REVIEW

Updates in adult-onset Still disease: Atypical cutaneous manifestations and associations with delayed malignancy Natalie Z. Sun, MD,a Elizabeth A. Brezinski, MD,b Jacqueline Berliner, MD,a Anna Haemel, MD,a M. Kari Connolly, MD,a Lianne Gensler, MD,c Timothy H. McCalmont, MD,a,d and Kanade Shinkai, MD, PhDa San Francisco, California Adult-onset Still disease (AOSD) is a systemic inflammatory disorder that is clinically characterized by a heterogeneous constellation of symptoms and signs. Though an evanescent eruption is the classic cutaneous finding, recent literature has highlighted atypical rashes associated with Still disease. A second emerging concept in presentations of AOSD is its association with malignancy. This review focuses on these concepts: the clinical spectrum of atypical skin manifestations and AOSD as a paraneoplastic phenomenon. PubMed-MEDLINE was screened for peer-reviewed articles describing atypical presentations of AOSD and cases associated with malignancy. Erythematous, brown or violaceous, persistent papules and plaques were the most common cutaneous finding (28/30 [93%]). Linear configurations were also rarely described. Of these patients, 81% concurrently had the typical evanescent skin eruption. There were 31 patients with associated malignancies, most commonly breast cancer and lymphoma. The diagnosis of malignancy did not precede or immediately follow a clinical presentation otherwise consistent with AOSD in a considerable subset of patients (42%). Understanding the cutaneous spectrum of AOSD and heightened awareness for its delayed association with malignancy may lead to improved recognition of cutaneous variants and reinforce the need for diagnostic evaluation and long-term follow-up for malignancy in patients with this clinical presentation. ( J Am Acad Dermatol http://dx.doi.org/10.1016/ j.jaad.2015.04.063.) Key words: adult-onset Still disease; evanescent rash; hyperferritinemia; paraneoplastic syndrome; persistent pruritic eruption.

INTRODUCTION Adult-onset Still disease (AOSD) is a systemic inflammatory disorder that is classically characterized by intermittent spiking fevers, an evanescent eruption, and arthralgias or arthritis with laboratory findings of leukocytosis and hyperferritinemia in the setting of a negative antinuclear antibody (ANA) test.1-3 Laboratory markers are suggestive of AOSD, but clinicians often rely on the typical evanescent eruption of light pink papules to make the diagnosis. Several classification criteria have been proposed; the Yamaguchi criteria are the most commonly used.2,4-6 The major criteria are high fever for [1 week, arthralgias for [2 weeks, leukocytosis ([10,000/mm3 with [80% polymorphonuclear From the Departments of Dermatology,a Rheumatology,c and Pathology,d University of California San Francisco, and the Department of Internal Medicine,b California Pacific Medical Center, San Francisco. Drs Sun and Brezinski contributed equally to this work. Funding sources: None. Conflicts of interest: None declared. Presented at the Medical Dermatology Society Meeting, Denver, CO, March 20, 2014.

leukocytes), and the typical skin eruption. Minor criteria include sore throat, lymphadenopathy and/ or splenomegaly, liver dysfunction (ie, transaminitis), and the absence of rheumatoid factor and ANA.2 Recently, small studies and case reports have described an atypical, persistent skin rash consisting of pruritic papules and plaques with various configurations with distinct histopathology in patients with active AOSD.7-21 This atypical rash often presents in addition to the typical rash but may also be the only skin manifestation, resulting in delayed diagnosis because of under-recognition. In addition to these reports of atypical cutaneous presentations, emerging literature highlights an increasing recognition of malignancy in association with Still disease,

Accepted for publication April 30, 2015. Reprint requests: Natalie Z. Sun, MD, Department of Dermatology, University of California San Francisco, 1701 Divisadero St, 3rd fl, San Francisco, CA 94115. E-mail: [email protected]. Published online June 5, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.04.063

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sometimes occurring years later. Additional laboratory workup and close clinical follow-up may be warranted once a diagnosis of AOSD is made. We review the literature on AOSD to highlight these emerging concepts in the recognition and management of patients with Still disease.

The atypical skin eruption was the presenting finding in 3 cases18,20 while it was reported to appear concurrently with systemic symptoms in the majority of cases.7,10-17,20,21 In these latter cases, atypical skin rash appeared as soon as 1 week18 and as late as 5 months10 after the classic symptoms of Still disease. The duration of the atypical eruption before presentation for evaluation ranged LITERATURE REVIEW OF CLINICAL from 2 to 3 weeks14,16,20 to CAPSULE SUMMARY 1 year.7 PRESENTATIONS IN PATIENTS WITH STILL Descriptors for the color of Adult-onset Still disease is a systemic DISEASE WITH the atypical eruption varied inflammatory disorder that is classically ATYPICAL SKIN from erythematous or brown characterized by an evanescent rash; RASHES in the majority of cases to, less reports of cutaneous variants in adultcommonly, violaceous.17 We searched PubMedonset Still disease have been published. MEDLINE for English and Linear configurations were Adult-onset Still disease has also been noneEnglish language artifrequently discussed.9,11-13,1618 reported in association with malignancy. cles available between JanuOther descriptions included ary 1, 1980 and October 15, prurigo pigmentosaelike,14,16 We present a current summary of 2013 for case reports or urticarial papules,10 lichenoid atypical cutaneous presentations of population-based studies of papules,11 dermatographismadult-onset Still disease and diagnostic atypical, persistent skin eruplike, dermatomyositis-like, considerations for associated tions in adult patients with and lichen amyloidosiselike malignancy. AOSD. Searching with the rashes.11,13 More than 1 morMeSH term ‘‘adult onset Still phology or distribution patdisease’’ and the terms ‘‘skin rash’’ or ‘‘persistent,’’ we tern was observed in several patients. The most retrieved 109 articles. Inclusion criteria included case commonly involved area was the back (14/19; 74%) reports or series reporting specific characteristics of followed by the chest (11/19; 58%). Photoaccentuation an atypical skin eruption in adults meeting the was noted in some patients.11,13 Yamaguchi criteria for AOSD. The abstracts were A majority of patients had abnormalities on screened for inclusion; 14 articles with 27 patients laboratory evaluation. One of the major criteria for were identified and reviewed. In addition, 3 patients classification of AOSD is leukocytosis, which was with Still disease from our clinical practice were present in 27 of 28 cases (96%). Transaminitis was included in this review (Figs 1-4). A summary of the present in 19 of 22 patients (86%). Ferritin [2000 g/ patient characteristics, presenting symptoms, rash, L (10 times the upper limit of normal) was found in laboratory findings, malignancy workup, and treat22 of 27 cases (81%), but otherwise ranged from 1266 ment, where reported, is presented here. An addito 73,000 g/L.9 tional article reported patient characteristics and The largest series describing 36 patients with laboratory findings among a group of 36 patients AOSD13 reported overall slightly lower incidences with the diagnosis of AOSD; however, only 28 of the of laboratory abnormalities compared to our review. 36 patients presented with persistent atypical rashes, The percentage of patients with leukocytosis in that and this article was therefore excluded from the study was 91% versus 96%; transaminitis was systematic review.13 The morphology, secondary observed in 72% compared to 86%; and ferritin [2000 g/L was seen in 67% versus 81% by our changes, and distribution of the atypical skin lesions review. These differences may be accounted for are described in detail in Table I. through inherent differences in patient cohorts, Overall, 25 of 30 (83%) patients were female, because that study also captured patients who did with a mean age of 34 years (range, 15-67 years). not have the persistent pruritic eruption. More than half of the 30 patients were Taiwanese A workup for malignancy was performed in a total or Asian (19/30; 63%), 5 patients were reported to of 19 patients who had the atypical eruption without be white or fair-skinned, 1 patient was Congolese, positive findings.7-10,12,14-16,18,21 The most common 1 patient was Hispanic, and the race or ethnicity of 4 patients was not reported. Of the 30 patients diagnostic procedure was a computed tomography with reported atypical persistent cutaneous scan of the abdomen that revealed hepatosplenolesions, 21 (70%) concurrently presented with megaly (5/19; 26%),8,9,14-16 lymphadenopathy (2/19; evanescent rash. 11%),14 pleural and pericardial effusion (1/19; 5%),9 d

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Abbreviations used: ANA: AOSD: GF:

antinuclear antibody adult-onset Still disease glycosylated ferritin

or no abnormal findings (1/19; 5%).10 Chest radiography, positron emission tomography, lymph node biopsy, and bone marrow biopsy were pursued in select cases,7-10,12,14-16,18,21 and a workup for malignancy was not described in 5 articles.11,13,17,19,20 The skin rash commonly resolved rapidly and permanently with the use of prednisone,8,10,12,14,15,19,21 prednisolone,7,9,16 or intravenous pulsed methylprednisolone.10,12,14,18 However, some patients required more potent or maintenance immunotherapy with systemic agents, including hydroxychloroquine, cyclosporine, methotrexate, anakinra, or tocilizumab (present article) to control or manage symptoms of Still disease, such as relapsing skin eruptions, fever, or arthralgias.9-12,14-16 Authors have noted that patients who had a dermatomyositis-like rash required more potent immunotherapy compared to patients who did not have this rash morphology.13 Histopathology of skin eruptions associated with AOSD Microscopic examination of the classic evanescent eruption of AOSD is said to consist of a sparse superficial infiltrate including neutrophils below a normal epidermis. In contrast, the atypical persistent eruption demonstrates a characteristic pattern of singly or grouped necrotic keratinocytes in the upper layers of the epidermis and a sparse superficial dermal infiltrate of neutrophils and sometimes eosinophils in the absence of vasculitis.10,11,13,22 Other variable features include mild vacuolar involvement of the basal layer of the epidermis with dyskeratotic keratinocytes, subcorneal neutrophils, and nuclear dust; eosinophils, if present, are typically rare or few in number.13 The biopsy specimens of the atypical rash obtained from patient 1 reported in this article (Fig 1) featured single dyskeratotic keratinocytes with a superficial dermal lymphohistiocytic infiltrate with neutrophils and eosinophils and is consistent with the reported findings in the persistent cutaneous form of this disorder (Fig 2). Interestingly, biopsy specimens obtained from patient 1 also featured an increase in interstitial mucin in the reticular dermis, which has previously been reported in the literature.22 The pathologic findings of the atypical persistent form of this disease are fairly specific and have been described in several case series of patients who fulfill the

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Yamaguchi criteria for AOSD, and it therefore seems likely that biopsy specimens that feature this pattern can be considered to be highly suggestive of AOSD in patients who do not yet fulfill the Yamaguchi criteria; additional study is needed to validate this conclusion.

ADULT-ONSET STILL DISEASE IN ASSOCIATION WITH MALIGNANCY AOSD may present with nonspecific symptoms (ie, fever, lymphadenopathy, and hyperferritinemia), and therefore malignancy is an important diagnosis to exclude in the initial evaluation of a patient suspected to have this disease. However, recent literature has highlighted the emerging concept that these malignancies may not be found until months or years later. Traditionally, lymphoma has been known to mimic symptoms of Still disease, but leukemias and solid tumors have also been found to occur in patients who otherwise fulfill the Yamaguchi criteria. Indeed, this diagnosis of malignancy can precede, occur at the time of, or follow AOSD-like symptoms by as many as 6 years.23 In these latter cases, discerning whether the symptomatology was related to malignancy can be difficult, particularly when an initial diagnostic workup is negative, but symptoms that are difficult to control with systemic corticosteroids and require maintenance immunosuppression may suggest another underlying process. PubMed was searched for case reports or case series of English and noneEnglish language articles describing an association with malignancy using the MeSH terms ‘‘adult onset Still disease,’’ ‘‘malignancy,’’ and ‘‘paraneoplastic’’ through October 15, 2013. Ninety-two articles were identified. Thirty articles describing 31 patients who fulfilled the Yamaguchi major and minor criteria were included. AOSD-like symptoms have been reported in the setting of multiple types of malignancies23-52 as described below and outlined in Table II. Overall, 17 of 31 (55%) patients were female, with a mean age of 51 years (range, 23-85 years), and the majority were between the ages of 40 to 69 years (24/ 31; 77%). The diagnosis of malignancy occurred after the diagnosis of AOSD had already been rendered in a significant number of cases (13/31; 42%) after a negative initial workup. The first report of 2 patients with AOSD-like symptoms in the setting of neoplasia was published in 1988.24 The first patient presented with fever, arthritis, leukocytosis, and an evanescent rash. Subsequent workup included a bone marrow biopsy, which demonstrated myeloproliferative syndrome. The second patient presented with similar symptoms and was diagnosed with a

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Fig 1. Adult-onset Still disease. Atypical skin eruption in association with Still disease in a 35year-old Hispanic woman with a 1-month history of intermittent fever of unknown origin, 25pound unintentional weight loss, lymphadenopathy, eosinophilia, polyarthralgias, weakness, and a severely pruritic skin rash that progressively generalized. Her physical examination was notable for erythematous to violaceous and brown thick, scaly papules coalescing into plaques on the frontal hairline and bilateral postauricular skin (A). She also had brown flat-topped papules on her bilateral shoulders and linear violaceous to brown scaly, excoriated, and lichenified plaques on the upper and lower aspects of her back (B). The patient’s medical history was notable for a presumed breast abscess treated with incision and drainage. Mammography and computed tomography scans revealed localized features and adjacent axillary lymphadenopathy consistent with postinflammatory changes without evidence of malignancy. Upon admission, the patient was afebrile, had a normal white blood cell count, and had a ferritin level of 11,405 g/L. An excisional inguinal lymph node biopsy and bone marrow biopsy were obtained to evaluate her lymphadenopathy and eosinophilia. The lymph node biopsy specimen revealed dermatopathic lymphadenopathy. The bone marrow biopsy specimen was significant for hypercellular marrow with trilineage hematopoiesis and leftshifted granulocyte hyperplasia without evidence of acute leukemia, lymphoma, myelodysplasia, metastatic tumor, or hemophagocytic lymphohistiocytosis.

Fig 2. Skin biopsy specimens obtained from the left postauricular scalp and left lateral aspect of the neck of the patient reported in Fig 1 reveal psoriasiform epidermal hyperplasia (A) beneath small mounds of parakeratosis (B) that include single dyskeratotic keratinocytes (C). There was a superficial dermal lymphohistiocytic infiltrate with admixed granulocytes and some perijunctional neutrophils and eosinophils present. Deeper in the dermis, an increase in mucin was apparent interstitially. (Hematoxylineeosin stain; original magnifications: A, 34; B, 310; C, 340.)

laryngeal carcinoma. In both cases, patients were treated for their malignancy and also with corticosteroids to control their AOSD-like symptoms. Predictably, AOSD-like symptoms were most strongly linked to lymphoma,26,28,31,38,40,41,43,44 and both B- and T-cell lymphomas have been reported

(8/31; 26%). Lymphadenopathy may occur in either AOSD or AOSD-like symptoms, but microscopic examination of lymph nodes reveals reactive hyperplasia in this context. In some cases of what is eventually diagnosed as lymphoma, no clinical lymphadenopathy is present or node biopsy

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Fig 3. Adult-onset Still disease. Clinical images of a 19-year-old Chinese woman who received a diagnosis of Still disease demonstrating a biopsy-confirmed atypical persistent pruritic rash involving the face (A), chest (B), back, and legs. The patient initially presented with fevers, leukocytosis, an elevated C-reactive protein level, an elevated erythrocyte sedimentation rate, hyperferritinemia ([5000 g/L), and migratory arthritis. The patient also had normal liver transaminases in the setting of slightly elevated alkaline phosphatase. Peripheral blood flow cytometry and bone marrow biopsy specimens did not reveal any evidence of hematologic malignancy or macrophage-activation syndrome. This patient required monthly methylprenisolone pulses with ongoing cyclosporine, prednisone, and tocilizumab to control her symptoms.

Fig 4. Adult-onset Still disease. A 21-year-old Cambodian woman with a diagnosis of Still disease with an atypical persistent pruritic rash confirmed by biopsy specimen involving the neck, trunk, and proximal extremities, here shown on the abdomen (A) and thighs (B). She presented with fevers, leukocytosis, hyperferritinemia, elevated C-reactive protein, an elevated erythrocyte sedimentation rate, cervical lymphadenopathy, arthralgias (of the knee and hand), and subjective weakness. Transaminase levels were normal.

specimens are nondiagnostic of lymphoma at the time of initial presentation40,43 to account for a paraneoplastic presentation and a diagnosis of AOSD is rendered.26,31,40,43 To a lesser degree, leukemias and myelodysplastic syndrome have also been linked to AOSD-like presentations,23,24,35,36,53 some not presenting until 6 years after the initial diagnosis of AOSD despite a normocellular marrow biopsy specimen at the time of initial presentation.23 The second strongest association for AOSD-like symptomatology is with breast cancer (6/31; 19%).25,27,30,32,34,48 In most cases, the breast cancer diagnosis was made in the workup of a breast nodule

with other AOSD-like symptoms that were difficult to control with corticosteroids or other nonsteroidal antiinflammatory medications. In 1 case, no rash was reported.30 Lung cancer and thyroid cancer have also been reported in association with AOSD-like symptoms (5/31; 16%).29,42,45-47 Both reported cases of thyroid cancer were of the papillary subtype.45,47 Both squamous cell carcinoma and adenocarcinoma subtypes have been reported in cases of lung cancer.29,46 Systemic symptoms, such as fever, arthritis, or rash, have been observed to resolve rapidly with definitive surgical tumor resection.29,46 Gastrointestinal

Primary morphology (n, reported ethnicity)

Secondary characteristics (ie, color, secondary changes)

Persistent papules and plaques (n = 1, white)

Erythematous

Persistent nonfollicular papules and plaques (n = 1, white) Persistent papules and plaques (n = 1, Japanese) Persistent papules and plaques (n = 1, white) Persistent generalized erythema (n = 2, Japanese) Fixed plaques (n = 1, ENR)

Brown with adherent scale

Persistent papules (n = 11, Taiwanese and Indonesian)

Persistent plaques (n = 1, Vietnamese) Prurigo pigmentosaelike persistent papular eruption (n = 1, ENR) Persistent papules (n = 1, Taiwanese) Persistent papules (n = 1, ENR) Persistent pigmented eruption (n = 1, African American) Persistent papules and plaques (n = 3, fair-skinned [n = 2], Asian [n = 1])

Erythematous, edematous plaque, and with linear pigmentation Erythematous and brown; ‘‘texture change’’ Erythematous, violaceous, dusky red, and brown; scaly, crusted, or lichenoid; poikilodermatous (n = 1); linear pigmentation (n = 6) Plaques Dark red to brown, with linear pigmentation Violaceous; scaly, crusted Erythematous and urticarial Erythematous Pink to erythematous; scaly, blanchable; in linear configuration (n = 1)

Erythematous, dusky red, and brown; scaly, crusted, or lichenoid; linear pigmentation

Evanescent rash

Reference 7

Yes

Kaur et al (1994)

Yes

Lubbe et al8 (1999)

Yes

Suzuki et al9 (2001)

No

Perez et al15 (2001)

Face, limbs, and trunk

Yes

Fujii et al18 (2003)

Arms, dorsal surfaces of the hands, upper aspect of the chest, and back With photoaccentuation; widely distributed

Yes

Affleck et al10 (2004)

Anterior aspect of the chest, neck, face, back, upper lateral abdomen, dorsal surfaces of the forearms, and shins bilaterally Forehead, neck, and upper and lower aspects of the back Trunk, with linear pigmentation on the chest and back Trunk and limbs

Yes (n = 9)

Lee et al11 (2005)

Trunk Chest and upper aspect of the back

Yes Yes

Thien Huong et al21 (2005) Tomaru et al16 (2006)

Forehead, neck, elbows, and knees Neck and upper trunk Neck

No Yes Yes

Yang et al17 (2006) Fernandez-Guarino et al20 (2006) Maza et al19 (2008)

Posterior aspect of the neck, back, upper abdomen; proximal extremities, back, abdomen, ankles; linear pigmentation on the upper aspects of the back and chest With photoaccentuation; widely distributed

Yes (n = 1)

Yes (n = 26/28)

Fortna et al12 (2010)

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Persistent eruptions (n = 28/36, Taiwanese); urticarial, lichenoid, linear and dermatographism-like; dermatomyositis-like; prurigo pigmentosaelike; lichen amyloidosiselike

Erythematous, edematous, and with linear pigmentation Erythematous

Distribution

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Table I. Summary of the literature on atypical skin rashes in patients with adult-onset Still disease

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Current report, patient 3, Fig 4 No

Current report, patient 2, Fig 3

Erythematous to red brown papules Persistent papules and plaques (n = 1, Asian)

Persistent papules and plaques (n = 1, Asian)

ENR, Ethnicity not reported.

Current report, patient 1, Fig 1 No

No

Periocular, cheeks, chest, back, shoulders, arms, dorsal surfaces of the hands, and proximal legs Neck, trunk, and proximal extremities

Cho et al14 (2013)

Erythematous and brown; reticulated Erythematous to violaceous, also brown; papules (including flat-topped) and plaques; linear violaceous to brown excoriated scaly and lichenified plaques Erythematous to brown papules coalescing into plaques Prurigo pigmentosaelike persistent papules and plaques (n = 1, ENR) Persistent papules and plaques (n = 1, Hispanic)

Anterior chest wall, abdomen, and back Frontal hairline, bilateral postauricular, and shoulders

Yes

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malignancies, including esophageal cancer, rectal cancer, and cholangiocarcinoma, have all been reported in association with AOSD-like presentations.33,40,49,50 Other reported malignancies include those with a mesenchymal component, such as sarcomatoid renal cell cancer, hepatic angiosarcoma, and mediastinal carcinoma with sarcomatoid elements37,39,51 and 1 report of metastatic melanoma.52 In the paraneoplastic setting, reported cutaneous findings were generally consistent with an evanescent eruption. They were described as persistent in only 2 instances; in a case of breast cancer with lymph node involvement, skin findings were described as a ‘‘generalized persistent pruritic rash and palpable erythematous nodules’’ on the legs.27 In another patient with breast cancer, symptoms of fever, arthralgias, and sore throat were seen with diffuse erythema multiformeelike lesions and petechiae on the legs.34 Generally speaking, the literature does not suggest a strong association between atypical cutaneous presentations of AOSD and paraneoplastic AOSD. The treatment of paraneoplastic AOSD-like symptoms is often challenging. Management of the symptoms of AOSD symptoms in the setting of malignancy required high-dose systemic glucocorticoids in 26 cases23-35,38-45,47,50-52 and additional systemic therapies in 6 cases, including cyclosporine,23,35,41 methotrexate,24,31 cyclophosphamide,31,35 and azathioprine.32 Importantly, multiple reports have reflected the relapse of symptoms while weaning off antiinflammatory therapy in the absence of definitive treatment of the primary malignancy.26,28,30,31,41,42,52 As discussed, complete clinical remission of AOSD-like symptoms has been achieved with surgical removal of the tumor, and 1 patient remained symptom-free 5 years later.25 The etiology of hyperferritinemia in patients with Still disease is unknown, and a diagnostic cutoff value is under debate.54 Ferritin levels of patients with atypical cutaneous AOSD ranged from 1266 to 73,100 g/L. Ferritin levels greater than normal3,55 or 5 times the upper limit of normal (5N) have been suggested as an indication of active AOSD.54 However, hyperferritinemia is not specific and is seen in hemochromatosis and Gaucher disease, cancers, and infection.56 Glycosylated ferritin (GF) has been investigated as a diagnostic marker, and the combination of GF #20% and high serum ferritin ([5N) may be the most specific indicator of AOSD.54 The role of interleukin (IL)-1, soluble IL-2 receptor, IL-6, IL-8, IL-18, tumor necrosis factorealfa (TNFa), and interferon-gamma (IFNg) in the

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Table II. Summary of the literature of adult-onset Still disease in the setting of neoplasia Case no.

Age/sex

1 2 3

58/F 45/M 52/F

Myelodysplastic syndrome Laryngeal carcinoma Breast carcinoma

Associated malignancy

4 5 6

52/F 62/M 49/F

Immunoblastic lymphoma Myelodysplastic syndrome Breast carcinoma

7 8

58/F 60/M

T-cell lymphoma Lung carcinoma

9 10 11

45/F 50/M 48/F

Breast carcinoma Diffuse large B-cell lymphoma Breast carcinoma

12

77/M

Esophageal carcinoma

13 14 15 16 17 18

49/F 25/M 43/M 63/M 53/F 40/F

Breast carcinoma Chronic myelogenous leukemia Acute lymphoblastic leukemia Mediastinal carcinoma Diffuse large B-cell lymphoma Hepatic angiosarcoma

19

32/F

Non-Hodgkin lymphoma

20

25/M

NK/T-cell lymphoma

21

62/M

22 23

53/F 23/F

Lung carcinoma (nonesmall cell type) Diffuse large B-cell lymphoma Hodgkin lymphoma

24 25 26 27 28

32/F 56/M 68/M 52/F 85/F

Papillary thyroid carcinoma Lung carcinoma Papillary thyroid carcinoma Breast carcinoma Rectal carcinoma

29

53/M

Cholangiocarcinoma

30 31

69/M 50/F

Renal cell carcinoma Melanoma

Cutaneous findings

Evanescent maculopapular rash Evanescent rash Evanescent nonpruritic nontender erythematous macules None Typical rash Persistent generalized pruritic rash with palpable erythematous nodules on the legs Evanescent generalized eruption Maculopapular rash on sacrum and posterior aspects of the elbows None None Evanescent maculopapular rash involving the face, hands, wrists, and buttocks Salmon-pink to violaceous eruption involving the face, chest, back, and shoulders Erythema multiforme Evanescent rash None Rash on the trunk and extremities None Evanescent nonpruritic pink macular rash Papules involving the neck and abdomen Macular salmon-pink eruption on the chest and abdomen Evanescent nonpruritic generalized maculopapular rash Maculopapular rash Faint blanching erythematous rash of the face and chest None Evanescent maculopapular rash Salmon-pink rash Transient macular rash Evanescent maculopapular rash on the back and thighs Nonpruritic erythematous macular rash Evanescent generalized rash Urticarial nonpruritic generalized maculopapular rash

Reference

Cabane et al24 (1987) Cabane et al24 (1987) Rogues et al25 (1993) Trotta et al26 (1993) Sugawara et al23 (1993) Drenth et al27 (1994)2

Kawasaki et al28 (1995) Routier et al29 (1997)

Neishi et al30 (2000) Sono et al31 (2000) Kianzowa et al32 (2002)

Shibuya et al33 (2003)

Komano et al34 (2004) Nakagawa et al35 (2005) Benitez-Velazco et al36 (2005) Yoshida et al37 (2006) Haider et al38 (2008) Mekinian et al39 (2008) Otrock et al40 (2008) Kato et al41 (2009) Bosch-Barrera et al42 (2009) Geurts et al43 (2009) Gratton et al44 (2010) Ahn et al45 (2010) Wu et al46 (2011) Inoue et al47 (2012) von Lilienfeld-Toal et al48 (2013) Okamoto et al49 (2013) Raza et al50 (2013) Yilmaz et al51 (2013) Liozon et al52 (2014)

F, Female; M, male; NK, natural killer.

pathophysiology of AOSD have been reported,57-59 and the therapeutic use of TNFa inhibitors, IL-1 blockers, and tocilizumab reflects this—yet the mechanism of atypical persistent eruptions is unclear. IL-6, implicated in the acute phase,60,61 and IL-

18, implicated as a marker of severity in classic AOSD,59 have both been elevated in cases of persistent eruption.9,62 Although cases of persistent eruptions and paraneoplastic presentations did not generally overlap in our review, there appears to be

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some overlap in cytokine profile between these 2 groups. In malignancy, these may account for fever, arthralgias, and constitutional symptoms that mimic classic AOSD. IL-18 is elevated in breast, esophageal, and hematologic malignancies and the soluble IL-2 receptor in lymphoma.63-66 TNFa, IFNg, and IL-6 levels are elevated in patients with breast cancer.27,34 Some cases of AOSD may actually reflect an early host antitumor response in occult malignancies that lie below the threshold of clinical detection. This suggests that close follow-up is warranted in patients with AOSD, particularly when symptoms are difficult to control. In conclusion, recent literature has highlighted 2 emerging concepts regarding AOSD: atypical cutaneous presentations and delayed association with malignancy. This review summarized the literature and promoted the understanding of these concepts. This improved awareness should facilitate clinician recognition of a variant of cutaneous AOSD and prompt not only diagnostic consideration but, importantly, ongoing follow-up for delayed-onset malignancy in all patients who carry a tentative diagnosis of AOSD. Additional studies in larger cohorts will be needed to better understand the prevalence and pathophysiology of these atypical presentations. REFERENCES 1. Bywaters EG. Still’s disease in the adult. Ann Rheum Dis. 1971; 30:121-133. 2. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol. 1992;19:424-430. 3. Schwarz-Eywill M, Heilig B, Bauer H, et al. Evaluation of serum ferritin as a marker for adult Still’s disease activity. Ann Rheum Dis. 1992;51:683-685. 4. Cush JJ, Medsger TA Jr, Christy WC, et al. Adult-onset Still’s disease. Clinical course and outcome. Arthritis Rheum. 1987; 30:186-194. 5. Calabro JJ, Londino AV Jr. Adult onset Still’s disease. J Rheumatol. 1986;13:827-828. 6. Reginato AJ, Schumacher HR Jr, 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. 7. Kaur S, Bambery P, Dhar S. Persistent dermal plaque lesions in adult onset Still’s disease. Dermatology. 1994;188:241-242. 8. Lubbe J, Hofer M, Chavaz P, Saurat JH, Borradori L. Adult-onset Still’s disease with persistent plaques. Br J Dermatol. 1999;141(4):710-713. 9. Suzuki K, Kimura Y, Aoki M, et al. Persistent plaques and linear pigmentation in adult-onset Still’s disease. Dermatology. 2001;202(4):333-335. 10. Affleck AG, Littlewood SM. Adult-onset Still’s disease with atypical cutaneous features. J Eur Acad Dermatol Venerol. 2005;19(3):360-363. 11. Lee JY, Yang CC, Hsu MM. Histopathology of persistent papules and plaques in adult-onset Still’s disease. J Am Acad Dermatol. 2005;52(6):1003-1008.

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