Gina M. Caputo, DO; Joseph M. Dyer, DO; Edward F. Ryan, DO Delaware County Memorial Hospital, Drexel Hill, Pennsylvania
Disclosure: The authors report no relevant conflicts of interest.
Diagnosis of an adult with acute generalized exanthem coupled with spiking fevers, arthralgias, and myalgias requires careful consideration. History and physical examination are basic necessities, while laboratory studies can be valuable adjuncts. The authors present a case of adult onset Still’s disease, discuss the differential diagnoses, and highlight the utility of high serum ferritin in identifying this febrile exanthem. (J Clin Aesthet Dermatol. 2015;8(11):53–55.)
A previously healthy woman in her thirties presented with spiking fevers, symmetric pink patches and plaques, and diffuse joint and muscle aches for the past week. The rash was nonpruritic and evanescent. Fevers peaked at 39 to 40°C once or twice a day with intervening defervescence. Generalized arthralgias and myalgias coincided with temperature elevations. The patient denied recent illness, travel, drug abuse, or weight loss. She lived with her boyfriend of 10 years and denied other sexual contact. Review of systems was positive for sore throat.
Physical examination revealed blanchable, salmon-colored macules coalescing into urticarial plaques distributed over bilateral lower extremities, upper extremities, and trunk (Figure 1). No petechiae, bullae, or ulcerations were noted. The oral mucosa was clear. Lymphadenopathy was not appreciated although cervical chains were tender to palpation, bilaterally. Cardiac exam revealed tachycardia without murmur or rub. Joints exhibited no frank effusion or erythema.
Laboratory studies were obtained. A complete blood cell count demonstrated leukocytosis (white blood cell count, 20.3 x 103/uL) with 91 percent granulocytes. Erythrocyte sedimentation rate was elevated at 74mm/hr, and serum ferritin was markedly elevated at 23,158ng/mL (normal, 10–291). Liver function tests showed elevated aspartate aminotransferase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH), respectively, at 97IU/L, 75IU/L, and 1,096IU/L. Initial antistreptolysin O antibody titers were weakly positive, but negative on recheck. Anti-nuclear antibody and rheumatoid factor were negative. Subsequent serologic studies were negative for Lyme disease, West Nile virus, cytomegalovirus, Epstein-Barr virus, parvovirus B19, human immunodeficiency virus, and syphilis.
A biopsy specimen was obtained and stained with hematoxylin-eosin (Figure 2 and Figure 3). Histopathologic examination revealed superficial perivascular infiltrate comprised of lymphocytes, few histiocytes, and occasional eosinophils. Echocardiography demonstrated normal left ventricular ejection fraction and no evidence of valvular regurgitation or vegetation. Repeat blood cultures were negative.
A diagnosis of adult onset Still’s disease (AOSD) was made. The patient’s symptoms were refractory to oral naproxen, but responsive to intravenous methyl-prednisolone. The patient was discharged home on a prednisone taper and instructed to follow-up with a rheumatologist for management.
Adult onset Still’s disease is a diagnostic dilemma and plausible alternatives must be considered. Serologic studies eliminated viral and bacterial causes in this case. Acute rheumatic fever was a noteworthy consideration in this case due to the erythema marginatum-like eruption, pyrexia, and elevated acute phase reactants. However, lack of cardiac involvement and a diminishing antistreptolysin O titer made this diagnosis less likely. Further, the histopathology of erythema marginatum demonstrates an interstitial and perivascular infiltration composed predominantly of neutrophils, not lymphohistiocytes.
A diagnosis of AOSD was established using the Yamaguchi criteria (Table 1 ). The major features of AOSD are quotidian high-spiking fevers, evanescent salmon-colored macular rash, polyarthralgia, lymphadenopathy, leukocytosis, hepatosplenomegaly, elevated liver enzymes, erythrocyte sedimentation rate, and ferritin levels. The onset of symptoms is oftentimes heralded by a sore throat, myalgias, and constitutional symptoms. The macular to maculopapular rash often favors the trunk, but lesions can also appear on extremities, including the palms and soles. It should be noted that, while nonspecific, our cutaneous biopsy findings were compatible with AOSD.
One peculiar feature of AOSD is an elevated serum ferritin level. Physiologically, ferritin is present in most tissues as a cytosolic protein, playing an important role in storing intracellular iron. As an acute phase reactant, ferritin levels increase in inflammatory states. In vitro studies by Tran et al demonstrated that ferritin production in cultured cells is upregulated by extracellular iron as well as the cytokines interleukin-1 and tumor necrosis factor alpha.
Serum ferritin values can be powerful adjuncts in making the diagnosis of AOSD,, where they are usually higher than other inflammatory diseases. Indeed, extreme elevation of serum ferritin up to 75,500ng/mL has been reported in AOSD. Several investigators agree that ferritin levels above 1,000ng/mL are suggestive of AOSD while levels greater than 4,000ng/mL are very specific for this diagnosis when accompanied by a compatible clinical picture. One case-controlled study in China reiterated the usefulness of serum ferritin, determining that a threshold value of 2,500ng/mL, along with Yamaguchi criteria, appeared highly specific for a true diagnosis of AOSD. The same study concluded that other non-AOSD inflammatory conditions seldom presented with serum ferritin levels above 750ng/mL. Measurement of serum ferritin may also correlate to prognosis; one article postulates that AOSD with high levels of serum ferritin may be associated with a chronic and relapsing course.
Treatment of AOSD has been empirical with an emphasis on the use of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, and biologic agents. NSAID monotherapy is only effective in 7 to 15 percent of cases. Most patients require corticosteroids at some point in their disease course. When long-term therapy is required, methotrexate may minimize or eliminate the need for oral corticosteroids. Modest success has been achieved with cyclosporine A, hydroxychloroquine, gold, penicillamine, and azathioprine.
Coupled with the Yamaguchi criteria, the marked elevation of serum ferritin in this case helped to clinch a diagnosis of AOSD. The authors’ report earnestly reaffirms the diagnostic utility of hyperferritinemia in this febrile exanthem.
1. Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Edinburgh: Mosby Inc; 2012.
2. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol. 1992;19:424.
3. Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J. 2011;434:365–381.
4. Tran TN, Eubanks SK, Schaffer KJ, et al. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood. 1997;90:4979–4986.
5. Fautrel B, Zing E, Golmard JL, et al. Proposal for a new set of classification criteria for adult-onset Still’s disease. Medicine. 2002;81:194–200.
6. Efthimiou P, Paik PK, Bielroy L. Diagnosis and management of adult onset Still’s disease. Ann Rheumatol Dis. 2006;65:564–572.
7. Meijvis SC, Endeman H, Geers AB, ter Borg EJ. Extremely high serum ferritin levels as diagnostic tool in adult-onset Still’s disease. Neth J Med. 2007;65:212–214.
8. Schiller D, Mittermayer H. Hyperferritinemia as a marker of Still’s disease. Clin Infect Dis. 1998;26:534–535.
9. Lian F, Wang Y, Yang X, et al. Clinical features and hyperferritinemia diagnostic cutoff points for AOSD based on ROC curve: a Chinese experience. Rheumatol Int. 2012;32:189–192.
10. Nagai Y, Hasegawa M, Okada E, et al. Clinical follow-up study of adult-onset Still’s disease. J Dermatol. 2012;39: 898–901.