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... Although a growing number of AoSD cases with a nonclassic variant of skin eruption have been reported, only a handful of cases have been flagellate dermatoses. [3][4][5][6] The histopathological findings of AoSD are nonspecific. The most commonly observed patterns include dyskeratotic/necrotic keratinocytes, perivascular inflammatory infiltrates of lymphocytes and neutrophils, dermal mucin and epidermal spongiosis. ...
... The flagellate pattern may be secondary to the Koebner phenomenon, may be associated with delayed malignancy or may be virally induced. 4,5 Differential diagnoses for flagellate dermatoses include dermatographism, Shiitake mushroom dermatitis, Chikungunya fever, bleomycin dermatitis, dermatomyositis and external or mechanically induced dermatosis. 3 Our patient's occupation as a physician raised suspicion for undetectable or resolved SARS-CoV-2 infection, as her clinical presentation of fever, arthralgia and sore throat represented overlapping symptoms between the Yamaguchi criteria and COVID-19. ...
We report a rare presentation of adult-onset Still disease (AoSD) with flagellate dermatosis and unknown trigger. Atypical skin findings have been increasingly reported for AoSD and may be associated with worse prognosis and systemic complications. Increased awareness of nonclassic skin findings in AoSD may lead to earlier diagnosis and treatment.
... Although the pathological findings of skin rashes in AOSD are generally nonspecific, superficial perivascular dermatitis was previously often observed in typical skin rashes [18][19][20] . On the other hand, interface dermatitis tends to be observed in atypical skin rashes, making it more important to distinguish between drug eruptions and other types of dermatitis [20][21][22] . In this study, interface dermatitis was significantly more frequent and superficial perivascular dermatitis was significantly less frequent in the elderly-onset group, which was consistent with the clinical features showing that atypical skin rash was more common and typical skin rash was less common in the elderly-onset group. ...
Recent studies have suggested that the clinical features of elderly-onset adult-onset Still’s disease (AOSD) differ from those of young and middle-aged-onset patients, whereas the details remain unclear, and cytokine profiles of elderly-onset AOSD have not been reported. To clarify the clinical features and cytokine profiles of elderly-onset AOSD, we examined patients with AOSD who developed the disease between January 2006 and September 2021. We divided the patients into the young and middle-aged-onset group (aged < 65 years) and the elderly-onset group (aged ≥ 65 years) and compared the groups in terms of patient characteristics, clinical symptoms, laboratory findings including serum interleukin (IL)-6 and IL-18, treatment, and prognosis. A total of 48 patients were examined (10 in the elderly-onset group). In the elderly-onset group, atypical rash was significantly more frequent, typical rash and splenomegaly were significantly less frequent, white blood cell count and neutrophil ratio were significantly higher and serum IL-6 levels were significantly lower. Serum IL-6 showed a significantly negative correlation with age at onset. Treatment and relapse were comparable between the 2 groups, whereas infections were significantly more frequent in the elderly-onset group. The clinical features and cytokine profiles of elderly-onset AOSD might differ from those of young and middle-aged-onset AOSD.
... 1,6 PPEs are clinically heterogeneous, and include urticarial eruptions, generalized erythema, lichenoid eruptions, linear flagellate papules and plaques, and eyelid erythema mimicking DM. 7 These persistent eruptions are better characterized in adults with SD than in children, as only few cases of PPEs have been reported in children with sJIA. 8 Recent studies have proposed an association between the presence of PPEs and worse prognosis in SD, perhaps due to the development of secondary MAS and the cytokine-rich environment (interleukin-18 especially) in which it develops. 9 MAS is a potentially fatal complication of SD that occurs in 10-15% of patients. ...
The typical rash of Still’s disease is an asymptomatic, salmon‐colored, macular, or maculopapular eruption that appears along with the fever spikes and fades when the body temperature drops. Although not included in the diagnostic criteria, there are other frequent, persistent, pruritic, and polymorphic skin manifestations of Still’s disease that have distinctive clinical features and specific histological findings. Among these atypical persistent pruritic eruptions (PPEs), periorbital erythema and linear flagellate papules and plaques can resemble the cutaneous manifestations of dermatomyositis (DM). The presence of these lesions in adult‐onset Still’s disease has been associated with worse prognosis and higher mortality rates, perhaps due to the development of a secondary macrophage activation syndrome (MAS). We report two cases of Still’s disease with persistent atypical DM‐like eruption, one in a pediatric patient (a very underreported finding) and the other in an adult. Both cases developed a secondary MAS.
... Although the pathological ndings of skin rashes in AOSD are generally nonspeci c, super cial perivascular dermatitis was previously often observed in typical skin rashes [16][17][18]. On the other hand, interface dermatitis tends to be observed in atypical skin rashes, making it more important to distinguish between drug eruptions and other types of dermatitis [18][19][20]. In this study, interface dermatitis was signi cantly more frequent and super cial perivascular dermatitis was signi cantly less frequent in the elderly-onset group, which was consistent with the clinical features showing that atypical skin rash was more common and typical skin rash was less common in the elderly-onset group. ...
Recent studies have suggested that the clinical features of elderly-onset adult-onset Still’s disease (AOSD) differ from those of young and middle-aged-onset patients, whereas the details remain unclear, and cytokine profiles of elderly-onset AOSD have not been reported. To clarify the clinical features and cytokine profiles of elderly-onset AOSD, we examined patients with AOSD who developed the disease between January 2006 and September 2021. We divided the patients into the young and middle-aged-onset group (aged <65 years) and the elderly-onset group (aged ≥65 years) and compared the groups in terms of patient characteristics, clinical symptoms, laboratory findings including serum interleukin (IL)-6 and IL-18, treatment, and prognosis. A total of 48 patients were examined (10 in the elderly-onset group). In the elderly-onset group, atypical rash was significantly more frequent, typical rash and splenomegaly were significantly less frequent, white blood cell count and neutrophil ratio were significantly higher and serum IL-6 levels were significantly lower. Serum IL-6 showed a significantly negative correlation with age at onset. Treatment and relapse were comparable between the 2 groups, whereas infections were significantly more frequent in the elderly-onset group. The clinical features and cytokine profiles of elderly-onset AOSD might differ from those of young and middle-aged-onset AOSD.
... 13 Necrotic keratinocytes have been described in the literature as a source of diagnostic error, confused with erythema multiforme. 17 However, erythema multiforme is an interface dermatitis in which at least some vacuolization of the basal layer is expected and in which necrotic keratinocytes are preferentially seen in the basal layer, although some may be present in higher layers. On the other hand, these are located in the upper layers of the epidermis in Still syndrome. ...
The skin is the largest and most exposed organ in the human body and the ideal place to look for signs that aid in the early diagnosis of systemic diseases with cutaneous effects. As the concepts that underpin our understanding of many of these diseases have evolved or expanded in recent years, there have also been changes in the criteria we use for early diagnosis, including our approaches to skin biopsy and dermatopathologic evaluation. This review focuses on some of the systemic processes with skin manifestations for which our basic understanding has changed most in recent decades.
... However, in a drug reaction, vacuolar interface and involvement of the basal layer with necrotic keratinocytes-findings not present in our patient's histology-are usually seen. 5 Our case is consistent with atypical presentations of AOSD found in more recent studies. Lee et al found that a distinct lichenoid eruption of papules and plaques was commonly observed in their study of 11 patients with AOSD. ...
Adult-onset Still’s disease (AOSD), the adult variant of systemic juvenile idiopathic arthritis, is a rare auto-inflammatory condition that presents with characteristic skin findings. There is no specific test available; diagnosis is usually based on the symptoms and evanescent rash found in patients. More recently, however, descriptions of atypical cutaneous and histological manifestations of AOSD have been published. We describe a case of atypical AOSD and discuss recent literature on this different cutaneous and histological presentation. Our results add to the growing discussion on atypical AOSD and suggest that this presentation may have been underreported and more common than previously thought.
Background
Small case series and case reports indicated atypical persistent pruritic eruptions (PPEs), another type of skin lesions in adult-onset Still’s disease (AOSD), imply a worse prognosis than typical evanescent rashes.
Objective
To investigate clinical characteristics and macrophage activation syndrome (MAS) occurrence in AOSD with PPEs.
Methods
A retrospective cohort study analyzed 150 AOSD patients with rashes at the First Affiliated Hospital of Zhejiang University from January 2013 to December 2019.
Results
AOSD with PPEs had higher lactate dehydrogenase (492.00 U/L vs 382.00 U/L, p<0.0001) and ferritin (6944.10 ng/mL vs 4286.60 ng/mL, p=0.033), and lower fibrinogen (5.05 g/L vs 5.77 g/L, p=0.014) than those with evanescent rashes. AOSD with PPEs had a higher incidence (17.4% vs 3.1%, p=0.006) and cumulative event rate for MAS (p=0.008), who tended to receive high-dose glucocorticoid (36% vs 20.3%, p=0.036). Multivariate analysis indicated PPEs (HR=5.519, 95%CI=1.138-26.767, p=0.034), aspartate aminotransferase (AST) >120 U/L (HR=8.084, 95%CI=1.728-37.826, p=0.008) and splenomegaly (HR=21.152, 95%CI=2.263-197.711, p=0.007) were independent risk factors for MAS.
Limitations
Single-center, retrospective nature, small sample size.
Conclusion
PPEs indicated increased severity and MAS occurrence than evanescent rashes. PPEs, AST >120 U/L and splenomegaly were risk factors for MAS in AOSD with skin involvement.
Adult-onset Still’s disease (AOSD) is a rare, systemic, inflammatory disorder characterized by spiking fevers, an evanescent eruption, arthritis, and multiorgan involvement. The disease has been recently classified as a polygenic autoinflammatory disorder at the “crossroads” of autoinflammatory and autoimmune diseases. The highly characteristic salmon-colored eruption is a cutaneous manifestation of a generalized inflammatory reaction and an important diagnostic criterion. In addition to the evanescent eruption, there are atypical persistent papules and plaques in many patients with AOSD. Emerging data suggest that AOSD with this typical evanescent eruption has a different clinicopathologic presentation and clinical course than AODS with atypical cutaneous manifestations.
It appears that there are two subtypes of AOSD with different immunologic profiles, including (1) a systemic disease with high fever, organ involvement, and elevated levels of ferritin, and (2) a chronic disease course with arthritis as the predominant finding. These observations provide novel insight into the disease pathogenesis, suggesting that the underlying mechanisms might differ between these two forms, partially explaining the reported differences in drug response.
Recent advances in the understanding of AOSD are summarized with a focus on the spectrum of cutaneous manifestations and its relationship to systemic inflammation.
Resumen
La piel es el órgano más extenso y más expuesto del cuerpo humano. Ello implica un magnífico terreno para el diagnóstico precoz de las enfermedades sistémicas que cursan con afectación sistémica y para las cuales la piel se vuelve un marcador diagnóstico. Las bases conceptuales y los criterios diagnósticos de muchas de estas entidades se han visto modificados o ampliados en los últimos años, con lo que la aproximación a la biopsia cutánea y la evaluación de los signos dermatopatológicos útiles en el diagnóstico precoz han variado también. En esta revisión intentamos hacer un enfoque de algunos de los procesos sistémicos con repercusión cutánea que más han variado conceptualmente en las últimas décadas.
The diagnosis of adult-onset Still's disease (AOSD) can be very difficult. There are no specific tests available, and diagnosis is usually based on a symptom complex and the well-described typical evanescent rash seen in the majority of patients. However, in recent years, other atypical cutaneous manifestations of AOSD have been reported. These atypical skin eruptions often present in addition to the typical evanescent rash but may also be the only skin manifestation, resulting in delayed diagnosis because of under-recognition.
In this study, we present 3 new cases of AOSD with atypical cutaneous manifestations diagnosed during a 30-year period in our department and review 78 additional cases previously reported (PubMed 1990?2016). These 81 patients form the basis of the present analysis.
The overall prevalence of atypical cutaneous manifestations in our AOSD population was 14%. These manifestations may appear at any time over the course of the disease, and usually occur in patients who have persistent and severe disease, with a considerable frequency of clinical complications (23%), including serositis, myopericarditis, lung involvement, abdominal pain, neurologic involvement, and reactive hemophagocytic syndrome.
The most representative and frequent lesion among the nonclassical skin rashes is the development of persistent pruritic papules and/or plaques. Interestingly, these lesions show a distinctive histological pattern. Other, less frequently observed lesions include urticaria and urticaria-like eruptions, generalized or widespread non-pruritic persistent erythema, vesiculopustular eruptions, a widespread peau d?orange appearance of the skin, and edema of the eyelids mimicking dermatomyositis without any accompanying skin lesion.
The great majority of these patients required medium or high doses of glucocorticoids (including intravenous methylprednisolone pulse therapy in some cases) and, in nearly 40%, a more potent or maintenance immunotherapy with immunosuppressant drugs and/or biologic agents (mainly anakinra or tocilizumab) to control or manage symptoms because of a polycyclic or chronic course. The development of atypical cutaneous manifestations seems to be associated with a potentially worse prognosis, with a mortality rate reaching 8% primarily because of infectious complications related to immunosuppressive therapy.
In conclusion, the appearance of atypical cutaneous manifestations is not uncommon in AOSD. Recognition of this clinical variant is crucial for the early diagnosis of AOSD, as it might imply persistent disease activity and the need for more aggressive treatment.
'Persistent pruritic papules and plaques' of Still's disease represents a recently described eruption seen in a subset of patients. Most cases reported in the literature to date have been associated with adult-onset Still's disease.
We present the clinical and histopathologic examinations of three female patients ranging in age from 15 to 54 years.
Our three patients each presented with clinical findings consistent with Still's disease. The youngest patient suffered from the juvenile form of Still's disease (systemic-onset juvenile rheumatoid arthritis). Each patient had a persistent, pruritic eruption with histopathologic findings of dyskeratosis confined to the upper layers of the epidermis as well as a sparse superficial dermal infiltrate containing scattered neutrophils.
These cases confirm the characteristic clinical and histopathologic findings of 'persistent papules and plaques of Still's disease' and show the potential for this eruption in both the adult and juvenile age groups.
Several micro-organisms, especially viruses, have been associated with juvenile and adult onset Still's disease. In the present study a search for probable triggering viral infections in five consecutive patients with early, active adult onset Still's disease has been made. In one patient echovirus 7 was identified as a probable triggering agent. Evidence of infection with this virus was acquired by virus cultures and serological tests. In two patients the illness was probably initiated by a rubella reinfection. Both had initially high stable monospecific IgG antibody titres but no IgM antibodies to this virus. In the remaining two cases no particular triggering viral infection could be designated. Evidence of a viral infection was thus found in three of these five patients. Adult onset Still's disease may represent a reaction pattern to certain infections.
Objectives: Still disease is a rare disorder characterized by seronegative arthralgias/arthritis, spiking fever, and either an evanescent salmon-colored rash or persistent papules and plaques. Methods: We describe the clinical and biopsy findings in 10 patients with the evanescent rash of Still disease. Results: Fourteen biopsy specimens were studied from seven women and three men with a mean age of 44.4 years. The skin lesions were typically erythematous macules, papules, or plaques with a median duration of 5 weeks. All patients had systemic symptoms, including fever and arthralgias. The infiltrate was predominantly lymphocytic in six biopsy specimens, approximately equal lymphocytic and neutrophilic in four biopsy specimens, and predominantly (although never exclusively) neutrophilic in four biopsy specimens. Other findings included focal vacuolar interface changes, neutrophilic eccrine hidradenitis, epidermal neutrophils, dermal mucin, and acanthosis associated with numerous upper epidermal dyskeratotic cells. Conclusions: It is important to be aware of the broad histologic spectrum that may be encountered in Still disease and to consider Still disease in the differential diagnosis of neutrophil-rich, lymphocyte-rich, and mixed inflammatory dermatoses. While the histologic findings seen in biopsy specimens of the evanescent rash are nonspecific, a distinctive variant also exists characterized by prominent epidermal apoptosis, especially involving the upper layers.
We have attempted to design classification criteria for adult Still's disease by analyzing the data obtained through a multicenter survey of 90 Japanese patients with this disease and of 267 control patients. The proposed criteria consisted of fever, arthralgia, typical rash, and leukocytosis as major, and sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and the absence of rheumatoid factor and antinuclear antibody as minor criteria. Requiring 5 or more criteria including 2 or more major criteria yielded 96.2% sensitivity and 92.1% specificity. However, an exclusion process will be needed for an accurate classification, since this disease is relatively rare.
Adult-onset Still's disease (AOSD) is a systemic disorder characterized by intermittent fever, evanescent rash, arthralgias or arthritis and predominantly neutrophilic leucocytosis. We report on a 16-year-old woman with Still's disease who developed, in addition to the typical rash, persistent papular lesions on her face, neck and upper and lower back. Although the presence of fixed skin lesions is not a characteristic feature of AOSD, their appearance at the onset of the disease and their evolution suggest that they represent a specific manifestation of the disease.
The characteristic rash of systemic juvenile idiopathic arthritis is a transient erythematous eruption associated with a quotidian spiking fever. Usually asymptomatic, it can be pruritic, with dermatographism at sites of scratching or pressure. An illness similar to this entity in adults is designated adult-onset Still disease. The relationship between the pediatric and adult disease is uncertain and differences in case definition have evolved. Specifically, a sustained arthritis for at least 6 weeks is required for a diagnosis of systemic juvenile idiopathic arthritis, whereas transient arthritis and arthralgia are accepted criteria in adult-onset Still disease. We describe five patients less than 16 years of age who presented with an acute illness characterized by fever and a distinctive skin eruption. Intense pruritus and linear erythematous lesions flared with a spiking fever, usually in the late afternoon and evening. Periorbital edema/erythema and nonlinear urticarial lesions were also seen. Two children had splinter hemorrhages of the nail beds and one girl developed a fixed, scaling, pigmented, linear eruption. Severe malaise, myalgia, arthralgia, and leukocytosis were present in every patient. Other systemic manifestations included sore throat, transient arthritis, abdominal pain, lymphadenopathy, hepatomegaly, splenomegaly, hyperferritinemia, and hepatic dysfunction. No patient had a sustained arthritis. The course of the disease was variable. One patient, diagnosed with macrophage activation syndrome, recovered on oral naproxen. Two patients responded to systemic corticosteroid therapy. One girl developed status epilepticus and died from aspiration and asphyxia. A boy with severe hepatitis developed renal failure and thrombotic thrombocytopenic purpura and was treated with plasmapheresis, dialysis, and systemic corticosteroids; he had recurrent episodes of rash and fever into adult life. These children did not fulfill the case definition of systemic juvenile idiopathic arthritis because they lacked a persistent arthritis. Adolescent and adult patients with the same clinical and laboratory findings are described under the rubric of adult-onset Still disease. Recognition of the distinctive urticarial skin eruption and spiking fever is important in the diagnosis of a disease with severe morbidity and potentially life-threatening complications.
Persistent plaques and linear pigmentation have been reported as specific skin lesions in some patients with adult-onset Still's disease (AOSD).
We sought to characterize the histologic findings of AOSD-associated persistent rash in 11 cases and correlate the histologic findings with the clinical features.
From 1988 to 2004, 17 cases fulfilling Yamaguchi's criteria for AOSD in our hospital were reviewed and 11 (65%) manifested persistent papules and plaques. The pathology of 13 biopsy specimens of persistent eruption from 9 patients was reviewed.
The 11 patients consisted of 3 men and 8 women with age of onset ranging from 19 to 67 years (average 34.7 years). Evanescent Still's rash was recorded in 9 patients. The persistent rash manifested as pruritic, red, violaceous, or brownish scaly or crusted lichenoid papules and plaques usually widely distributed over the trunk, neck, face, and extensor sides of the extremities. Lesions arranged in a bizarre linear pattern resulting from scratching were noted in some patients. Three patients died of severe disease, systemic complications, or both. The histology of persistent papules and plaques was characterized by: (1) multiple individual necrotic keratinocytes, singly or in aggregates, mainly located in the upper epidermis, including the normal or parakeratotic horny layer; and (2) infiltration of lymphocytes and neutrophils in the papillary and middermis. Other less common findings included basal vacuolar alteration, nuclear dust, and subcorneal or intracorneal pustules.
A clinically and pathologically distinct form of persistent lichenoid eruption was commonly observed in our patients with AOSD. The combination of multiple individual necrotic keratinocytes in the upper epidermis and a dermal infiltrate of neutrophils allow for histologic differentiation of this persistent eruption from most other lichenoid and interface dermatitides and may facilitate an earlier diagnosis of AOSD.