Adult-onset Still's disease (AOSD), originally described in 1896 by G. F. Still, is a multisystemic inflammatory disorder with features that do not meet the criteria for classic rheumatoid arthritis, but are similar to those encountered in children with systemic-onset juvenile rheumatoid arthritis (1). AOSD is usually seen in persons 16–35 years of age and is typically characterized by high-spiking quotidian (sometimes double quotidian) fever, arthralgia/arthritis, evanescent salmon-colored maculopapular rash, sore throat, lymphadenopathy, hepatosplenomegaly, and serositis (2, 3). The incidence of AOSD is estimated at 0.22 out of 10,000 among men >16 years of age and 0.34 out of 10,000 among women of the same age (4). Laboratory data typically reveal marked hyperferritinemia, anemia, thrombocytosis, and leukocytosis (3, 5). We describe the case of a patient with AOSD and ischemic retinopathy (Purtscher-like retinopathy) later complicated by thrombotic thrombocytopenic purpura (TTP).
A 27-year-old man presented with a 1-week history of sore throat; left elbow, knee, and thigh pain; generalized fatigue; and fever. His physical examination was remarkable for an erythematous posterior pharynx with pus drainage. A throat swab was positive for group A Streptococcus and oral penicillin treatment was initiated.
One week later, the patient presented to the clinic with persistent fevers. A chest radiograph revealed a right lower lobe infiltrate. He was treated with azithromycin. Two weeks later, the patient presented with persistent fever, night sweats, chest pain, nausea, fatigue, lethargy, myalgia, right knee and thigh pain, and was unable to ambulate. Upon physical examination, the patient's temperature was 38.9°C, blood pressure was 134/80 mm Hg, heart rate was 137/minute, and respiratory rate was 26/minute. Cardiac examination was notable for a pericardial friction rub. Skin examination revealed a nonpruritic, pink evanescent maculopapular rash involving the anterior chest. The right thigh was tender to palpation on musculoskeletal examination. The patient was subsequently admitted to the hospital. His initial laboratory data revealed a white cell count of 27.2 1000/μl (normal 3.5–11) with a differential count of 23% bands, 53% neutrophils, 1% lymphocyte, 5% myelocyte, 4% promyelocyte, and 4% metamyelocyte; he had a normocytic anemia with a hemoglobin of 10.6 gm/dl (normal 13.5–17.5 gm/dl) and a normal platelet count. His peripheral smear was unremarkable. The kidney function test result was within normal limits, with a mildly abnormal liver function profile (protein and albumin levels 5.9 and 2.6 gm/dl, respectively [normal 6–8.3 and 3.5–5.0 gm/dl, respectively]) and a mildly elevated serum glutamic pyruvic transaminase level of 53 units/liter (normal 8–35 units/liter). The patient's erythrocyte sedimentation rate and C-reactive protein levels were markedly elevated at 93 mm/hour (normal 0–15 mm/hour) and 234 mg/liter (normal <5 mg/liter), respectively. Electrocardiogram revealed a sinus tachycardia. Initial chest radiograph revealed bibasilar consolidation, and a computed tomography (CT) scan of the chest, abdomen, and pelvis revealed trace pleural effusion. No lymphadenopathy was visualized. His initial urinalysis was unremarkable and a transthoracic echocardiogram revealed a small pericardial effusion.
Further workup including a cytomegalovirus (CMV) titer, coxsackievirus titer, human immunodeficiency virus enzyme-linked immunosorbent assay, Leptospira antibody, Lyme titer, West Nile virus titer, rheumatoid factor, antinuclear antibody, serum protein electrophoresis, Epstein-Barr virus (EBV) IgG, hepatitis serologies, and serum complement levels were all within normal limits. The patient's blood and urine cultures remained negative. A purified protein derivative for tuberculosis was negative. Tests for syphilis including rapid plasma reagin and treponemal immunofluorescent antibody were nonreactive.
The patient's abnormal laboratory data included his antistreptolysin O level, which was elevated, as well as his lactate dehydrogenase (LDH; 697 units/liter, normal 116–245 units/liter) and ferritin (3,249 ng/ml, normal 20–300 ng/ml) levels. The diagnosis of AOSD was made and the patient was started on pulse dose intravenous methylprednisolone sodium 1 gm daily for 3 days.
One week after admission, the patient developed worsening dyspnea at rest and on exertion with increasing oxygen requirement. A repeat chest radiograph and pulmonary embolus protocol CT scan showed interval worsening of the pleural effusions with pulmonary edema, borderline enlarged axillary lymph nodes, and worsened pericardial effusion. There was no hemodynamic compromise of the pericardial effusion as later confirmed on transthoracic echocardiogram. A thoracentesis revealed a transudative pleural effusion with negative cultures. Cytology was negative for malignant cells.
At this point, the patient also developed blurry vision, which progressively worsened in the left eye. On ophthalmologic examination, his best-corrected visual acuity was 20/40 in the right eye and 20/300 in the left eye. Slit lamp examination was unremarkable. The vitreous cavity was clear. The funduscopic examination showed multiple peripapillary cotton-wool spots bilaterally with marked macular edema. The findings were worse in the left eye (Figures 1A and 1B). Optical coherence tomography (Zeiss Stratus OCT Ver 3.0, Carl Zeiss Meditec, Dublin, CA) indicated central macular thickness of 308 microns in the right eye and 646 microns in the left eye with subretinal serous fluid (Figures 1C and 1D). Fluorescein angiography demonstrated precapillary occlusion with areas of hypofluorescence correlating with the multiple peripapillary cotton-wool spots, and pinpoint areas of early hyperfluorescence that leaked in the late phase (Figure 1E). Indocyanine green angiography was not performed. These findings were consistent with Purtscher-like retinopathy. Blood pressure was within normal limits at this time, and the platelet count was 322,000 K/ul.
Three days later, there was an acute drop in the patient's platelet count and hemoglobin with values of 60 K/ul and 6.6 gm/dl, respectively. A peripheral smear revealed schistocytes. Additionally, the patient developed acute renal failure with a serum blood urea nitrogen level of 50 mg/dl (normal 7–20 mg/dl), creatinine level of 1.5 mg/dl (baseline 0.7 mg/dl), and an anion gap of 20. A Coombs' test result was negative. Coagulation profile and disseminated intravascular coagulation panel were within normal limits, prompting a diagnosis of TTP. A bone marrow biopsy sample revealed a hypercellular marrow with hemolytic anemia and thrombocytopenia, as well as features suggestive of stress erythropoiesis. There was no evidence of lymphoma on the bone marrow aspirate and bacterial and viral cultures of the specimen were negative. Emergent plasmapheresis was initiated for the TTP. Urine analysis was positive for protein but there were no casts. A 24-hour urine collection revealed a proteinuria level ∼6.76 gm with an unremarkable kidney ultrasound. The patient, however, refused a kidney biopsy. His liver function also started to worsen at this time, revealing a cholestatic pattern with a total bilirubin of 6.5 mg/dl (normal 0.1–1.0 mg/dl) and conjugated bilirubin of 1.9 mg/dl (normal 0–0.3 mg/dl). Cyclophosphamide therapy was later added to augment the corticosteroid and plasmapheresis regimen.
With initiation of aggressive immunosuppressive therapy, the patient's symptoms began to improve: his fever resolved, his ferritin level decreased from 3,249 ng/ml to 614 ng/ml, and his LDH level decreased from 2,309 units/liter to 419 units/liter. With improvement in his liver function, the patient was started on vincristine therapy. His platelet count then increased to normal limits and his renal function stabilized at a creatinine level of 3.3 mg/dl. His dyspnea improved as his pleural effusions stabilized with improvement in his pulmonary edema; cardiac function also stabilized on repeat echocardiograms. Cyclophosphamide and vincristine therapy were eventually discontinued, and our patient was discharged on prednisone therapy with plans for an extended taper.
At the time of discharge, ∼1 month after his initial eye examination, his visual acuity was 20/50 in the right eye and 20/400 in the left eye. Funduscopic examination showed persistent peripapillary cotton-wool spots and improvement of macular edema. Optical coherence tomography showed improvement of macular edema and resolution of the subretinal serous fluid. The central macular thickness was 253 microns in the right eye and 355 microns in the left eye (Figure 2). However, the visual acuity did not improve, most likely secondary to the macular ischemia. The patient refused to have a repeat fluorescein angiogram at this time. The patient was subsequently scheduled to return to the clinic after discharge, but was lost to followup.
AOSD is an uncommon rheumatic disorder that affects adults in their twenties and thirties with rare onset after age 60. It is considered a variant of rheumatoid arthritis and is mostly a diagnosis of exclusion. Men and women are affected in equal proportions (6).
Yamaguchi et al divided the diagnostic criteria for this disease into 4 major and 4 minor criteria (1). Major criteria were fever of ≥39°C lasting ≥1 week, arthralgias lasting ≥2 weeks, typical rash, and leukocytosis (≥10,000/ml) including >80% granulocytes. Minor criteria were sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibody. A total of >5 criteria, including 2 major criteria, were required for diagnosis with a sensitivity of 96.2% and specificity of 92.1% (1). Our patient met all of the inclusion criteria. In addition, other differential diagnoses for AOSD including vasculitides, connective tissue diseases, malignancies, infections, and granulomatous disorders (2) were excluded by the battery of tests performed during the patient's hospital visit. Viral infections are sometimes implicated as the triggering event in AOSD and include EBV, CMV, rubella, echovirus, mumps, parainfluenza, and parvovirus (7).
Our patient had group A Streptococcus implicated as the initial etiology of his pharyngitis. This was treated with penicillin with some improvement in his sore throat. There are no known case reports implicating strep throat in AOSD; however, pharyngitis is described as one of the minor diagnostic criteria of this disease. AOSD-associated sore throat is typically autoimmune in origin, and usually resolves within a few days (4). It is possible that the finding of a Streptococcus pharyngitis was incidental in the course of our patient's AOSD diagnosis. In addition, the patient could have had a superimposed AOSD-associated sore throat, which subsequently resolved on its own as is typical of this disease.
The ophthalmologic findings in our patient were consistent with a vasculitis. Systemic vasculitis has been documented histologically in skin and liver biopsy samples from patients with AOSD (4). This systemic inflammation and vasculitis in AOSD may cause microangiopathy leading to precapillary arteriole occlusion resulting in Purtscher-like retinopathy as illustrated in our patient.
Purtscher's retinopathy was originally described as large peripapillary cotton-wool spots, intraretinal hemorrhages, and retinal edema in patients with severe head trauma (8). Fluorescein angiography typically shows arteriolar obstruction and leakage. The mechanism is thought to involve complement activation leading to leukoembolization of retinal arterioles (8). In the absence of trauma, the condition is referred to as Purtscher-like retinopathy (9, 10). Purtscher-like retinopathy has been described only once in association with AOSD, but has been reported in numerous systemic conditions, including acute pancreatitis, chronic renal failure, amniotic fluid embolism, and autoimmune diseases such as systemic lupus erythematosus, TTP, scleroderma, dermatomyositis, and Sjögren's syndrome (9). Recently, Purtscher-like retinopathy has been described in acute renal allograft rejection (11). In such cases, the retinopathy and visual impairment usually follow the manifestation of the disease process. Of note, however, Patel et al (8) and Ong et al (12) described 2 cases of patients whose Purtscher-like retinopathy preceded manifestations of TTP. Diamond (13) has also described Purtscher-like retinopathy in a patient with AOSD complicated by TTP, although in that case, the eye manifestations occurred concurrently with the TTP.
Our patient had Purtscher-like retinopathy in the setting of AOSD prior to onset of TTP. Whether he developed this retinopathy because of AOSD or as a preceding manifestation of TTP remains unknown.
Purtscher-like retinopathy in our patient could be viewed either as a complication (maybe even a prognostic indicator) of AOSD or as a sign of imminent TTP. Regardless, aggressive immunosuppressive therapy would be required to offset further progression of AOSD and associated retinopathy, or to prevent the occurrence of TTP. The purpose of this case report is to emphasize the importance of inquiring about visual changes in patients presenting with symptoms, or a diagnosis, of AOSD with or without concurrent TTP. If discovered early in the disease process, ischemic changes associated with retinopathy, and therefore permanent visual impairment or loss, could be prevented with aggressive immunosuppressive therapy.
Dr. Sweiss had full access to all of the data in the study and takes responsibility for the integrity of the data.
Study design. Dr. Sweiss.
Acquisition of data. Drs. Volkov, Rezaei, and Sweiss.
Analysis and interpretation of data. Drs. Sweiss, Volkov, and Rezaei.