Purtscher-like retinopathy as the manifestation of adult Still’s disease

To determine cytokines and MHC class II alleles in Japanese patients with adult Still's disease (ASD) and clarify the association between those profiles and chronic articular disease. Of 35 patients with ASD (13 men, 22 women, mean age at onset 34.0 yr), 17 (49%) had chronic arthritis (>6 months, chronic articular ASD) and 18 (51%) lacked chronic arthritis (systemic ASD). Cytokines and cytokine receptors in sera were measured by ELISA. Correlations of each cytokine with disease activity or C-reactive protein (CRP) were determined. MHC class II alleles were examined by polymerase chain reaction methods. In chronic articular ASD, female gender was more frequent and liver dysfunction and myalgia were rarer than in systemic ASD. In active disease, the white blood cell count was lower, but total IgG was greater in patients with chronic articular ASD than in those with systemic ASD. Tumour necrosis factor (TNF) alpha, soluble TNF receptor 2 and interleukin (IL)-18 were increased in both types of ASD, even in remission. Soluble IL-2 receptors, IL-4 and IL-18 levels were correlated with disease activity or CRP value only in chronic articular ASD. Interferon gamma and IL-8 remained increased only in chronic articular ASD, even when disease activity, including IL-6 and CRP, was low. DRB1*1501 (DR2) and DRB1*1201 (DR5) alleles were more frequent in chronic articular than in systemic ASD, whereas DQB1*0602 (DQ1) was frequently observed in both types of ASD. The present study suggests that ASD with chronic articular disease has distinct clinical, cytokine and immunogenetic profiles.

Intravenous tocilizumab (TCZ-IV) was approved for the treatment of adult Still's disease (ASD) in Japan in May 2019 based on its efficacy and safety in a phase III randomized controlled trial. This study determined treatment patterns in patients with ASD and assessed oral glucocorticoid (GC) dose changes after TCZ-IV administration in Japanese clinical practice. Patients in the Medical Data Vision database aged 16 years or older with one or more of International Classification of Diseases, 10th revision codes M061 (ASD) or M082 (systemic juvenile idiopathic arthritis) during January 2017-March 2021 (cohort 1) and those initiating TCZ-IV during May 2019-March 2021 (cohort 2) were included. In cohort 1, the proportion of patients who were prescribed interleukin-6 inhibitors (mainly TCZ-IV) increased from 10.8% (January-April 2019 [before TCZ-IV approval]; n = 2002) to 18.3% (January-March 2021 [after TCZ-IV approval]; n = 2008). In cohort 2 (n = 193), 84.5% of patients were on oral GCs (≤5 mg/day: 23.8%) at index date (initial TCZ-IV prescription date); 46/70 (65.7%) were on oral GC at 5 mg/day or higher 12 months after TCZ-IV treatment (primary outcome). After 12 months of treatment, the TCZ-IV retention rate was 73.6% and the TCZ-IV administration interval was every 4 weeks and every 2 weeks in 31.9% and 27.7% of patients, respectively. The use of interleukin-6 inhibitors increased by 7.5% points in Japanese patients with ASD ~2 years after TCZ-IV approval, suggesting that an unmet medical need existed. This study suggests the potential GC-sparing effect of TCZ-IV in patients with ASD in clinical practice.

Adult Still's disease (ASD) is a systemic inflammatory disorder of unknown origin. Several reports have suggested a triggering infection in ASD. We describe a case of ASD associated with acute Mycoplasma pneumoniae infection. The close temporal relationship between ASD and acute infection strongly suggests that M. pneumoniae triggered ASD. We suggest that M. pneumoniae should be added to the list of infectious agents that may play a role in its etiology.

There is an unmet need for the treatment of adult Still's disease (ASD), the pathogenesis of which may involve interleukin-6 (IL-6). We report the first series of patients with ASD treated with tocilizumab (TCZ), a humanized anti-IL-6 receptor antibody. All ASD patients treated with TCZ in France between July 2006 and July 2009 after failure to all available therapies were included in this cohort study. The main outcome measures were the European League Against Rheumatism (EULAR) improvement criteria and resolution of systemic symptoms at the 3- and 6-month followup periods. Fourteen patients with refractory ASD were included. At the start of TCZ treatment, despite a mean prednisone dosage of 23.3 mg/day, based on a 28-joint count, mean tender joints were 10.5, mean swollen joints were 7.9, and the mean Disease Activity Score in 28 joints was 5.61. Recurrent systemic involvement, including fever and rash, was present in 7 patients. TCZ was administered at 5-8 mg/kg every 2 or 4 weeks (8 mg/kg/month, n = 9). Eleven patients successfully completed the 6-month study; 1 withdrew due to necrotizing angiodermatitis, another due to chest pain at each TCZ infusion, and a third due to systemic flare. A good EULAR response was observed in 64% of patients (9 of 14) at 3 months and EULAR remission was observed in 57% (8 of 14) at 6 months. Systemic symptoms were resolved in 86% of patients (6 of 7). Moreover, corticosteroid dose was reduced by 56%. No other severe adverse effects occurred. TCZ is a promising new treatment for ASD.

Adult Still's disease (ASD) is rarely complicated by pulmonary hypertension (PH). A 76-year-old woman experienced ASD relapse with repeated exacerbation of PH and interstitial lung disease. Although she had been treated with immunosuppressive agents and pulmonary vasodilators, the ASD relapsed with fever, rash, increased inflammatory responses and exacerbated interstitial lung disease, and PH. The pathology of PH appeared to encompass groups 1 [pulmonary arterial hypertension (PAH)], 1' [pulmonary veno-occlusive disease (PVOD)], and 3. Remission induction therapy with high-dose glucocorticoid and tocilizumab was administered, and switching or adding pulmonary vasodilators was also attempted. As the disease activity of ASD decreased, the mean pulmonary arterial pressure and pulmonary vascular resistance improved. PH is an extremely rare form of organ dysfunction in individuals with ASD. Like other systemic autoimmune diseases, PH (PAH or PVOD) can determine the prognosis of ASD. Because of PH's rarity, it is important to sufficiently evaluate its pathology, considering the possibility that PH is not clinically classified as PAH (group 1), and to administer immunosuppressive therapy and vasodilators according to the pathology.

The rubella virus (RV) genome was detected using polymerase chain amplification techniques in several peripheral blood cell populations in patients with adult Still's disease (ASD) and normal controls (NC), including mononuclear cells (PBMC), B-cells, T-cells, monocyte/macrophages, and polymorphonuclear leukocytes (PMN). Five of 6 ASD patients and 3 of 6 NC subjects had detectable RV genome. Viral genomic load was significantly higher in ASD than in NC subjects (4.4 fold higher, p = 0.03). Interestingly, a differential cellular distribution of viral genome was observed between ASD and NC individuals. RV genome was detected more frequently in the PBMCs of ASD (5 of 6) patients compared to 2 of 6 NC. The viral genome was more localized to the PMN compartment equally in ASD and in NC subjects. On further cellular analysis, RV genome was detected in B-cells and macrophages but not T-cells in one patient. Existence of a differential viral genomic reservoir between ASD and NC suggests that this may play a role in the pathogenesis of disease manifestations and may reflect the inability to clear latent virus.

Adult Still’s disease (ASD) is a rare systemic inflammatory disorder in which ocular manifestations have rarely been described. We report a 29-year-old Japanese woman with a rare case of refractory ASD complicated by Purtscher-like retinopathy. She was diagnosed with ASD and started on a high dose of oral prednisolone. Two days after the initiation of the treatment, she presented with blurred vision in the left eye, and the funduscopic examination revealed bilateral Purtscher-like retinopathy. Despite treatment with high-dose oral prednisolone for 2 weeks, she developed macrophage activation syndrome. Considering the severity of ASD, intravenous pulse methylprednisolone therapy and tocilizumab injection were administered. Although all the laboratory data and Purtscher-like retinopathy gradually improved, nerve fiber layer defect (NFLD) in both eyes appeared and visual field defect remained corresponding to the NFLD. In conclusion, Purtscher-like retinopathy might be useful as a poor prognostic factor of ASD, which needs appropriate systemic immunosuppressive treatment. Early detection and long-term follow-up of Purtscher-like retinopathy is important because it has the possibility of developing permanent visual field defect.

Background: The disproportionate ferritin response encountered in some patients with adult Still's disease (ASD) may reflect a fundamental aspect in the pathophysiology of ASD.Methods: An observational case–control study of 22 ASD patients followed for 63 months. Baseline laboratory data were compared with age‐ and gender‐matched controls with new‐onset rheumatoid arthritis (RA). Serum levels of ferritin and C‐reactive protein (CRP) and the ferritin/CRP ratio were related to clinical outcome in ASD through nonparametric statistical analyses.Results: Compared to RA patients, haemoglobin levels were lower (11.8 vs. 13.5 g/dL; p = 0.009) and leucocyte counts (17.1 vs. 8.6 109/mL; p<0.001), erythrocyte sedimentation rate (ESR) (84 vs. 38 mm; p = 0.001), CRP (154 vs. 27 mg/L; p<0.001), aspartate aminotransferase (ASAT) (52 vs. 23 U/l; p = 0.004), serum ferritin (8750 vs. 62 µg/L; p<0.001) and ferritin/CRP ratios (9.7 vs. 1.7; p<0.001) were higher in ASD patients at baseline. Six patients (27%) achieved sustained remission (monocyclic disease), while 16 patients (73%) developed chronic disease (progressive in 27%, relapsing/remitting in 46%). The levels of ESR and CRP or other baseline variables were not associated with outcome. However, baseline serum ferritin was significantly higher in ASD patients with chronic disease (p = 0.04), while a cut‐off of five times the normal upper level (NUL) was 100% sensitive and 60% specific for predicting chronic disease.Conclusion: An exaggerated ferritin response with levels>5 times the NUL and high ferritin/CRP ratios is useful for distinguishing between ASD and RA patients. Ferritin levels>5 times the NUL are also associated with a chronic disease course.

Adult Still's disease (ASD) is a rare disorder of unknown aetiology, characterized by an evanescent, erythematous, maculopapular rash, fever, arthralgia, and a variety of systemic features. We report a case which illustrates the typical features of ASD, and manifests the hitherto unreported complication of diffuse cutaneous mucinosis.

A 30‐year‐old Chinese woman presented with fever of 104 °F, diffuse arthralgias, multiple pruritic erythematous papules and plaques, and pharyngitis. Three weeks prior to admission, she had received empirically a single intramuscuiar injection of penicillin for the pharyngitis. Several days later, fever, arthraigias, and an eruption were observed. The patient was started on oral prednisone, 40 mg daily, and tapered to 15 mg daily during a 21‐day period. The persistence of these findings led to subsequent hospitalization.On physical examination, the patient appeared acutely ill, with fever of 102.5 °F and multiple annular and polycyclic urticarial plaques, ranging from 0.5 to 3.0 cm in diameter, symmetrically located on the neck, upper part of the back, upper aspect of the chest, and flexural aspect of the forearms and arms (Fig. 1). There was evidence of asymmetric arthritis involving the wrists, knees, and elbows. Abnormal laboratory tests on admission included a white cell count of 21.1 × 103/mm3 with 94.8% granulocytes, normochromic normocytic anemia with hemoglobin of 10.0 g/dL, an erythrocyte sedimentation rate of 115 mm/h, lactate dehydrogenase of 373 units/mL (normal: 100–225 units/mL), and a serum iron of 32 μmol/L (normal: 50–150 μg/dL). At this juncture, a clinical diagnosis of serum sickness induced by penicillin was considered most likely. Despite the continuation of prednisone, 15 mg daily, spiking fevers, skin lesions, and joint symptoms persisted for 2 weeks. Additional studies did not reveal infection, collagen vascular disease, or malignancy; these included repeated blood cultures, antistreptolysin O titer (ASLO), rapid plasma reagin (RPR), serologic analysis for hepatitis virus, Lyme disease, Mycoplasma pneumoniae, cytomegalovirus, and parvovirus, as well as complement factors, rheumatoid factor, antinuclear antibody, sequential chest X‐rays, total body gallium scan, conventional electrocardiograms, and a transthoracic echocardiogram. An abdominal sonogram showed mild splenomegaly with a normal‐sized liver. A serum ferritin level was profoundly elevated at 20,440 μg/L (normal: 15–200 μg/L).A skin biopsy specimen obtained from an urticarial plaque on the arm showed a mild superficial perivascular lymphocytic infiltrate with occasional neutrophils. There were no features of vasculitis. The epidermis was intact (Figs 2 and 3).A diagnosis of adult Still's disease (ASD) was ultimately based upon the absence of diagnostic markers in the blood and tissue for infection, collagen vascular disease, and malignancy, in conjunction with exceptionally high serum levels of ferritin.Aspirin was started at 3.9 g daily and oral prednisone was maintained at 15 mg daily. Two weeks later, the patient was afebrile with complete resolution of the cutaneous findings. Two months after discharge, the patient was symptom‐free with the exception of mild arthralgias involving both knees. A repeated ferritin level was 460 μg/L. The white cell count remained elevated at 15.1 × 103/mm3, presumably as a consequence of corticosteroid therapy.

Objectives. A nationwide survey was conducted to assess the number of patients, clinical aspects, treatment, and prognosis of adult Still's disease (ASD) in Japan.Methods. A primary questionnaire was sent to randomly selected medical institutions in order to estimate the number of patients. We sent a secondary questionnaire to the same institutions to characterize the clinical manifestations and treatment of ASD.Results. The estimated prevalence of ASD was 3.9 per 100,000. Analysis of 169 patients showed a mean age at onset of 46 years. The main clinical symptoms were fever, arthritis, and typical rash in agreement with previous surveys. Oral glucocorticoids were used to treat 96% of the patients, while methotrexate was used in 41% and biological agents were used in 16%. Lymphadenopathy and macrophage activation syndrome were significantly associated with increased risk of relapse (P < 0.05, each). Patients who achieved remission after tocilizumab therapy had significantly longer disease duration (6.2 years) than patients who did not (1.9 years) (p < 0.05).Conclusions. The 2010–2011 nationwide survey of ASD identified important changes in treatment and improvement of prognosis compared with previous surveys.

To determine the origin of the increased serum ferritin that occurs in adult Still's disease (ASD), we analyzed subunits of the serum ferritin as follows. Gel filtration with Sepharose CL-6B demonstrated that the molecular weight of serum ferritin was about 490 kDa. Western blot analysis revealed only L-subunits (molecular weight 19 kDa) in patients with serum ferritin levels higher than 1,000 ng/ml. Patients with serum ferritin levels higher than 1,000 ng/ml, however, showed G-subunits (molecular weight 23 kDa) in addition to the L-subunits. When concanavalin A (Con-A) Sepharose 4B was used in an absorption test, the percentage absorption was extremely low in the patients with serum ferritin levels higher than 1,000 ng/ml. Isoferritin patterns of the patients determined by chromatofocusing revealed traces of acidic ferritin. The findings suggested that glycosylated ferritin does not account for the major portion of the increased serum ferritin.

Still's disease in children (systemic juvenile idiopathic arthritis - JIA) and adult Still's disease (ASD) are considered as systemic autoinflammatory diseases of unknown etiology, which are based on similar immunopathogenetic mechanisms associated with genetically determined disorders of the mechanisms of innate immunity. ASD was first described 50 years ago by the English rheumatologist Eric George Lapthorne Bywaters. The molecular basis of ASD immunopathogenesis is the activation of innate immunity associated with NLRP3 inflammasome-dependent mechanisms of inflammation, characterized by the overproduction of “pro-inflammatory” cytokines - interleukin (IL) 1 and IL-18, inducing the synthesis of other proinflammatory inflammatory mediators. A review of new data concerning the mechanisms of immunopathology, clinical polymorphism, laboratory biomarkers and the possibilities of ASD pharmacotherapy is presented.Particular attention is paid to the prospects for the use of monoclonal antibodies to IL-1β - canakinumab. The problems associated with the generality of clinical and laboratory disorders, pathogenetic mechanisms and pharmacotherapy of ASD and coronavirus disease 2019 (COVID-19) are considered.

Adult Still's disease reflects a Th2 rather than a Th1 cytokine profile

A 25-year-old Japanese man was diagnosed with steroid-resistant Adult Still's Disease (ASD) in August 2000. No evidence of chronic myelogenous leukemia (CML) had been found during admissions in 2000 and 2001. In August 2002, he was diagnosed with CML with a peripheral white blood count of 69,940/microl and positivity for Philadelphia chromosome and BCR/ABL fusion gene on bone marrow aspiration. No case of CML was reported to develop from ASD. Because a diagnosis of ASD is based on the exclusion of other diseases, we must be cognizant of the possibility of the development of concurrent diseases.