Typical evanescent and atypical persistent polymorphic cutaneous rash in an adult Brazilian with Still's disease: a case report and review of the literature.

Adult onset Still's disease (AOSD) is a systemic auto-inflammatory condition of unknown etiology, characterized by high fever, an evanescent, salmon-pink maculopapular skin rash, arthralgia or arthritis and leukocytosis. AOSD can also present with atypical cutaneous manifestations, such as persistent pruritic coalescent papules or plaques and linear lesions that have highly distinctive pathological features and are usually associated with severe disease. Herein, we present a 31-year-old Brazilian man with both typical Still's rash and atypical persistent polymorphic cutaneous manifestations associated with severe systemic inflammatory response syndrome. Eosinophils that are consistently lacking in the AOSD-associated skin lesions were evident in the skin biopsy of the persistent atypical cutaneous manifestations and were either drug-related or AOSD-associated.

Introduction

Adult onset Still’s disease (AOSD) is a systemic auto-inflammatory condition of unknown etiology, characterized by intermittent spiking high fever, an evanescent, salmon-pink or erythematous maculopapular skin rash, arthralgia or arthritis and leukocytosis with at least 80 % neutrophils [1]. Other common symptoms include sore throat, lymphadenopathy, hepatomegaly, and splenomegaly [2]. High serum ferritin levels, elevated ESR and high CRP levels, absent antinuclear antibody (ANA) and rheumatoid factors (RF) are the most common laboratory findings [3, 4]. We report a case of AOSD in a 31-year-old Brazilian man presenting with both typical Still’s rash and atypical non-evanescent polymorphic cutaneous manifestations.

Case presentation

A 31-year-old Brazilian male presented with high quotidian fever and night sweats, non-productive cough, lower back pain and erythematous rash for two weeks. The fever occurred almost daily and ranged from 39 to 40 °C. The rash started from both hands and was characterized by multiple erythematous confluent roundish macules and papules that coalesced to form large, irregular erythematous plaques (Fig. 1). The rash lasted for a few days and then appeared with a different morphology on the flexor surfaces of his arms as an extensive erythematous linear urticarial eruption (Fig. 2a). Subsequently the rash appeared on his upper and lower trunk as multiple intensely pruritic linear urticarial streaks (Fig. 2b). Ibuprofen has been used intermittently to alleviate back pain as well as the fever with minimal relief. He denied any contacts with sick individuals, insect or animal bites and his last trip was to Brazil 10 months ago. He has been sexually active in a monogamous relationship.

Fig. 1

Typical evanescent rash: Multiple non-pruritic confluent erythematous macules and papules on the dorsal surface of both hands that coalesced to form irregular erythematous plaques

Fig. 2

Atypical urticarial rash: a linear urticarial eruption on the flexor surface of arms. b Multiple intensely pruritic linear urticarial streaks on the upper and lower trunk

On admission, his temperature was 39 °C and a persistent pigmented plaque V shaped was evident on his anterior chest extending down the midline to the umbilicus (Fig. 3). Further skin examination revealed a confluent salmon-pink papular eruption on his lower back area and a persistent pigmented plaque on the upper area of his back. Besides mild splenomegaly and a tender right wrist, left second and third proximal interphalangeal joints with no signs of swelling or erythema, the rest of the physical exam was unremarkable. Laboratory profile revealed severe neutrophilic leukocytosis (30,000, normal values 4800–10,800/mcL), and a highly elevated serum ferritin levels (>10,000, normal values 17.90–464.00 ng/mL). Autoantibodies (including ANA, ANCA, RF and anti-CCP) were negative. Blood cultures excluded common viral and bacterial infections and RPR were negative. Serological tests for Hepatitis B and C, HIV, Epstein-Barr and Cytomegalovirus were negative. Borrelia burgdorferi, Bartonella henselae, Rickettsia typhi, RMSF, Typhus and Parvovirus B-19 serologies were negative as well. Parasites for malaria or Babesia microti were undetectable on peripheral blood smear. Transthoracic echocardiogram was negative for vegetations and computed tomography (CT) of the neck, chest and abdomen revealed only borderline mild splenomegaly.

Fig. 3

Atypical persistent rash: persistent pigmented plaque V shaped on the anterior chest extending down the midline to the umbilicus

The clinical and laboratory findings were consistent with the diagnosis of AOSD according to Yamaguchi criteria [2]. He was started on 50 mg of prednisone. After 2 weeks of treatment, he returned to our hospital with very high daily spiking fever up to 39.5 °C, perfuse sweating, hypotension, elevated liver enzymes and severe leukocytosis with neutrophil predominance. No new skin lesions were noted. The patient was admitted to intensive care unit due to suspected systemic inflammatory response syndrome and was started on broad-spectrum antibiotics and intravenous fluids. Since the blood cultures were negative, antibiotics were discontinued. Anakinra 100 mg daily subcutaneously was added to 50 mg of prednisone with dramatic resolution of his febrile episodes. The patient was discharged with instructions to gradually taper prednisone.

After 1 week of treatment with Anakinra and while on 40 mg of prednisone the patient remained afebrile but new erythematous plaques appeared on lower abdominal quadrants and a skin biopsy was performed (Fig. 4). Skin biopsy showed a normal epidermis, with an inflammatory infiltrate in the dermis surrounding superficial blood vessels and adnexal structures, and the interstitium as well (Fig. 5a). The inflammatory infiltrate composed of lymphocytes, neutrophils and eosinophils (Fig. 5b). Because of the persistent cutaneous manifestations, the patient was advised to apply on the persistent eruptions of his chest and abdomen triamcinolone cream 0.5 % twice daily. After 1-month follow-up, the skin rash on the above areas almost resolved.

Fig. 4

Atypical persistent pruritic eruption: edematous erythematous plaques on lower abdominal quadrants. Stich denotes the site of skin biopsy

Fig. 5

a Hematoxylin and eosin (H&E) stain showing periadnexal and perivascular infiltrate of inflammatory cells surrounding blood vessels, hair follicles and the interstitium (in between the vessels and adnexal structures). Original magnification at ×100. b H&E stain showing perivascular inflammatory infiltration of lymphocytes, neutrophils and eosinophils. Original magnification at ×400

Discussion

Review of literature, via the PubMed search, using the terms adult onset Still’s disease, cutaneous manifestations and eruptions from 1985 to 2014 to retrieve data on the diversity in clinical manifestations and histopathological findings of polymorphic Still’s rash, was performed (Table 1). AOSD is a rare young adult systemic autoimmune disorder with diverse clinical manifestations and occasionally unwanted serious organ damage like acute liver failure, adult respiratory distress syndrome, disseminated intravascular coagulation, and hemophagocytic syndrome [5-10]. Thus, early recognition of AOSD is crucial and should be always considered in the differential diagnosis of a systemic inflammatory syndrome, particularly when extensive microbiological workup is negative.

Table 1

Clinical manifestations and histopathological findings of Still’s disease

Author/Year	No of patients/ age (range) /Sex	Clinical presentation	Laboratory findings	Cutaneous manifestation	Skin Histology	Treatment
Wouters et al. [12]	1/66 /F 1/62/M	Polyarthritis, fever, splenomegaly	Leukocytosis, anemia, increased ESRand liver enzymes	Evanescent macular nonpruritic rash on trunk, limbs	-	NSAIDs, Penicillamine
Phillips et al. [21]	1/51/F	Arthralgia, sore throat, lethargy, night sweats	Leukocytosis, anemia, increased ESR, liver enzymes & ferritin	Evanescent erythematous maculopapular pruritic rash on trunk, limbs, face	Perivascular infiltrate in upper dermis and dermal mucin deposition	NSAIDs, Methotrexate
Tay et al. [27]	1/33/F	Fever, arthralgia, malaise, sore throat, headache, lymphadenopathy, hepatomegaly	Leukocytosis, anemia, increased ESR, CRP & immunoglobulins	Evanescent urticarial-like erythematous maculopapular pruritic rash on trunk, limbs	Edema of the upper dermis with perivascular neutrophils and eosinophils	NSAIDs, Prednisolone
Setterfield et al. [30]	1/32/F	Arthralgia, sore throat, fever, anorexia, weight loss	Leukocytosis, anemia, increased ESR, CRP & ferritin	Persistent urticarial annular pruritic lesions on trunk and limbs	Dermal edema, perivascular neutrophilic infiltrate	NSAIDs
Lubbe et al. [33]	1/16/F	Fever, arthritis, sore throat, pericardial effusion, hepatosplenomegaly	Leukocytosis, anemia, increased ESR, CRP & ferritin	Evanescent maculopapular lesions on chest, persistent brownish papules and plaques on face, neck, back	Parakeratosis, acanthosis and scattered intraepithelial keratinocyte necroses	NSAIDs, Prednisone
Salaffi et al. [36]	1/55/F	Fever, arthralgia, fatigue	Leukocytosis, anemia, increased ESR, CRP & ferritin	Urticarial pruritic rash on trunk, limbs and face	Dermal edema with perivascular and interstitial neutrophilic infiltrate	NSAIDs, Prednisone, Methotrexate
Suzuki et al. [18]	1/25/M	Fever, arthralgia, fatigue	Leukocytosis, anemia, increased ESR, CRP, liver enzymes & ferritin	Persistent papules and plaques on trunk, linear pigmentation on chest and back	Mild perivascular infiltration of neutrophils and lymphocytes.	NSAIDs, Prednisolone, Methotrexate
Perez et al. [43]	1/39/M	Polyarthritis, sore throat, fever, chills, lymphadenopathy, hepatosplenomegaly	Leukocytosis, increased ESR, CRP liver enzymes & ferritin	Erythematous papules and plaques on neck, trunk, limbs	Perivascular infiltrate of dermal vessels with eosinophils, histiocytes, lymphocytes and neutrophils within vessels	NSAIDs, Prednisone
Lee et al. [25]	1/46/F	Arthralgia, high fever, headache, nausea, splenomegaly	Anemia, thrombocytopenia, increased ESR, liver enzymes &ferritin	Vesicular and pustular eruption on hands and feet	Fibrin deposit in the vessels, subepidermal bulla and ischemic necrosis of epidermis	NSAIDs, Corticosteroids
Elezoglou et al. [42]	1/47/M	Fever, arthralgia, malaise, sore throat, hepatosplenomegaly glomerulonephritis	Leukocytosis, anemia, increased CRP, liver enzymes & ferritin, cryoglobulinemia	Evanescent maculopapular pruritic rash on head, trunk, buttocks, groin, annular purpuric plaques on ankles and shins	Leuko-cytoclastic vasculitis	Methyl-prednisolone, Methotrexate
Thien Huong et al. [17]	1/23/F	Fever, polyarthralgia, polyadenopathy, myalgia	Leukocytosis, increased ESR & ferritin	Persistent pigmented plaques on trunk	-	Corticosteroids
Tomaru et al. [23]	1/34/F	Fever, polyarthralgia, lymphadenopathy	Leukocytosis, increased CRP, liver enzymes & ferritin	Persistent pruritic erythematous papules with linear arrangement and pigmentary changes on chest and back, evanescent salmon-pink eruption on lower extremities	Mild acanthosis, exocytosis, dyskeratotic cells and liquefaction degeneration in the basal layer, with lichenoid inflammatory reaction	Corticosteroids, Cyclosporine, Methotrexate
Criado et al. [31]	1/52/F	Fever, polyarthralgia, sore throat, mild hepatomegaly, lymphadenopathy	Leukocytosis, increased ESR, CRP, & ferritin, hypergammaglobulinemia	Lenticular urticaria-like rash on face, thorax, abdomen, hands	Interstitial edema in reticular and papillar dermis with neutrophils and leukocytes around vasculitis-free vessels.	NSAIDs, Methotrexate, Thalidomide
Yang et al. [35]	1/47/F	Fever, polyarthralgia, sore throat, myalgia, pleural effusion, splenomegaly	Leukocytosis, elevated liver enzymes & ferritin	Persistent violaceous scaly maculopapular rash with linear lesions on forehead, neck, elbows, knees	Necrotic keratinocytes in the upper epidermis and perivascular infiltrate of lymphocytes and neutrophils	Methyl-prednisolone, Azathioprine
Wolgamot et al. [39]	1/55/F	Fever, polyarthralgia	Leukocytosis, increased ESR, CRP& ferritin	Pruritic maculopapular rash, plaques on face, extremities, trunk	Pattern with dyskeratotic keratinocytes in upper epidermis and stratum corneum	Prednisone, Methotrexate, Etanercept, Anakinra
Yanai et al. [41]	1/43/M	Fever, arthralgia, myalgia, myositis	Increased fibrinogen CRP, creatine kinase & ferritin	Salmon-pink rash on upper arm	Perivascular lymphocytes infiltration and fragmentation of blood cells compatible with leukocytoclastic vasculitis	NSAIDs, corticosteroids
Fortna et al. [40]	3/15-54/F	Fever, polyarthralgia, myalgia, sore throat	Leukocytosis, increased ESR, CRP, liver enzymes & ferritin	Pruritic erythematous blanchable papules and plaques on back, neck, abdomen, limbs	Hyperkeratosis with patchy parakeratosis, areas of dyskeratosis to upper layers of epidermis, and mild acanthosis.	Methyl-prednisolone, Methotrexate, Anakinra
Criado et al. [26]	2/27-34/F1/26/M	Fever, arthritis, sore throat, lymphadenopathy, pleural effusion, splenomegaly	Leukocytosis, anemia, increased ESR, CRP & liver enzymes, hyperferritinemia	Urticarial pruritic rash, linear lesions (dermographism) on trunk, limbs, face	Perivascular and interstitial inflammatory cell infiltrate of lymphocytes and neutrophils with leukocytoclasia.	Prednisone, Chloroquine, Methotrexate,
Nagai et al. [34]	18/16-60/F	Fever, arthralgia, sore throat, splenomegaly, lymphadenopathy	Leukocytosis, increased CRP, liver enzymes & ferritin	Evanescent salmon-pink maculopapular eruption, persistent papules and plaques with linear erythema similar to prurigo pigmentosa, edema of eyelids mimicking dermatomyositis	Parakeratosis and necrotic keratinocytes in epidermis, inflammatory infiltrates of lymphocytes in the papillary and mid-dermis	Corticosteroids, Methotrexate, Mizoribine Cyclosporin, Cyclophosphamide
Lee et al. [14]	30/17-67/F6/17-67/M	Fever, arthralgia, sore throat, splenomegaly, lymphadenopathy	Leukocytosis, elevated liver enzymes & ferritin	Evanescent rash, persistent pruritic urticarial, violaceous papules and plaques, dermatographism-like, prurigo pigmentosa-like and dermatomyositis-like eruption on trunk, neck, face, limbs	Normal epidermis with perivascular infiltrate of neutrophils, nectrotic keratinocytes in upper epidermis.	NSAIDs, Corticosteroids, Methotrexate, Azathioprine
Yoshifuku et al. [16]	1/27/F	Fever, polyarthralgia, sore throat, hepatosplenomegaly lymphadenopathy	Leukocytosis, increased CRP, elevated liver enzymes & ferritin	Pruritic pigmented erythematous plaques and dark-reddish papules on abdomen and back	Mild hyperkeratosis, and presence of dyskeratotic keratinocytes in upper epidermis	Corticosteroids, Cyclosporin,
Said et al. [37]	1/23/M	Fever, sore throat, myopericarditis, arthralgia, hepatosplenomegaly	Leukocytosis, increased ESR &CRP, elevated ferritin, raised cardiac enzymes	Urticated and erythematous plaques and papules on the dorsum of right hand and fingers	Superficial and deep perivascular infiltrates of lymphocytes and neutrophils	Corticosteroids,NSAIDs, Azathioprine
Cho et al. [24]	1/38/F	Fever, polyarthralgia, sore throat hepatosplenomegaly lymphadenopathy	Leukocytosis, elevated liver enzymes & ferritin	Prurigo pigmentosa-like persistent papules and plaques on anterior chest, abdomen, back	Parakeratosis, and perivascular infiltrations of lymphocytes, eosinophils and neutrophils in upper dermis	Methyl-prednisolone, Methotrexate, Hydroxychloroquine
Sarkar et al. [19]	1/36/M	Fever, arthritis, hepatosplenomegaly hemophagocytic lymphohistiocytosis	Leukocytosis, anemia, increased ESR, CRP, liver enzymes & ferritin, hypoalbuminemia	Pigmented patches and plaques on chest, dermal and mucosal hyper-pigmentation	Multiple necrotic keratinocytes in aggregates in upper epidermis	Corticosteroids
Cossi et al. [38]	1/35/M	Fever, cough, dyspnea myopericarditis	Increased CRP, liver enzymes & ferritin hypergammaglobulinemia	Pruritic erythematous-edematous plaques on trunk, upper limbs	Epidermal spongiosis, dermal infiltrate of perivascular lymphocytes and histiocytes, intra- vascular CD15+neutrophils	Methyl-prednisolone, Immunoglobulin IV Methotrexate

The typical skin rash of AOSD is an evanescent salmon-pink non-pruritic or mildly pruritic maculopapular rash, with nonspecific histologic characteristics comprised of a superficial perivascular lymphocytic and scattered neutrophilic infiltrate in the upper epidermis [11-13]. The lesions often develop on the extremities and over the trunk during the peak of the fever and then resolve. AOSD can also present with various atypical cutaneous manifestations and persistent pruritic eruptions (PPEs) are common [14].

PPEs are polymorphic both in morphology and distribution patterns. The more common patterns include lichenoid, linear and dermographism-like eruptions [14], persistent pruritic coalescent papules and plaques [15-17] with linear pigmentation [18], dermal and mucosal hyperpigmentation [19], amyloidosis-like skin eruption [20], generalized peau d’orange appearance of the skin [21], generalized persistent erythema [22], prurigo pigmentosa-like eruption [23, 24], vesiculopustules [25], urticaria [26, 27] and fixed papular lesions [28]. The latter are characterized by atypical wheals, present for more than 24–36 h, with symmetrical distribution [29, 30]. Pruritic lesions are usually evident with the presence of linear dermographism from scratching, as was evident in our patient. The most common atypical rash manifestation in AOSD includes the persistent pruritic coalescent papules and plaques and linear lesions [31].

In addition to the typical maculopapular evanescent Still’s rash, our patient had also an atypical persistent pigmented eruption manifested with different cutaneous morphology and geographic distribution over his body. The linear urticarial streaky and dermographism-like eruptions on upper extremities and torso sequentially gave place to persistent erythematous plaques on his chest and abdomen. We believe that this type of polymorphic cutaneous eruption may be a predictor of severe systemic inflammatory disease like in our case, and could be associated with activation of macrophages and natural killer cells in addition with increased production of IL-2, interferon-γ and tumor necrosis factor (TNF)- α. High levels of IL-8 were demonstrated in Still’s rash and this cytokine is considered as the inducer of the acute phase of inflammatory cascade in AOSD [32]. We believe that the cutaneous response to Anakinra was slower than the systemic one, since the febrile episodes resolved rapidly after initiation of Anakinra whereas the skin lesions persisted. The introduction of Anakinra therapy in our patient may have slightly exacerbated the pre-existing cutaneous lesions and caused new ones at the initiation of the treatment probably due to its immune modulating effects. Anakinra has been shown to cause interstitial granulomatous drug reaction [33, 34]. The application of topical corticosteroids facilitated the resolution of the cutaneous manifestations.

The histological features of persistent eruptions include parakeratosis [35], necrotic keratinocytes in the upper epidermis and a perivascular and interstitial inflammatory infiltrate of lymphocytes and neutrophils in the upper- and mid-dermis [36-39]. In urticarial lesions the histopathologic findings demonstrate an intense infiltrate of mature CD15+ neutrophils between the dermal collagen bundles. This clinicopathological entity has recently been described as neutrophilic urticarial dermatosis (NUD) [40].

Dyskeratosis and dermal mucinosis represent distinctive cutaneous lesions of AOSD [41, 42]. The presence of fibrin thrombi in the small vessel with scarce inflammatory cell infiltration, suggestive of vasculopathy [25] has also been observed in cases of AOSD. Leukocytoclastic cutaneous vasculitis [43, 44] with mixed cryoglobulinemia [44] in AOSD has been described only rare in the literature.

Eosinophils that are commonly seen in drug-induced eruption are consistently lacking in the AOSD-associated skin lesions [14]. Perez et al. described a case of AOSD-related persistent erythematous rash characterized by papules and plaques in which skin biopsy revealed perivascular infiltration of the small vessels in the dermis by eosinophils, histiocytes and lymphocytes [45]. In our case, the histopathology findings of the new persistent cutaneous eruption included the presence of several perivascular eosinophils not just in the dermis but also in the interstitium. The eosinophilic cutaneous manifestation could be either drug-related (i.e. antibiotics, Anakinra) or AOSD-associated.

Treatment of AOSD has been empirical. Non-steroidal anti-inflammatory drugs (NSAIDs), oral corticosteroids, disease modifying anti-rheumatic drugs (DMARDs), methotrexate (MTX), cyclosporine, azathioprine, sulfasalazine and minocycline have been used to treat this rare disease. Recently effective biologic agents including TNF-a, IL-1 and IL-6 antagonist have been used for steroid-resistant AOSD [46]. Laskari et al. provided evidence that Anakinra monotherapy or in combination with a DMARD, such as MTX may be the treatment of choice for patients with refractory Still’s disease [47]. MTX is recommended in patients with polyarthritis and allows for steroid dose sparing in AOSD [48]. Our patient did not respond to corticosteroid treatment, but showed dramatic response to initiation of Anakinra treatment.

In summary, AOSD can manifest with atypical skin lesions that have highly distinctive but non-pathognomonic pathological features and are usually associated with severe disease. Still’s rash can mimic various disorders with maculopapular, urticarial, linear and lichenoid manifestations and skin biopsy of those atypical cutaneous lesions is strongly recommended before or during the treatment course of AOSD because it allows rheumatologists and pathologists to recognize those specific distinctive histopathological characteristics and put the correct diagnosis.