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CASE PRESENTATION

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. HOSPITAL AND CLINIC COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

Chief symptom

A 26-year-old white man with a systemic lupus erythematosus (SLE) flare and acute multiorgan ischemia.

History of the present illness

The patient was in his usual state of health until 2 months before admission, when he developed pain and stiffness in his right shoulder, neck, and back after playing softball. His symptoms progressively worsened despite manipulation by a chiropractor, and he developed new pain in his soles. This was diagnosed as plantar fasciitis and he was given a topical steroid injection and a short course of methylprednisolone. This treatment improved his pain, but at its completion, he developed disabling diffuse arthralgias in his shoulders, elbows, knees, and feet, along with fevers, anorexia, and weight loss. Worsening symptoms prompted hospitalization in another institution 3 weeks before admission, where he was febrile up to 103°F and hypertensive (144/100 mm Hg). An extensive evaluation revealed elevated inflammatory markers, including erythrocyte sedimentation rate (ESR; 102 mm/hour), C-reactive protein level (56 mg/liter), positive antinuclear antibodies (ANAs; >1:640), strongly positive anti–double-stranded DNA (anti-dsDNA) titers, low levels of C4 (9 mg/dl, normal range 16–38), prolonged prothrombin time (16.2 seconds, normal range 10–13), prolonged activated partial thromboplastin time (60 seconds, normal range 27–38), and positive lupus anticoagulant (LAC) by dilute Russell's viper venom time. His urine analysis showed proteinuria (0.440 gm protein/gm creatinine), hematuria (11–25 red blood cells [RBCs]/high-power field [hpf]), and pyuria (3–10 white blood cells [WBCs]/hpf). Antibodies to Sm/RNP, Ro/SSA, and La/SSB; anticardiolipin antibodies; antineutrophil cytoplasmic antibodies (ANCAs); and anti–cyclic citrullinated peptide antibodies were negative, and creatine phosphokinase was normal. An infectious disease evaluation was performed and was negative for all pathogens, including Lyme disease, human immunodeficiency virus, and viral hepatitis. Renal ultrasound and Doppler were performed and were negative for renal pathology and venous thrombosis. He was placed on prednisone 10 mg orally twice daily, losartan 50 mg daily, and aspirin 81 mg daily, and his fevers resolved with some improvement in joint pains. Two weeks before admission, he was evaluated by a rheumatologist who discontinued aspirin in anticipation of a kidney biopsy to rule out lupus nephritis. Laboratory evaluation again revealed persistent proteinuria (2+), hematuria (10–20 RBCs/hpf), C4 hypocomplementemia (C3 111 mg/dl, C4 9 mg/dl), and strongly positive anti-dsDNA. The patient could not tolerate tapering of prednisone to 15 mg and he stayed at 17.5 mg daily.

He presented to our clinic 3 days before admission and his scheduled kidney biopsy. Over the course of the previous week he had developed a few small tender erythematous skin lesions and some skin excoriation on his fingers and palms. He also experienced numbness of his fingertips and bilateral soles for 2 or 3 days. Weight loss of 30–33 pounds over the course of 3 months with decreased appetite, nausea, and mild diarrhea was noted. On examination, he appeared ill with a blood pressure (BP) of 140/100 mm Hg, and a heart rate of 96 beats per minute. There were a few erythematous lesions on his palate, as well as small tender erythematous nonblanching lesions in his palms, fingertips, and toe tips with rare splinter hemorrhages. He had dysesthesia/hypoesthesia in bilateral palms and fingertips, as well as bilateral soles extending to the lateral side of his ankles. In addition, there was mild weakness of toe dorsiflexion at the left second, third, and fourth toes, as well as left foot dorsiflexion (4 of 5). There was bilateral joint line tenderness in his metacarpophalangeal joints and ankles. The overall picture suggested inadequately treated severe SLE with nephritis, arthritis, mononeuritis multiplex, and vasculitis. On the same day, one dose of pulse glucocorticoids (GC) of 1 gm intravenous (IV) methylprednisolone was administered, and prednisone was increased to 60 mg daily. Losartan was increased to 100 mg daily and he was started on amlodipine 5 mg daily, hydroxychloroquine (HCQ) 400 mg, esomeprazole 40 mg daily, alendronate 70 mg weekly, as well as calcium and vitamin D.

On Monday, 3 days later, the patient was brought back to the clinic in a wheelchair, looking pale and very weak. Over the weekend, his BP had remained high, despite medications. His nausea, malaise, and diarrhea had worsened and he had developed overnight postprandial midabdominal pain consistent with abdominal angina. He denied chest pain or dyspnea, although later he admitted to “chest discomfort,” which was only perceived after it resolved. His BP was 133/87 mm Hg and his heart rate was 111 beats per minute, with no fever or hypoxia. Electrocardiogram demonstrated sinus tachycardia and elevated ST segments on precordial leads (V1–V6) (Figure 1). He was transferred to the coronary care unit.

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Figure 1. Electrocardiogram demonstrating ST elevations in precordial leads in V1–V6.

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Medical history

His medical history was positive for mononucleosis in high school and right knee arthroscopy for a meniscal injury.

Family history

The patient's parents were alive and well at ages 59 (father) and 55 (mother) years. His paternal grandfather died at the age of 32 years from a cerebrovascular accident. A paternal great uncle had rheumatoid arthritis.

Social history

The patient had smoked for 6 years up until 5 months before presentation. There was only social alcohol use and no illicit drug use. He was single but in a stable relationship.

Medications and allergies

His medications upon admission were prednisone (60 mg/day), HCQ (400 mg/day), losartan (100 mg/day), amlodipine 5 mg daily, and esomeprazole (40 mg/day). He had no known drug allergies.

Physical examination and tests

Physical examination was unchanged except for the vital signs, as noted above. Of note, there was no jugular vein distension and no murmur, gallop, or rub. His abdomen was soft and not tender or distended with normal bowel sounds and no hepatosplenomegaly. His peripheral pulses were normal throughout and the Allen test was normal bilaterally. There was no evidence of synovitis in any joint. Trace positive for occult blood brown stool was noted on rectal examination. Laboratory tests revealed anemia, elevated troponin (8.54 ng/ml that peaked to 18.7 ng/ml that night) with normal creatinine but persistent mild proteinuria (0.3 gm protein/gm creatinine), and microscopic hematuria (4–10 RBCs). Urine toxicology screen was negative. He was hypocomplementemic with an ESR of 91 mm/hour, a positive anti-dsDNA and LAC (before initiation of anticoagulation), and normal platelets (Table 1). Cardiac and abdominal computed tomography (CT) angiograms were performed later on the day of admission. The right coronary artery was the dominant vessel and there was no evidence of significant aortic or coronary artery plaque. Ejection fraction (EF) was 44%, with a severely hypokinetic to akinetic apical wall and mild dyskinesia of the distal anterior wall. Cardiac catheterization was not performed because there was concern that further instrumentation might cause thrombosis. Abdominal CT angiograms revealed several small peripheral wedge-shaped defects scattered throughout both kidneys consistent with infarcts (Figure 2). There was no evidence of arterial narrowing or aneurysmal formation seen in the large and medium-sized arteries of the abdomen. Renal veins were widely patent bilaterally. Transthoracic echocardiogram confirmed segmental wall motion abnormalities and showed an EF of 55%. Transesophageal echocardiogram was performed the next day and ruled out endocarditis, but demonstrated linear strands on the atrial side of mitral leaflets, consistent with Lambl's excrescences. An endoscopy was performed on the third hospitalization day for his persistent abdominal pain and it revealed mild Candida esophagitis, for which nystatin swish and swallow was started. The gastric antrum revealed “mild erythema, possibly vasculitic in origin.”

Table 1. Laboratory values*
 AdmissionHospital day 43 months laterNormal values
  • *

    WBCs = white blood cells; CRP = C-reactive protein; anti-dsDNA = anti–double-stranded DNA; aCL = anticardiolipin antibody; β2GPI = β2-glycoprotein I antibodies; LAC = lupus anticoagulant; PT = prothrombin time; PTT = partial thromboplastin time; AST = aspartate aminotransferase; ALT = alanine aminotransferase.

  • Receiving warfarin.

WBCs, per nl11.113.16.463.5–10.7
Hemoglobin, gm/dl1211.114.613–17
Platelets, per nl210312164160–400
CRP level, mg/dl3.52<0.70–1
C3, mg/dl7710379–152
C4, mg/dl8.515.416–38
Anti-dsDNA4+2+Negative; scale 0–4+
aCL IgG, units/ml250–14
aCL IgM, units/ml280–7
aCL IgA, units/ml30–14
β2GPI IgG, units/mlNegative<20
β2GPI IgM, units/mlNegative<10
β2GPI IgA, units/mlNegative<10
LACPositiveNegative
PT, seconds12.32320.79.4–11.6
PTT, seconds40.939.243.622.4–34.8
Troponin, ng/ml18.714.30–0.04
Amylase, units/liter5130–110
Lipase, units/liter3423–300
AST, units/liter9225315–40
ALT, units/liter7758467–56
Albumin, gm/dl2.82.753.5–5
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Figure 2. Computed tomography angiogram scan on the day of admission showing renal infarcts.

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CASE SUMMARY

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. HOSPITAL AND CLINIC COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

This 26-year-old white man presented with a 2-month history of diffuse arthralgia/arthritis, fever, weight loss, nephritic syndrome (hypertension, proteinuria, hematuria), and positive ANAs, anti-dsDNA, and LAC tests. His disease got progressively worse, and a few days before admission he developed tender erythematous skin lesions on his palms, along with peripheral asymmetric sensory and motor symptoms. Two days before admission and despite pulse IV and high oral GC therapy, he got precipitously ill with marked abdominal symptoms and malaise that culminated in an acute transmural myocardial infarction (MI). Further diagnostic evaluation showed “clean coronaries and abdominal arteries,” but also multiple kidney infarcts, and gastric erythema on upper endoscopy.

DIFFERENTIAL DIAGNOSIS

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. HOSPITAL AND CLINIC COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

This patient appeared to have new onset of lupus-like disease with 3 or 4 American College of Rheumatology criteria for SLE, including arthritis, ANAs, immunologic criteria (anti-dsDNA and LAC), and possibly nephritis (1). His lupus was very active with rapid (over a few weeks) development of skin vasculitis with small tender purpuric macules on his palms and splinter hemorrhages on his nails, as well as mononeuritis multiplex 6 days before admission. This was followed by precipitous ischemic involvement of multiple organs with an acute MI, abdominal angina, and multiple kidney infarcts. Although acute MI is most commonly due to accelerated atherosclerosis in SLE, the latter was excluded in this case based on the cardiovascular imaging studies (2). Furthermore, myocarditis was unlikely based on the regional hypokinesis findings in imaging studies, which were consistent with a left anterior descending artery (LAD) obstruction as the cause of ischemia.

In order to explain the acute widespread ischemia, we considered such pathogenic processes as embolic disorders, vasospastic disease, paraproteinemias, thrombotic microangiopathy (TMA), catastrophic antiphospholipid syndrome (CAPS), and systemic vasculitis. Embolic disorders include septic or Libman-Sacks endocarditis, atrial myxoma, and atheroemboli, but there was evidence for none of these on our imaging studies. In addition, the urine toxicology screen was negative and along with the negative social history practically excluded a drug-induced vasospastic process. Laboratory tests were negative for paraproteins and cryoglobulins.

TMA, best exemplified by the thrombotic thrombocytopenic purpura (TTP) syndrome, is characterized by diffuse microvascular thrombosis and manifests clinically with thrombocytopenia due to consumption in platelet microthrombi and microangiopathic hemolytic anemia (MAHA) due to the fragmentation of RBCs during their pass through stenotic small vessels (3). Other systemic disorders that may present similarly include such heterogeneous disorders as hemolytic uremic syndrome; malignant hypertension; severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome; disseminated intravascular coagulation; disseminated malignancy; scleroderma renal crisis; SLE; and APS (4, 5). Activation of microvascular endothelial cells is believed to be an important pathogenetic factor in many of these disorders. TTP may occur in patients with SLE (2% in a recent study) (6), especially with active disease. It is treated with plasma exchange in addition to immunosuppressive therapy. There was no thrombocytopenia or hemolysis in our case to suggest TMA.

The more likely diagnoses in our differential were systemic small-/medium-vessel vasculitis and CAPS, as discussed below.

Systemic vasculitis in SLE

Our patient's manifestation was consistent with small- or medium-vessel vasculitis, but not large-vessel disease. In fact, large-vessel vasculitis is probably rare in SLE (7). The most common form of vasculitis in SLE is probably glomerulonephritis, affecting the glomerular capillaries. Pulmonary capillaritis with alveolar hemorrhage is a rare but severe manifestation of the disease. Excluding these disorders, vasculitis was noted in approximately 11–36% of SLE patients in two large retrospective studies, and mainly affected the small vessels of the skin (7, 8). The most common skin lesions were erythematous punctate lesions on the fingertips and palms (such as in this case), followed by palpable purpura. Histologically, leukocytoclastic followed by lymphocytic vasculitis were the most common pathologies (8). Medium-vessel vasculitis comprised 14–15% of all vasculitis cases and presented mainly with mononeuritis multiplex, and less commonly with digital necrosis and visceral involvement, with necrotizing vasculitis of the vessel wall on histology. There was overlap between the 2 entities. Lupus vasculitis appears to be associated with livedo reticularis, high disease activity, antiphospholipid antibodies (aPL), high ESR, hypocomplementemia, and anti-La, among other manifestations (7, 8). Small/medium-size vasculitis has rarely been reported in the kidneys of patients with lupus nephritis and morphologically resembles microscopic polyangiitis (9). Regarding internal organ vasculitic involvement, abdominal vasculitis with lupus enteritis is probably the most common (7, 10–12). Coronary vasculitis is rare but well documented as a cause of acute MI (13). Angiographically, it manifests as a coronary aneurysm or arteritis (13, 14). Regarding possible vasculitic processes that may affect lupus patients, ANCA-associated vasculitis is uncommon, but cryoglobulinemia is not and when present in high levels, it should prompt exclusion of hepatitis C (7, 15). Our patient's tests were negative for ANCAs and cryoglobulins and there was no angiographic evidence of coronary arteritis or polyarteritis nodosa (PAN)–like abdominal vasculitis. Nevertheless, the punctate skin lesions, the mononeuritis multiplex, the high inflammatory markers, the persistent hypocomplementemia, and the aPL were consistent with a small-/medium-vessel vasculitis due to active lupus.

APS

Our patient arguably had at least one clinical and one laboratory criterion, and therefore fulfilled the international preliminary classification criteria (Sapporo) for APS, except for the fact that there were only 3 (rather than 6) weeks between the 2 positive LAC tests (16). Unfortunately, the patient was placed immediately on anticoagulation therapy and could not be retested for LAC until the present time. Notably, the revised criteria for APS are stricter and require an interval of at least 12 weeks between the clinical event and the aPL test, which was not present in our case (17). In addition, we did not have angiographic or histologic proof of thrombosis. Nevertheless, we strongly believe based on the available evidence that the ischemic events in the heart (acute MI), the kidneys, and most likely also the gastrointestinal (GI) tract were due to thrombosis.

Among patients with lupus, predictive factors of thrombosis may include male sex, LAC, constantly positive aPL, shorter disease duration, smoking, active disease, and higher doses of GC (18–20). Regarding the occurrence of acute MI in young SLE patients, Korkmaz et al reviewed the literature of 49 SLE patients who had an acute MI and were age <35 years (13). The authors recognized 3 groups. Group III (n = 22) had atherosclerosis and had active disease much less often than the other 2 groups and with longer lag periods from the diagnosis of SLE. Group II (n = 12) had evidence of coronary aneurysms/arteritis on angiogram, and group I (n = 16) had either coronary thrombosis (n = 11, according to angiography or clinical judgment) or normal coronaries (n = 5). The majority of these patients (93%) had aPL, which represented a much higher prevalence than in the 2 other groups and received anticoagulation and antiplatelet therapy. It was presumed that clear coronary vessels could be due to resolution of thrombosis/spontaneous thrombolysis, coronary vasospasm, coronary emboli from Libman-Sacks endocarditis/mural ventricular thrombus, or microthrombi. In 2 of these cases, endomyocardial biopsy samples failed to show vasculitis, and in another, autopsy showed arteriolar thrombosis (21, 22). All had presence of aPL. Spontaneous thrombolysis of an LAD thrombus while receiving enoxaparine therapy has been reported in a 19-year-old patient with APS and acute MI (23). Another SLE patient with aPL developed acute MI due to distal LAD thrombosis after rapid normalization of thrombocytopenia (24).

Kidney involvement in this case was characterized by hypertension, mild proteinuria, microscopic hematuria, and renal infarcts on CT angiograms (Figure 2). He could have had early lupus nephritis before the development of the cortical infarcts. In that case, the infarcts could be the result of emboli, vasculitis, or multifocal thrombosis due to APS. Alternatively, he could have had APS nephropathy all along. Embolic disease was unlikely, given the absence of Libman-Sacks endocarditis or cardiac thrombus on transesophageal echocardiogram. True lupus renal vasculitis is very rare in SLE and there is no documented association with cortical infarcts, making this a less likely etiology (9). APS nephropathy almost universally is characterized by hypertension, often severe and occasionally malignant (25). Various degrees of proteinuria (usually mild), microscopic hematuria, and renal insufficiency may be present (25). Nochy et al have analyzed the vascular pathology of this disease in 16 patients with primary APS (25). TMA, the single acute histologic form of microthrombosis, was seen in 31% of the patients in conjunction with fibrous intimal hyperplasia in all of them. The latter was the more common pathology seen (75%), and could be associated with arteriolar fibrous or fibrocellular occlusions (68%) or organizing thrombosis (37%). Focal cortical atrophy (62%), involving the subcapsular cortex in an irregular distribution, was characterized by “an ensemble” of dense interstitial fibrosis, massive tubular atrophy, and thyroidization; fibrous intimal hyperplasia with organized thrombosis and arteriolar occlusions; and groups of globally sclerotic and/or cystic glomeruli. The authors considered this lesion analogous to the cortical infarcts on CT imaging and as a way to differentiate this disease from other TMA-associated disorders (with the exception perhaps of malignant hypertension). They considered both focal cortical atrophy and fibrous intimal hyperplasia lesions as a possible consequence of tissue ischemia and the activation of the renin–angiotensin system. In view of the above, and given the lack of histologic data in our case, we cannot be sure whether at the onset of his renal disease, our patient had early lupus nephritis, APS nephropathy, or both. It is very likely, however, that his renal infarcts were due to multifocal thrombosis in renal vessels too small to be visualized on a CT angiogram (such as arcuate, interlobular arteries), including TMA, which does not always manifest with MAHA and thrombocytopenia (25).

Abdominal angina was a prominent symptom of our patient and was associated with nausea, diarrhea, and antral erythema on esophagogastroduodenoscopy. The symptoms suggested bowel ischemia, but a CT angiogram was negative for vasculitis and thrombosis. A presentation of acute abdominal pain was examined in a few lupus studies. In one, presentation in lupus (n = 15) was compared to that of PAN (n = 5), and was found to be more insidious (on average, 34 days compared to 11 days before crisis) and less often with acute surgical abdomen (11). Symptoms often had a cramping quality and were associated with anorexia, nausea, vomiting, and diarrhea, such as in our patient. Vasculitis occurred in 82% of those requiring laparotomy and affected smaller vessels (and less extensive areas of ischemia) compared to PAN. In another study, acute abdominal pain in 36 active SLE patients was due to vasculitis (by histopathology; n = 19), mesenteric or hepatic arterial thrombosis (n = 3), and non–SLE-related complications (n = 14), whereas all 15 patients with quiescent disease had non–SLE-related problems (10). In both of these studies, central nervous system lupus, thrombocytopenia, and cutaneous vasculitis were more common in SLE patients with GI vasculitis. A third study of acute abdominal pain in 38 SLE patients demonstrated multifocal ischemic “lupus enteritis” based on several CT imaging features, including bowel wall thickening in the absence of mesenteric thrombosis (11). These patients had a drop of their WBCs at presentation compared to control patients. The authors hesitated to call these enteritis cases vasculitis without histologic proof, and considered the possibility of reversible ischemic bowel disease, given the improvement after high-dose GC therapy. The outcome in this study was much better, perhaps because of earlier treatment from the onset of symptoms.

CAPS

CAPS is an accelerated form of APS characterized by multiorgan failure and a mortality rate of approximately 44%, even after therapy (26, 27). Classification criteria for the syndrome are shown in Table 2 (25). Only approximately 1% of patients with APS present with CAPS (26). The “CAPS Registry” has been created to assist the study of this rare syndrome and is available free online (www.med.ub.es/MIMMUN/FORUM/CAPS.htm). Approximately 70% of patients are female. Among all patients, 46% have primary APS, 40% have SLE, 5% have lupus-like disease, and 9% have other autoimmune diseases. In at least half of the cases, a precipitating factor has been implicated: infection (22%), surgery (10%), anticoagulation withdrawal (8%), medication (7%), obstetric complications (7%), neoplasia (5%), and SLE flare (3%). The manifestations of CAPS depend on organ involvement as well as the development of systemic inflammatory response syndrome (SIRS) (28). Intraabdominal thrombotic complications affecting the kidneys, adrenal glands, spleen, intestine, and pancreas are most common, and patients frequently present with abdominal pain or discomfort. The most common manifestations according to organ distribution include renal disease (71%), pulmonary (64% with adult respiratory distress syndrome more prevalent than pulmonary embolism, and with pulmonary hemorrhage less often), cerebral (62%; infarcts, encephalopathy, seizures, or cerebral venous occlusions), cardiac (51%; mostly valve disease), and skin (50%; livedo reticularis, purpura, or skin necrosis). MIs were the presenting features in 25% of patients. Only 5% of cases had peripheral nerve involvement, as our patient did. SIRS is probably the underlying mechanism of adult respiratory distress syndrome, cerebral edema, and myocardial dysfunction, and is due to cytokine activation such as tumor necrosis factor, interleukin-1, interleukin-6, and macrophage migration inhibitory factor (28). The presence of SLE is a poor prognostic factor in CAPS (29). Our patient had at least indirect evidence of thrombotic involvement in at least 3 organs/tissues: his heart, the kidney, and the GI tract. His manifestations developed simultaneously, starting with his GI symptoms. Therefore, if we allow for the lack of confirmation of his LAC test at least 6 weeks apart, he appears to fulfill the classification criteria for probable CAPS (26). The precipitating factor in our case was active SLE flare with vasculitis.

Table 2. Preliminary criteria for the classification of catastrophic antiphospholipid syndrome (CAPS) (26)
1. Evidence of involvement of 3 or more organs, systems, and/or tissues
 Usually clinical evidence of vessel occlusions confirmed by imaging techniques when appropriate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension (> 180/100 mm Hg), and/or proteinuria (> 500 mg/24 hours)
2. Development of manifestations simultaneously or in less than a week
3. Confirmation by histopathology of small-vessel occlusion in at least one organ or tissue
 For histopathologic confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist occasionally
4. Laboratory confirmation of the presence of antiphospholipid antibodies (aPL): lupus anticoagulant and/or anticardiolipin antibodies
 If the patient had not been previously diagnosed as having an APS, the laboratory confirmation requires that presence of aPL must be detected on 2 or more occasions at least 6 weeks apart (not necessarily at the time of the event), according to the proposed preliminary criteria for the classification of definite APS
Definite CAPS
 All 4 criteria
Probable CAPS
 All 4 criteria except for involvement of only 2 organs, systems, and/or tissues
 All 4 criteria, except for the absence of laboratory confirmation at least 6 weeks apart due to the early death of a patient never tested for aPL prior to the CAPS event
 1, 2, and 4
 1, 3, and 4 and the development of a third event in more than a week but less than a month, despite anticoagulation

HOSPITAL AND CLINIC COURSE

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. HOSPITAL AND CLINIC COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

The patient was treated aggressively for severe SLE-related vasculitis and CAPS. He was given anticoagulation therapy with IV eptifibatide (24 hours), clopidogrel (3 days), IV heparin as a bridge to oral warfarin, and aspirin 81 mg daily. Methylprednisolone 20 mg was infused every 8 hours, and IV cyclophosphamide 500 mg was infused on hospitalization day 5. Losartan was continued and beta-blockers were added. The patient felt “relief in his chest” on the second hospital day, and relief of abdominal pains on day 4. He received fluconazole for 3 days for Candida esophagitis and was switched to nystatin thereafter. He was discharged from the coronary care unit on day 6 on warfarin, aspirin 81 mg, methylprednisolone 64 mg daily, HCQ 400 mg, losartan, atenolol, esomeprazole, atovaquone (for Pneumocystis jiroveci pneumonia prophylaxis), alendronate weekly, calcium, and vitamin D. He received additional IV cyclophosphamide 1,000 mg 2 weeks later, and thereafter 4 more monthly infusions of IV cyclophosphamide (at ∼0.75 mg/m2 of body surface area) before he was started on azathioprine 150 mg daily. His GC dosage was tapered to methylprednisolone 8 mg/day by 4 months, and was discontinued by 6 months. The international normalized ratio has been maintained between 2 and 3. His proteinuria resolved by 3 months, and microscopic hematuria resolved by 8 months. His hand numbness resolved within 1 month but the symptoms in his feet did not improve with persistent residual mild left foot weakness and bilateral hypoesthesia. During his treatment he developed GC-induced myopathy and acne, which resolved with tapering of steroids. A repeat cardiac nuclear exercise test 6 months later revealed apical scar but no ischemia and a normal EF. A transthoracic echocardiogram 1 year later showed mild apical hypokinesis and was otherwise normal. No lupus flares have occurred during followup. Anti-dsDNA titers normalized 2 months after hospitalization but then increased again to 2–3+ (scale of 1–4). C4 levels have remained somewhat decreased, ranging from 12– 18 mg/dl (normal range 16–38) over the last 2 years, whereas C3 levels have been normal.

DISCUSSION

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. HOSPITAL AND CLINIC COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

This was a challenging case of a young man who within a period of 2 months developed clinical manifestations of active SLE with vasculitis in his skin and peripheral nerves, and then became precipitously ill with multiorgan ischemia, most likely due to CAPS. He was aggressively treated with antiplatelet agents and anticoagulation as well as GC and cyclophosphamide and achieved rapid and lasting recovery.

Differentiation between systemic vasculitis and diffuse vascular thrombosis, mainly due to CAPS, and TTP can be a challenge in a patient with SLE and severe multiorgan ischemia. Because of the severity of the presentation, physicians often need to make prompt therapeutic decisions based on limited available data that are derived mainly from blood tests and imaging studies, such as in our case. We did not consider it necessary to perform a biopsy, as this might have delayed the institution of anticoagulation therapy and was unlikely to change our management. A biopsy of the skin lesions or the sural nerve would probably show vasculitis, judging from the available literature and the fact that mononeuritis multiplex is relatively rare in CAPS (7, 8, 27). A biopsy of the kidney would have probably shown APS nephropathy features (such as focal cortical atrophy) with or without early class III/IV proliferative lupus nephritis. Again, we thought we needed to treat for both inflammation/vasculitis and CAPS, and therefore the distinction would not matter. Therapy for CAPS for a non–life-threatening condition calls for effective anticoagulation with IV heparin and high doses of GC (30). In our case, we also used cyclophosphamide for his severe vasculitis. Notably, this therapy is associated with improved survival in SLE-CAPS, but a worse outcome in patients with primary CAPS (29). We did not use plasma exchange or IV gamma globulin therapy, as his condition appeared to improve rapidly on our regimen and there was no clinical evidence for a TTP-like illness, including the absence of MAHA and thrombocytopenia.

We avoided direct instrumentation of the coronaries, out of concern that this might injure the endothelium and thus aggravate the prothrombotic state in this acute setting. Indeed, surgical procedures are thought to be the initiating factor in 10% of patients with CAPS (27), and perioperative management of APS patients asks for minimization of the time without anticoagulation (31). In addition, some authors recommend minimization of intravascular manipulation for access and monitoring in APS patients perioperatively (31).

Blood vessel inflammation in SLE is the result of the interplay of many factors and it may represent a spectrum of pathologies, from frank vasculitis to a leukoocclusive vasculopathy (32). Important pathogenic factors in lupus blood vessel involvement include activated endothelial cells with up-regulation of their adhesion molecules, activated neutrophils expressing CD11b/CD18 (CR3), activated platelets, and complement activation, all features of active disease (32–36). When associated with local immune complex deposition, these factors may lead to vasculitis modeled by the Arthus lesion, or otherwise may lead to a leukoocclusive vasculopathy modeled by the Shwartzman phenomenon (32). Such leukothrombi have been observed in central nervous system lupus with brain infarcts and lupus enteritis cases, and have been proposed as the cause of pulmonary leukosequestration with reversible hypoxemia and SIRS (32, 36). A rapid response to high-dose GC has been noted (36). Endothelial apoptosis and dysfunction associated with impaired vascular repair have also been noted in patients with lupus (35, 37). They are likely mediated by high levels of type I interferon (IFN), and are perhaps responsible for the early atherosclerosis in SLE (37). We and other groups have previously shown that high messenger RNA expression by quantitative real-time polymerase chain reaction of type I IFN–inducible genes in peripheral blood mononuclear cells from patients with SLE is associated with high disease activity in a cross-sectional study (38), and that this correlates with type I IFN activity in the serum (39). Our patient indeed had high levels of type I IFN in his serum 2 days before admission, consistent with high disease activity and perhaps vascular activation (Kirou KA and Crow MK: unpublished observations). These levels dropped dramatically early after aggressive therapy with only a small increase several months later.

The mechanisms by which aPL induce thrombosis in APS have not been fully elucidated, but likely include activation of complement, endothelial cells, monocytes, and platelets (40, 41). A more widespread activation of endothelial cells and complement may be more prominent in CAPS. Interestingly, eculizumab (C5 inhibitor) has been used successfully along with anticoagulation and immunosuppression to prevent CAPS recurrence in a patient after renal transplantation (42). Nevertheless, a link between active vascular inflammation and thrombosis in lupus is self-intuitive, and we believe that our patient's lupus flare was probably the trigger for his LAC-mediated thrombosis. In fact, several studies have suggested a link between inflammation and thrombosis and were recently reviewed (43). For example, active vasculitis in ANCA-associated vasculitides as well as Behçet's disease is associated with deep venous thrombosis (43). It is believed that disruption of the endothelial layer due to the vasculitic process exposes active tissue factor, which in turn leads to activation of coagulation factors. Tissue factor may also be expressed in circulating detached endothelial cells or activated by cytokines in intact endothelium. Interestingly, in a mouse model of TMA induced by aPL, genetic reduction of tissue factor levels prevented glomerular injury (41).

In addition to anticoagulation with IV heparin, we also used a combination of potent antiplatelet agents to treat our patient whose dominant clinical manifestation was the acute MI. It is not possible to dissect the relative contribution of antiplatelet agents and anticoagulation to the final successful outcome. Of note, the role of antiplatelet agents in CAPS is not clear (44). In cases associated with severe thrombocytopenia, these agents should be avoided until platelet numbers recover with therapy. Interestingly, the surviving cases of group I patients with acute MI in the study by Korkmaz et al received both antiplatelet and anticoagulant agents (13).

Our patient developed CAPS right after therapy with pulse GC and while off aspirin therapy. Discontinuation of aspirin probably contributed to the development of CAPS. It is unclear whether GC also contributed to his thrombosis. However, data from Cushing's syndrome patients, anecdotal evidence of thrombosis after GC, and limited evidence from a lupus cohort study may support such a possibility (18, 45, 46). It may be prudent to try to initiate high-dose GC therapy, or at least pulse GC, only after initiation of anticoagulation therapy in patients with CAPS/probable CAPS, and thereafter make an effort to taper the dose of GC as fast as the clinical condition would allow. Whether aspirin alone would suffice in other patients at high risk for thrombosis (but without thrombosis yet) is unknown, but probably a good idea. The high risk for thrombosis in our case, we believe, was due to the presence of the LAC and vascular inflammation. Of course, in vasculitis cases where LAC is absent, such as in Wegener's granulomatosis, rapid control of the vascular inflammation with GC is necessary and should largely negate any prothrombotic effects of GC themselves.

In conclusion, we have presented the case of a young male SLE patient with positive LAC who very quickly after his diagnosis progressed to develop severe systemic vasculitis and then probable CAPS. He was successfully treated with aggressive anticoagulation, antiplatelet, and immunosuppressive therapy with an excellent, rapid, and long-lasting response. Rapid recognition of the syndrome and proper management are critical for a favorable outcome in this disease.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. HOSPITAL AND CLINIC COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Kirou had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Cherian, Duculan, Amigues, Crow, Kirou.

Acquisition of data. Cherian, Duculan, Amigues, Kirou.

Analysis and interpretation of data. Cherian, Duculan, Amigues, Crow, Kirou.

REFERENCES

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. HOSPITAL AND CLINIC COURSE
  6. DISCUSSION
  7. FINAL DIAGNOSIS
  8. AUTHOR CONTRIBUTIONS
  9. REFERENCES