Still's disease

Clinical Response With High-Dose Pulse Methylprednisolone Therapy

Adult-onset Still's disease, the adult variant of the systemic form of juvenile arthritis, is an uncommon systemic inflammatory disorder of unknown etiology characterized by high spiking fevers, neutrophilic leukocytosis, arthritis, and an evanescent rash. There is often a delay in reaching a firm diagnosis. Differential diagnoses include infection, malignancy, and various immunologic disorders. Increased ferritin levels are of particular value in establishing the diagnosis. Clinical response to high-dose corticosteroids may be dramatic. We report a case of a 29-year-old woman who had recently been investigated for fever of unknown origin, and who presented to our hospital with high fever and hypotension. Her condition rapidly deteriorated with the development of ARDS, disseminated intravascular coagulation, and shock. The patient had a markedly elevated serum ferritin concentration of 26,000 ng/mL. High-dose pulse methylprednisolone therapy resulted in a remarkable clinical improvement. Such a severe case of systemic inflammatory response syndrome, masquerading as septic shock, has not been reported previously.

(CHEST 1999; 115:1738-1740)

Key words: ARDS; disseminated intravascular coagulation; hyperferritinemia; septic shock; Still's disease

Abbreviation: DIC = disseminated intravascular coagulation

Adult-onset Still's disease, the adult variant of the systemic form of juvenile arthritis, is characterized by neutrophilic leukocytosis, high spiking fevers, evanescent rash, and arthritis.[1] Severe systemic manifestations include pleuritis, pericarditis, disseminated intravascular coagulation (DIC), and liver dysfunction ranging from elevated transaminases to fulminant hepatic failure.[1] A hemophagocytic syndrome has been described that is associated with pancytopenia and extremely elevated serum ferritin levels ranging from 1,000 to 250,000 ng/mL.[2,3] Although there are no characteristic serologic markers, in the appropriate Clinical setting, a serum ferritin level [is greater than] 1,000 ng/mL may assist in establishing the diagnosis. Life-threatening complications include fulminant hepatic failure, DIC, ARDS, cardiac tamponade, and pancytopenia.[1,4,5] Treatment with high-dose pulse methylprednisolone may attenuate the severity of multiorgan involvement.[6]

Although DIC and ARDS have occurred in patients with Still's disease, the clinical syndrome of severe systemic inflammatory response syndrome masquerading as septic shock is extremely rare and, to our knowledge, has not been reported. We present a case of a 29-year-old woman with adult-onset juvenile rheumatoid arthritis presenting with hyperferritinemia, systemic inflammatory response syndrome, ARDS, DIC, and hyperdynamic shock, who responded dramatically to IV pulse methylprednisolone therapy.

CASE REPORT

A 29-year-old married woman presented with a history of chills and fever of up to 105 [degrees] F for 4 weeks, associated with arthralgia, myalgia, and a petechial rash that initially started in the lower extremities and then became generalized. She had been in good health until the onset of this illness. Her past history was significant for fever of unknown origin, sore throat, and joint pains at the age of 9 years. An extensive work-up at that time was inconclusive and a diagnosis of possible juvenile rheumatoid arthritis or acute rheumatic fever was entertained. She was treated with penicillin. Prior to this hospitalization, she was investigated extensively as an outpatient for fever of unknown origin. Her medications included a combined oral contraceptive pill, APC (aspirin, acetaminophen, and caffeine), and ibuprofen.

On presentation to the hospital, her pulse rate was 118 beats/min; temperature, 40 [degrees] C; BP, 80/50 mm Hg; respiratory rate, 22/min; and arterial oxygen saturation, 80% with a 100% nonrebreathing mask. Her clinical examination was notable for a petechial rash involving her lower limbs, scattered crackles on chest examination, and mild tenderness in the right upper quadrant of the abdomen with mild hepatomegaly. The patient rapidly decompensated, and because of worsening respiratory distress and hypotension, she required endotracheal intubation, ventilatory support, and vasopressors.

The initial laboratory evaluation revealed a WBC count of 16.6 x [10.sup.9]/L with 38% bands; hemoglobin, 10.1 g/dL; platelet count, 142 x [10.sup.9]/L; erythrocyte sedimentation rate, [is greater than] 100 mm/h; lactate dehydrogenase, 508 IU/L; aspartate aminotransferase, 28 IU/L; alanine aminotransferase, 32 IU/L; and a total bilirubin of 13 [micro]mol/L (0.8 mg/dL). Postintubation arterial blood gas analysis on assist-controlled ventilation, with a fraction of inspired oxygen of 100% and a positive end-expiratory pressure of 10 em [H.sub.2]O, showed a pH of 7.40; [PCO.sub.2], 27 mm Hg; [PO.sub.2], 49 mm Hg; serum bicarbonate, 17 mmol/L; and an arterial saturation of 85%.

A bedside chest radiograph demonstrated dense bilateral alveolar infiltrates (Fig 1) consistent with ARDS. Because of poor oxygenation and high airway pressures, the patient was ventilated with pressure-control ventilation with an inspiratory pressure of 25 cm [H.sub.2]O and a positive end-expiratory pressure of 15 cm [H.sub.2]O. A pulmonary artery catheter was inserted. With a norepinephrine infusion at 20 [micro]g/min, the following hemodynamic parameters were obtained: pulmonary artery pressure, 32/26 mm Hg; pulmonary capillary wedge pressure, 16 mm Hg; cardiac index, 4.0 L/min/[m.sup.2]; and systemic vascular resistance, 474 dyne [multiplied by] s [multiplied by] [cm.sup.-5]. Serum lactate concentration was 5 mg/dL. A mini-BAL and blind-protected specimen brush sampling was performed, and quantitative bacterial culture, viral culture, and stain for Pneumocystis carinii were negative. A CT scan of the chest and abdomen showed bilateral alveolar infiltrates and mild hepatosplenomegaly. An echocardiogram revealed a dilated and hyperdynamic left ventricle with no valvular abnormalities or vegetations. Serum ferritin levels were [is greater than] 26,000 ng/mL (normal: 10 to 200 ng/mL) and iron studies were normal. The next day, the petechial rash worsened, a salmon-colored maculopapular rash was noted on the patient's buttocks and lower limbs, and she developed evidence of DIC. Bone marrow aspiration was performed and showed mild myeloid hyperplasia, but was nondiagnostic for erythrophagocytosis and negative for iron stain and bacterial and mycobacterial culture. A skin biopsy of the rash was consistent with DIC.

The patient was started on treatment with the broad-spectrum antibiotics levofioxacin and doxycycline; the drugs were stopped on day 6, after all cultures and serologic tests proved negative. IV pulse methylprednisolone of 1,000 mg every 24 h for 3 days was initiated, followed by maintenance therapy at 60 mg IV every 8 h. Within 24 h of the start of steroid therapy, the patient's temperature defervesced, her oxygenation improved, and she was weaned off vasopressors. The results of an extensive serologic (including HIV), immunologic, and infectious work-up proved negative. The patient was discharged to the step-down unit and extubated 7 days later. The patient made a full recovery and was received methylprednisolone 40 mg daily after hospital discharge. The serum ferritin level was 900 ng/mL at the time of discharge. During follow-up over the next few months, the patient required maintenance doses of corticosteroids for control of joint pain.

DISCUSSION

Adult-onset Still's disease, the adult variant of the systemic form of juvenile rheumatoid arthritis, is characterized by high spiking fevers, an evanescent rash, and arthritis. Case series report a variety of multisystem involvement, including generalized lymphadenopathy (74%), hepatosplenomegaly, abnormalities in liver function tests (60 to 80%), neutrophilic leukocytosis (90%), normocytic normochromic anemia, pneumonitis (27%), pleuritis (31%), pericarditis (26%), and neurologic involvement (9%).[1,4,5] The erythrocyte sedimentation rate is elevated in [is greater than] 90% of cases.[5] Hyperferritinemia, with serum ferritin levels [is greater than] 1,000 ng/mL, correlates with disease activity and is a characteristic hallmark of the disease.[2-4] The sensitivity and specificity of hyperferritinemia in the diagnosis of Still's disease are reported to be 67% and 85%, respectively.[2-4] In contrast to the hyperferritinemia encountered with acute and chronic inflammatory processes and hemochromatosis, in Still's disease, the percentage of ferritin that is glycosylated is markedly reduced.[7]

The etiology of markedly elevated serum ferritin levels is unclear. Some authors report that hyperferritinemia is due to the release of ferritin from damaged hepatocytes.[7] Release of ferritin may occur from hyperactive histiocytes that have engnlfed erythrocytes during a hemophagocytic crisis.[2] Cytokines such as tumor necrosis factor-[Alpha], [Gamma]-interferon, interleukin 1, interleukin 6, and inflammatory prostaglandins have been implicated in the cellular pathophysiology of hyperferritinemia.[7] This proinflammatory milieu may result in increases in hepatocyte ferritin messenger RNA synthesis.[7] A fall in ferritin levels parallels the recovery phase, with normalization of the serum ferritin level a reliable indicator of therapeutic success.[2-4]

Because of the varied systemic manifestations of Still's disease and the difficulties in differentiating this disease from infectious diseases, hematologic disorders, and systemic vasculitides, the diagnosis is usually one of exclusion. Thus, it is not unusual for delays in diagnosis to occur. Recognition of the syndrome and an elevated serum ferritin [is greater than] 1,000 ng/mL assist in establishing a prompt diagnosis.

Treatment for severe or life-threatening systemic manifestations involves high-dose pulse therapy with 1,000 mg of methylprednisolone or equivalent doses of other glucocorticoids.[6] In steroid-refractory disease, plasmapheresis, IV Ig, and other immunosuppressive agents have been employed with little success.[1,2]

REFERENCES

[1] Reginato AJ, Schumacher HRJ, Baker DG, et al. Adult onset Still's disease: experience in 23 patients and literature review with emphasis on organ failure. Semin Arthritis Rheum 1987; 17:39-57

[2] Coffernils M, Soupart A, Pradier O, et al. Hyperferritinemia in adult onset Still's disease and the hemophagocytic syndrome. J Rheumatol 1992; 19:1425-1427

[3] Kumakura S, Ishikura H, Munemasa S, et al. Adult onset Still's disease associated hemophagocytosis. J Rheumatol 1997; 24:1645-1648

[4] Wouters JM, van de Putte LB. Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases. Q J Med 1986; 61:1055-1065

[5] Pouchot J, Sampalis JS, Beaudet F, et al. Adult Still's disease: manifestations, disease course, and outcome in 62 patients. Medicine 1991; 70:118-136

[6] Khraishi M, Fam AG. Treatment of fulminant adult Still's disease with IV pulse methylprednisolone therapy. J Rheumatol 1991; 18:1088-1090

[7] Van Reeth C, Le Moel G, Lasne Y, et al. Serum ferritin and isoferritins are tools for diagnosis of active adult Still's disease. J Rheumatol 1994; 21:890-895

(*) From the Medical Intensive Care Unit (Dr. Iglesias), University of Massachusetts Medical Center, Worcester, MA; the Department of Internal Medicine (Dr. Sathiraju), St. Vincent Hospital, Worcester, MA; and the Department of Medicine (Dr. Marik), Washington Hospital Center, Washington, DC.

Manuscript received August 13, 1998; revision accepted January 4, 1999.

Correspondence to: Paul E. Marik, MD, Department of Medicine, Washington Hospital Center, 110 Irving Street NW, Washington, DC, 20010-2975; e-mail: pem4@mhg.edu

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