Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. It is characterized by daily high spiking fevers associated with an evanescent rash, arthritis, and multiorgan involvement (1, 2). Here we report a patient with AOSD-associated thrombotic microangiopathy (TMA) combining central nervous system and renal involvement, associated with 2 severe and unusual complications: Purtscher-like retinopathy and extremity gangrene. Interestingly, renal biopsy showed decreased expression of glomerular vascular endothelial growth factor (VEGF), which could have triggered the TMA and may represent a new pathophysiologic mechanism in human TMA.
A 36-year-old woman presented with a 3-week history of high fever, diffuse arthralgia and myalgia, sore throat, and evanescent rash. At admission, her temperature was 38°C (intermittent fever, up to 39.6°C during the disease course). There was a maculopapular erythematous rash and diffuse arthralgia involving both shoulders, elbows, wrists, and knees, without evidence of synovitis. Chest examination evidenced a bilateral pleural effusion, and lower extremity pitting edema was noted. There was no cardiac murmur and her blood pressure was 109/65 mm Hg. No lymphadenopathy was detected, and the liver and the spleen were not felt. The initial neurologic examination was normal except for blurred vision.
The white blood cell count was 17,800/mm3 (78% neutrophils), the hemoglobin level was 11.4 gm/dl, and the platelet count was 269,000/mm3. The C-reactive protein (CRP) level was 403 mg/liter. Aspartate and alanine aminotransferase levels were 90 and 25 IU/liter, respectively (normal values <31 and <34, respectively). Cultures of blood and urine showed no growth. Extensive infectious evaluations, including testing for human immunodeficiency virus, hepatitis B and C virus, cytomegalovirus, Epstein-Barr virus, Borrelia, Bartonella, Rickettsia, Chlamydia, Mycoplasma pneumoniae, Legionella, Toxoplasma, Salmonella, and syphilis, were negative. Tests for the following were negative: rheumatoid factor, antinuclear and double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies, anticardiolipin and anti–β2-glycoprotein I antibodies, and lupus anticoagulant. The level of serum complement (CH50, C3, and C4) was normal, and tests for serum cryoglobulins were negative. Thoracic and abdominal computed tomography (CT) scans revealed both pericardial and bilateral pleural effusions and moderate hepatomegaly. Transthoracic echocardiography showed a moderate noncompressive pericardial effusion, with no evidence of valvular vegetations. The serum creatinine level was 101 μmoles/liter, urinalysis was normal, and proteinuria on urine sampling was elevated to 0.115 gm/mmole of creatinine.
The serum ferritin level was 14,800 μg/liter (normal range 10–140) and the lactate dehydrogenase (LDH) level was 1,609 IU/liter (normal value <248). The serum triglycerides level was 2.45 mmoles/liter (normal range 0.45–1.70). Despite normal bone marrow aspiration and biopsy results, a hemophagocytic syndrome was suspected and intravenous immunoglobulins (IVIGs) were administered (0.6 gm/kg/day for 3 days), with no efficacy.
The patient's condition rapidly worsened as she developed purpuric lesions on distal lower extremities, acute renal failure (serum creatinine level 600 μmoles/liter, proteinuria 1.78 gm/day), and intravascular hemolysis (hemoglobin level 9.6 gm/dl, haptoglobin level <0.07 gm/liter [normal range 0.5–1.7], elevated LDH level [1,953 IU/liter], increased indirect bilirubin serum level, and 2% schistocytes on blood smear) associated with thrombocytopenia (platelet count 100,000/mm3). TMA was then suspected. Biopsy of a lower extremity purpuric lesion disclosed dermal capillary thrombi associated with mild polymorphous inflammatory infiltrate. Transjugular liver and kidney biopsies were performed. Liver biopsy examination disclosed no evidence of extramedullary hemophagocytic syndrome. The examination of renal tissue demonstrated diffuse TMA with fibrin thrombi in preglomerular arterioles and glomerular capillaries. Proximal tubules showed IVIG-induced osmotic nephrosis-like lesions. Neither interstitial inflammatory infiltrate nor intrarenal hemophagocytosis was observed (Figure 1A). Staining for VEGF-A (Clone C1; Santa Cruz Biotechnology, Santa Cruz, CA) showed absence of glomerular VEGF expression (Figures 1B and C) compared with 5 other cases of TMA (underlying diseases included IgA nephropathy, malignant hypertension, gemcitabine administration, antiangiogenic therapy, and mixed connective tissue disease, one case each), all of which disclosed marked podocyte staining. Staining against synaptopodin, a specific marker of podocytes, revealed normal podocyte expression.
The patient fulfilled the Yamaguchi et al classification criteria (2) and a diagnosis of AOSD-associated TMA was considered. The serum ferritin level remained markedly elevated (18,350 μg/liter), and glycosylated ferritin was at 6%. The serum interleukin-18 (IL-18) level (enzyme-linked immunosorbent assay [ELISA] kit; MBL, Nagoya, Japan) was highly elevated (4,560 pg/ml, normal range 82–170), but serum IL-1β (ELISA kit; R&D, Abingdon, UK) was undetectable. An extended etiologic search found no other cause of secondary TMA: ADAMTS-13 activity was 35% (well above the severe deficiency level [<5%] associated with TMA) (3), no Salmonella, Shigella, or Shiga toxin-producing Escherichia coli were identified in stools, and polymerase chain reaction amplification for Shiga toxin genes 1 and 2 was negative. Serum complement factors B, H, and I antigens were within the normal range, and mutations for complement factors H, I, and membrane cofactor protein (CD46) were not found.
One week after admission, generalized and repeated tonicoclonic seizures occurred. Cerebral CT scan and magnetic resonance imaging (MRI) were normal, and cerebrospinal fluid examination was unremarkable. Anticonvulsivant therapy was administered while mechanical ventilation was initiated. Broad spectrum antibiotic therapy, corticosteroids (methylprednisolone 1 mg/kg/day), plasma exchange therapy, and hemodialysis were started. Despite improvement of the neurologic signs, this treatment had only little efficacy on the Still's disease features (spiking high fevers and skin rash) and TMA, with persistence of hemolytic anemia and renal failure. Lower extremity lesions deteriorated to severe ischemic digital gangrene of the feet (Figure 2A). Of note, the patient did not receive any catecholamine support.
Resistance to corticosteroids led to the addition of IL-1 receptor antagonist (IL-1Ra) therapy (anakinra 100 mg/day subcutaneously). This combination therapy allowed gradual resolution of fever, hyperferritinemia, and hemolytic anemia, and normalization of acute-phase reactants. Renal function progressively recovered and proteinuria disappeared. The patient had persistent blurred vision. Cerebral MRI found no sign of associated TMA posterior reversible encephalopathy. Funduscopic examination revealed bilateral papilledema, with discrete retinal hemorrhage reminiscent of Purstcher-like retinopathy (Figure 2B) that was confirmed by fluorescein angiography. At the end of the followup, 7 months after presentation, the patient was still receiving corticosteroids that were gradually tapered to 15 mg/day of prednisone and anakinra 100 mg/day. She had no clinical evidence of articular or systemic disease activity. The CRP level was 1 mg/liter and renal function was normal (serum creatinine level 100 μmoles/liter), as were hemoglobin (14.4 gm/dl), leukocytosis (9,800/mm3), haptoglobin, LDH, and ferritin serum levels. The serum IL-18 level remained mildly elevated (450 pg/ml). Her visual acuity had gradually but incompletely improved. Despite this major improvement, amputation of both forefeet was needed.
Here we report a rare case of AOSD-related TMA that dramatically improved with anakinra and corticosteroid combination therapy. The etiology of AOSD still remains unknown, but overexpression of Th1 cytokines and IL-18 may have a critical role (1).
Treatment of AOSD should be adapted to the severity of the clinical presentation and may include corticosteroids, disease-modifying drugs such as methotrexate, or anti–tumor necrosis factor agents. More recently, IL-1 blockade has emerged as a possible new therapeutic option. In a study of 15 AOSD patients resistant to therapy, including methotrexate and tumor necrosis factor α–blocking agents, IL-1Ra was shown to be effective in most patients (4). Response to therapy was rapid and sustained. In our patient, IL-1Ra treatment was very effective, and this report adds further evidence for the usefulness of this agent in severe and complicated AOSD, although serum IL-1β remained undetectable.
Various histopathologic features of kidney involvement have been reported in AOSD, including AA amyloidosis, interstitial nephritis, or collapsing glomerulopathy (1). The association of AOSD with TMA is rare, and only 13 cases have been previously reported in the English literature (5–16) (Table 1). In most cases, TMA occurred during an AOSD flare, and AOSD treatment was associated with TMA resolution, which argues for a pathophysiologic link between AOSD and TMA. Kidney biopsy was performed in 5 patients, and showed glomerular and arteriolar TMA. Neurologic involvement with seizures or altered consciousness was present in all cases. Treatment of AOSD-associated TMA included corticosteroids, plasmapheresis, cyclosporine, vincristine, or azathioprine (Table 1). To our knowledge, our case is the first to have been successfully treated with IL-1Ra. A severe complication of AOSD- associated TMA was visual impairment, which occurred in 4 of the 13 reported cases, and was reminiscent of Purtscher's retinopathy, as in our patient (Figure 2B). Purtscher's retinopathy was originally described as large peripapillary cotton-wool spots, intraretinal hemorrhages, and retinal edema in patients with severe head trauma (17). Fluorescein angiography typically shows arteriolar obstruction and leakage. In the absence of trauma, the condition is referred to as Purtscher-like retinopathy, which has been reported in various systemic conditions, including AOSD, systemic lupus erythematosus, or TMA (7, 17). Patients whose Purtscher-like retinopathy preceded manifestations of TMA have also been described (7). Interestingly, our patient presented with blurred vision at admission, before the occurrence of TMA, suggesting that Purtscher-like retinopathy was already present. In AOSD-associated TMA, Purtscher-like retinopathy could be viewed either as a complication of AOSD, TMA, or both.
Table 1. Main characteristics of 13 previously reported patients with TMA and AOSD*
The cutaneous gangrene that our patient developed was a consequence of diffuse microangiopathy with evidence of intradermal TMA, and underscores another severe complication of AOSD-associated TMA. A single case of AOSD-associated TMA with digital gangrene has been reported, but a cutaneous biopsy was not performed (5).
Multiple mechanisms may be involved in TMA pathogenesis (decrease of ADAMTS-13 activity, complement regulatory proteins dysfunction, or direct endothelial toxicity due to infections by Shiga toxin-producing microorganisms), but remain unclear in AOSD-associated TMA. In 2 patients, decreased ADAMTS-13 activity related to autoantibodies against this protease was reported (14, 16) (Table 1). In our patient, complement regulatory gene mutations or Shiga toxin-producing microorganism infection were absent, and ADAMTS-13 activity was only moderately decreased, well above the severe deficiency level (<5%) associated with TMA (3).
Glomerular VEGF might have a role in AOSD-associated TMA. In our patient, glomerular VEGF expression was absent, whereas expression of other podocyte markers, such as synaptopodin, remained normal. Decreased VEGF expression was not observed in 5 cases of TMA used as controls, excluding the hypothesis that the loss of VEGF expression was a consequence of renal TMA. Several experiments support the hypothesis that decreased or absent podocytic VEGF expression can lead to TMA (18). Several cases of TMA have been observed under anti-VEGF antibody therapy (18, 19).
The exact mechanisms by which glomerular VEGF was decreased in our patient remain unclear. However, it has been recently shown that IL-18 may have some antiangiogenic effect with inhibition of VEGF production (20). Of note in our case, TMA was associated with high serum IL-18 levels, which dramatically decreased with TMA resolution. Whether or not this mechanism may be important in other systemic diseases associated with TMA needs to be studied. However, these results disclose a new potential mechanism of spontaneous renal TMA, and highlight the role of glomerular VEGF decrease in triggering human TMA.
AOSD-related TMA is a life-threatening event that should be promptly recognized to initiate aggressive treatment. IL-1Ra (anakinra) is a promising therapy that seems to have dramatic efficacy in this disorder. Our data show that decreased glomerular VEGF expression could have a key role in TMA pathogenesis, and open new perspectives in the study of TMA pathophysiology.
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 submitted for publication. Dr. Pouchot 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. El Karoui, Lebrun, Charles, Arlet, Nochy, Pouchot.
Acquisition of data. El Karoui, Karras, Lebrun, Charles, Arlet, Orssaud, Nochy, Pouchot.
Analysis and interpretation of data. El Karoui, Karras, Lebrun, Charles, Arlet, Jacquot, Orssaud, Nochy, Pouchot.
We thank Dr. G. S. Hill for his careful editing of the manuscript, and Dr. S. Chollet-Martin for her technical assistance.