrant cramping and abdominal pain that were present for an average of 34 days (range, 11 to 74 days) prior to the crisis. The majority of patients had accompanying anorexia, nausea, and vomiting, with diarrhea and melena in approximately one-third. Fever was universally present, and a significant tachycardia, in 85 percent. In more than three-quarters, there was direct and rebound abdominal tenderness at the time of the acute event. Abdominal distention was present in the majority, but a classic surgical abdomen with abdominal guarding and rigidity occurred in only 31 percent of patients, and late in the course of disease. Approximately two-thirds of patients had hypoactive bowel sounds, but completely absent bowel sounds, also late to develop, were again noted in only 31 percent. Early in the course, abdominal roentgenograms were not very revealing but, subsequently, one-quarter had diffuse small bowel distension with air-fluid levels. One of these and three additional patients, (four of 15) developed intra-abdominal free air. On barium contrast studies, one patient each had a “gasless bowel,” “thumb-printing” thought to be secondary to submucosal hemorrhage, and the colon “cut off sign,” that is, distention of the small bowel and colon up to the splenic flexure.
Eleven (73 percent) of the 15 patients with SLE had exploratory laparotomy for acute abdominal events. Six of these patients had intestinal perforations, five colonic and one in the small intestine. In general, small vessels were involved, resulting in discrete, localized lesions so that even in the one patient with multiple perforations there were skip areas with normal-appearing bowel in between (Figure 1). Three patients had “pre-perforations” in that there was evidence of vasculitis but the bowel wall was still intact. Resolution of the abdominal syndrome in these patients occurred with corticosteroid augmentation. Four years later one of these patients had a second acute abdomen and at exploration was found to have pancreatitis. She died five days later and postmortem examination revealed arteritis in a mesenteric as well as a peripancreatic artery. Thus, of the 11 patients with SLE requiring operative intervention, nine (82 percent) were found to have evCllnlco-Laboratory Features of PA
TABLE V
Feature Fever Central or peripheral nervous system disease’ Arthritis/arthraigia Skin rash Peripheral vascuiitis Myaigia Nephritis Serositis Hepatomegaiy Anemia Leukocytosis Thrombocytosis Thrombocytopenia+ Rheumatoid factor Antinuclear antibody Cryogiobuiins Hypocompiementemia Hepatitis-associated antigen
Abdornieal (5 FstteW
NonsWomirlsi (11 patients)
5 5
7 4
4 4 3 3 3 1 1 3 4 4 5 4 1 1 1 0
5 7 7 7 7 4 3 7 7 7 0 3 0 3 3 2
p <0.05. + p
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Figure 1. Patient F.B. with systemic lupus erythematosus. Small, 1 to 2 cm perforations in segment of left transverse colon. Serosa was normal proximal and distal to perforated site.
Figure 2. Patient D. W. with polyarteritis. Large segment of intestinal ischemia with edematous loops of bowel and early gangrene.
idence of intra-abdominal arteritis. Only two had polyserositis without gross evidence of vasculitis at surgery. Four patients with acute abdominal syndromes promptly responded to corticosteroid augmentation alone while surgery was being considered. Two of these patients subsequently died, one and five years later, both of sepsis. Postmortem examination revealed evidence of healed mesenteric vasculitis in both. Eight (53 percent) of the 15 patients with SLE and acute abdomens died as a result of the abdominal crises. Six of the seven surviving patients represent those most recently seen and aggressively treated. Of our seven survivors, all had the prednisone dosage increased to divided doses ranging from 80 to 150 mg/day. Five of these patients had surgical intervention as well. Polyarteritis Nodosa. With several exceptions, the abdominal syndrome seen in patients with PA is clinically similar to that in SLE. In PA the pain was more often sharp and intense rather than cramping and was present for only an average of 11 days (range, one to 39 days) prior to the abdominal crisis. Additionally, all patients had significant fever, tachycardia, abdominal distension, direct and rebound tenderness. Four of the five had abdominal guarding and rigidity with absent bowel sounds in three and markedly decreased sounds in the fourth. The more classic signs of an acute surgical abdomen in patients with PA reflected more diffuse involvement of larger vessels resulting in ischemia and gangrene of larger segments of bowel than was seen in patients with SLE. At surgery, all five patients were found to have gross evidence of mesenteric arteritis with infarcted bowel and intestinal perforations
(Figure 2). Four patients had large ischemic segments of the small bowel with resulting perforation and the fifth had multiple necrotic segments of both small and large intestine. Four of the five patients died within two to 61 days of the abdominal crisis. One patient survived a transmural jejunal infarction with perforation treated with resection and corticosteroid augmentation. Five months later, he succumbed to cryptococcal meningitis. Interestingly, autopsy results did not reveal further evidence of active mesenteric vasculitis at the time of his death. In contrast, only two (18 percent) of the 11 PA patients without abdominal involvement died.
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COMMENTS Gastrointestinal manifestations of SLE were first emphasized by Osler in 1895 [6]; and abdominal pain has long been recognized as a prominent manifestation of both SLE and PA [7-131. Recently, several excellent reviews have been written on this subject [ 14-161. Hoffman and Katz [ 171 point out that abdominal pain is the most common symptom of lupus-induced gastrointestinal involvement and has many potential causes. Severe gastrointestinal symptoms occurred in 19 (18 percent) of the 105 patients reported by Harvey et al. [ 181, and 10 (19 percent) of the 52 autopsied patients in this series had arteritis involving the gastrointestinal tract [ 181. Subsequent cases of documented mesenteric arteritis in SLE have been numerous [ 1,2,13,16,1 g-271. Similarly, symptoms referable to the gastrointestinal tract occur in more than 50 percent of patients with PA [ 7,12,28,29]. In a recent study by
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Travers et al. [ 121, seven (54 percent) of 13 patients with PA had demonstrable involvement of the mesenteric arteries on angiography. Pive had aneurysms and the remaining two had arteriopathy without aneurysmal formation. Although gastrointestinal involvement can occur in any of the connective tissue diseases, it is of most concern in SLE and PA, not only because of its greater frequency but also in view of the numerous clinical entities that can simulate the abdominal involvement by these two disorders [ 1,2,17]. The differential diagnosis includes not only lesions specifically related to these vasculitides and/or their therapies [ 1,2,10,12-201, but also the entire spectrum of intercurrent problems causing acute abdominal syndromes [30-351. Necrotizing enterocolitis with pneumatosis intestinalis has been reported in SLE and PA [30], as has spontaneous rupture of the liver or the spleen [32-351. Primary or spontaneous peritonitis may occur in patients with SLE [31]. In addition, in SLE, not only inflammatory disease df the mesenteric arteries, but also the sterile serositis of SLE can produce nearly identical clinical pictures. Since it is clear that, in contrast to other rheumatic diseases, SLE and PA more frequently have diseaserelated abdominal crises, it is important to recognize the clinical and laboratory features that relate to mesenteric arteritis and to delineate the clinical aspects of the abdominal syndrome which characterize and help to differentiate it from other intraabdominal disorders. As previously pointed out by ourselves [2,27] and Pollack et al. [26], the diagnosis of an acute surgical abdomen due tq SLE could be made with confidence only when the patient had concomitant disease activity in other organs. The index of suspicion should be particularly high in those patients who have peripheral vasculitis, neurologic involvement, thrombocytopenia, or rheumatoid factor positivity, all of which occur significantly more often in those with abdominal crises. In the PA patients, although it is noteworthy that all five (100 percent) had manifestations of peripheral arteritis and nervous system involvement, more striking was the thrombocytopenia that occurred in all five. Only one (6 percent) of 17 patients reported by Travers et al. [ 121 and none of our 11 PA patients without abdominal involvement had thrombocytopenia. Rheumatoid factor was positive initially in three (60 percent) of the five patients with PA. At the time of the acute abdomen, four patients were retested with conversion to seropositivity in one, increased titer in two, and unchanged high titer in the remaining patient. In contrast, rheumatoid factor seropositivity was found in only three (27 percent) of our 11 PA patients without abdominal involvement. Since our overall prevalence of rheumatoid factor (44 percent) is similar to the 47 percent reported by Travers et al.
AN0 POLYARTERITIS NODOSA-ZIZIC
ET AL.
[ 121, it would be of interest to know the association, if any, with acute abdomens in the latter group. Such a correlation, however, may relate to degree of seropositivity, which was more marked and sustained in our patients. In addition to having a high index of suspicion in those with the previously mentioned disease-related risk factors, the character of the abdominal syndrome is of value in the differential diagnosis. It is particularly important not to delay therapy until all of the classic signs of an acute abdomen develop, since abdominal guarding or rigidity and absent bowel sounds often occur extremely late, if at all. In part, this may be due to steroid masking of abdominal signs, as has been reported in steroid-treated patients with perforated peptic ulcers [36-391. Steroid suppression of tissue inflammation makes it essential to pursue the differential diagnosis of acute or recurrent abdominal pain with more than usual intensity. In both SLE and PA, it is difficult to detect the gastrointestinal involvement with routine radiography. Upper gastrointestinal contrast studies were helpful in only 20 percent and barium enemas, in none. Although abdominal x rays may reveal pneumoperitoneum, this occurs late and is of little value in the nonsurgical management of the patient. It would appear that many of the macroscopic lesions seen at autopsy do not lend themselves to recognition by roentgenography. [25,28]. As in one of our patients in whom mesenteric arteriography localized at the site of gastrointestinal bleeding and subsequent perforation, this procedure may be helpful, which has been emphasized by others [12,40,41]. Management of the acute abdomen in SLE and PA is a challenging therapeutic and surgical problem. Pollack et al. [26] successfully treated five of six patients with SLE and severe abdominal symptoms with corticosteroid augmentation alone, but an additional four required surgical intervention as well [26]. In the series of Matolo and Albo [ 421, it is noted that six of 10 medically treated patients with acute abdominal syndromes or hemorrhage died, whereas all four surgical patients survived. Of our seven survivors, two responded to increased corticosteroids alone and five also required surgical intervention. As previously pointed out by us and others, the progression of clinical symptoms and signs despite augmented medical therapy should be followed promptly by laparotomy [2,13,17,26]. Our experience in abdominal PA remains problematic, since all five of these patients have succumbed despite augmented corticosteroid therapy and surgical intervention in ail and the addition of cyclophosphamide therapy in two. Such grave prognosis is found by others as well. In the series of Travers et al., [ 121, four of the five patients who died had had severe abdominal pain,
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with three deaths being the result of bowel infarction and renal failure. The clinical association of rheumatoid factor in high titer in rheumatoid arthritis patients with vasculitis has been shown by many [43-471. A variety of anti-gamma globulin factors has been implicated in the pathogenesis of rheumatoid vasculitis, including conventional 19s rheumatoid factor [43,48], a low molecular weight (7s) immunoglobulin M (IgM) [49,50], an immunoglobulin G (IgG) with antiglobulin activity [50], and cryoprecipitable antigamma activity [51]. Numerous experimental studies have also implicated IgM rheumatoid factor in vascular damage. Baum et al. [52] demonstrated that rheumatoid factor reacting with antigen-antibody complexes becomes deposited on endothelium when infused in rat mesentery, suggesting that the deposition of rheumatoid factor mediates vasculitis. Recently lzui and Eisenberg [53] have studied the MRL/l mouse strain, which spontaneously develops a
ET AL
lupuslike syndrome, vasculitis, and arthritis associated with high levels of anti-DNA antibodies and rheumatoid factors [ 531, and they report IgG-rheumatoid factor complexed with IgG-anti-DNA in this murine model. These investigators suggest that these rheumatoid factors and antinuclear antibodies, singly or in combination, may be pathogenetic for the inflammatory lesions. Whether or not thrombocytopenia is a feature of this murine syndrome has not been studied. Such would be of interest, however, in view of the observations of Yeatts et al. [54], showing release of vasoactive amines from platelets exposed to insoluble complexes. In view of these experimental observations and the statistically significant association between rheumatoid factors and mesenteric arteritis in our patients, the possibility of a pathogenetic role for certain of the anti-gamma globulin antibodies should be further explored; such studies are in progress.
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