Chronic relapsing thrombotic thrombocytopenic purpura in adult onset Still's disease. (Case Report).

Abstract: We report the first known case of chronic relapsing thrombotic thrombocytopenic purpura associated with adult-onset Still's disease. The patient presented with diffuse arthralgias, sore throat, and a maculopapular rash involving the trunk and extremities; she was hospitalized with fever and confusion. Thrombocytopenia, renal failure, and microangiopathic hemolytic anemia developed within several days. After a diagnosis of thrombotic thrombocytopenic purpura was made, she responded well to a series of plasma exchanges. Evaluation for infection, autoimmune disorders, and malignancy was negative. She was discharged to home in good condition, with normal renal function and normal platelet count. Two more episodes of TTP developed 7 and 9 months after the first hospitalization. The diagnosis of adult-onset Still's disease was then determined on the basis of clinical and laboratory criteria. She was successfully treated with plasma exchange, prednisone, and azathioprine. She later had splenectomy and has subsequently been without recurrence of thrombotic thrombocytopenic purpura for 2 years.

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Adult onset Still's disease (AOSD) is a systemic disorder of uncertain etiology characterized by spiking fever, evanescent rash, arthritis, and involvement of various organs. (1) The diagnosis is one of clinical suspicion, requiring the exclusion of infection, malignancy, and systemic disease. (2) This disease entity is rarely associated with thrombotic thrombocytopenic purpura (TTP), a hematologic disease of many etiologies characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic abnormalities, and renal disease.

Case Report

A 45-year-old woman presented to an outpatient clinic with a 2-week history of diffuse myalgias, arthralgias, joint swelling, painful fingertips, sore throat, and an intermittent, maculopapular rash involving the majority of the trunk, face, and legs. Symptoms occurred 1 week after treatment with oral cefixime for otitis media. She was treated empirically with oral prednisone for a possible drug allergy. Laboratory data included a white blood cell (WBC) count of 28,000/[mm.sup.3], with a differential of 84% neutrophils, 9% band forms, 2% lymphocytes, and 5% monocytes. Hemoglobin was 14.9 g/dl, and platelet count was 275,000/[mm.sup.3]. Outpatient serology tests for hepatitis B virus, hepatitis C virus, cytomegalovirus, Epstein-Barr virus, parvovirus, rubella virus, Chlamydia, Streptococcus, Neisseria, Treponema, Borrelia, and Toxoplasma were negative. A punch biopsy of the rash was negative for vasculitis. Serology tests for antinuclear antibodies (ANA), rheumatoid factor (RF), cytoplasmic antineutrophilic cy toplasmic antibody (c-ANCA), perinuclear antineutrophilic cytoplasmic antibody (p-ANCA), antiphospholipid antibody, anticardiolipin antibody, antimicrosomal antibody, anti-Smith antigen (anti-Sm), anti-double-stranded DNA (anti-dsDNA) antigen, the antibodies specific for Sjogren's syndrome (anti-SSA and anti-SSB), anti-single-stranded binding protein antiribonucleoprotein (anti-RNP), and lupus anticoagulant were all negative.

Arthralgias waxed and waned for 3 more days, then the patient became acutely obtunded. In the emergency department, she had a temperature of 102.7[degrees]F, blood pressure 110/60 mm Hg, heart rate 76 beats/mm, normal hemoglobin, WBC count 14,500/[mm.sup.3], with a differential count of 36% band forms, 50% neutrophils, 2% lymphocytes, 5% monocytes, and 2% eosinophils. The platelet count had decreased to 33,000/[mm.sup.3]. Electrolyte levels and kidney function tests were normal. Liver transaminase levels were slightly elevated, and lactate dehydrogenase level was 890 U/L.

She was treated empirically with intravenous corticosteroids and antibiotics for suspected sepsis, disseminated intravascular coagulation, or autoimmune disease. Serology tests and blood cultures remained negative. The peripheral blood smear showed schistocytes. A presumptive diagnosis of TTP was made. She subsequently underwent a series of plasma exchanges (Fig. lA). Several days later, renal failure required hemodialysis. After multiple plasma exchanges and hemodialysis, mental status, platelet count, and renal function returned to normal. After 3 weeks of hospitalization, she was discharged in good condition.

Two months later, discoloration and pain of her fingertips recurred and then disappeared in several days. Seven months after the first hospitalization, a small migrating rash of the hands appeared several days after she had handled shrimp. The rash disappeared in 1 day and then reappeared within 3 days. She was administered oral prednisone for a suspected shrimp allergy. The rash migrated to her trunk, face, and extremities. Diffuse amthralgias, joint swelling, sore throat, and intermittent chills also developed. Platelet count was normal. Within 4 days she became lethargic and confused. She was brought to the emergency department, where tonicoclonic seizures developed. Renal function tests were normal, platelet count was 128,000/[mm.sup.3], liver transaminase levels were slightly elevated, LDH level was 555 U/L, and ferritin level was elevated at 13,969 ng/ml. Blood smear did not show any schistocytes. Evaluation for infection and autoimmune diseases was negative. The index of suspicion for recurrent TTP was high, so plasma exchanges were initiated (Fig. lB). Within days, her platelet count decreased to 57,000/[mm.sup.3], WBC count was 16,000/[mm.sup.3], and hemoglobin level was normal. Skin biopsy showed a mild lymphocytic superficial perivascular dermatitis. Adult-onset Still's disease was diagnosed on the basis of clinical and laboratory criteria. Platelet count normalized after several days of plasma exchange. She was discharged in good condition without any residual symptoms.

Two months later, she again discovered a migrating rash on the trunk, and within days became lethargic and obtunded. There was no known exposure to antibiotics or shellfish. She was severely thrombocytopenic, and again responded well to a series of plasma exchanges (Fig. 1 C). Evaluation for infection, malignancy, and systemic disease remained negative. Serology tests for deficiencies or inhibitors of von Willebrand factor-cleaving protease inhibitor were also negative. She was discharged in good condition, and 1 month later had an elective laparoscopic splenectomy because of the frequent TTP relapses. TTP did not recur during the 20 months after splenectomy. She remains asymptomatic on low-dose prednisone and azathioprine.

Discussion

Adult-onset Still's disease is a rare adult variant of the systemic juvenile rheumatoid arthritis, usually characterized by spiking fever, evanescent maculopapular rash, sore throat, polyarthralgia, arthritis, lymphadenopathy, serositis, and myalgia. (3-5) Initially described in 1897 by G.F. Still as chronic polyarthritis in children, this disease was not described in adults until Bywaters (6) reported it in 1971. Because there are no pathognomonic signs or features of AOSD, diagnosis is based on a set of clinical and laboratory criteria after infection, malignancy, or autoimmune disease etiologies are excluded. (7-9) Our patient fulfilled the strongest criteria for the diagnosis of AOSD, proposed by Yamaguchi et al, (3) yielding a 96.2% sensitivity and 92.1% specificity. These criteria include no evidence of infection, autoimmune disease, malignancy, and elevated ferritin. Serum ferritin levels were extremely high, a laboratory finding in up to 70% of patients with active AOSD. (9-12)

The incidence of AOSD is about 0.16/100,000 population, with no sex bias. There are with two peak age distributions between the ages of 15 and 25 years and between the ages of 36 and 45 years, but patients older than 60 years of age can be affected. (13) Approximately one-fourth of patients with AOSD have a history of allergies. (13) Allergic reactions to shrimp and cefixime were suspected in our patient.

Adult-onset Still's disease is even less common in association with complications of TTP, a disease first described by Moschowitz in 1924, (14) with an incidence of one new case per million per year. (8,15) Thrombotic thrombocytopenic purpura has been described in five AOSD case reports. To our knowledge, a relapsing type of TTP associated with AOSD has never been described in the literature. (8,16-18) Thrombotic thrombocytopenic purpura is associated with an ever-growing list of bacterial and viral infections, inflammatory and immunologic disorders, neoplasms, transplantation, pregnancy, and drugs. (19-21) It is progressive and universally fatal without intervention. (22) The treatment of choice is plasma exchange. (19, 23) More than one-third of patients who survive an acute episode of TTP will have at least one relapse during the next 10 years. (24) Relapses after an initial response can be managed successfully with additional plasma exchange, corticosteroids, azathioprine, and/or splenectomy. (22,25,26) O ur patient was successfully treated for three different TTP episodes with plasma exchanges and combination therapy with prednisone and azathioprine. After the third episode of TTP, splenectomy was performed. Maintenance therapy for AOSD usually includes nonsteroidal anti-inflammatory drugs, systemic corticosteroids, or methotrexate. (5,27,28) Our patient is currently on prednisone and azathioprine without complications or recurrence of TTP.

The dual diagnosis of AOSD and TTP has interested scientists and physicians since it was first described. Many etiologies and pathogenetic mechanisms have been proposed, but no associations have been found to explain their coexistence. Although TTP has been observed in AOSD, the chronic relapsing type has never been reported. Our patient was successfully treated with plasma exchange in the acute setting and empirically with corticosteroids, azathioprine, and splenectomy after multiple relapses. The chronic state of these two described disorders may represent an immunologic phenomenon. Future studies concerning the pathophysiology of AOSD may shed light on the formation and modulation of platelet thrombi observed in TTP.

[FIGURE 1 OMITTED]

Accepted November 6, 2001.

References

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RELATED ARTICLE: Key Points

* Adult-onset Still's disease (AOSD) is a systemic disorder of uncertain cause characterized by fever, rash, and arthritis.

* Thrombotic thrombocytopenia purpura (TTP) is a hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic abnormalities, and renal disease.

* Remission was achieved in the present case by performing a splenectomy after temporary improvement with plasma exchange, steroids, and azathioprine.

From the Departments of Internal Medicine and Pathology, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, LA.

Reprint requests to Francis R. Rodwig, Jr., MD, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, LA 70121. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association

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