Clinical features of elderly-onset Adult-onset Still's disease.

OBJECTIVES: To clarify the characteristics of patients with elderly-onset Adult-onset Still's disease (AOSD). METHODS: Patients were classified into elderly-onset (>60 years: 47 patients) and younger-onset (≤60 years: 95 patients) groups according to their age at diagnosis of AOSD. Clinical features, treatments, and prognosis were compared between the elderly-onset and younger-onset groups. RESULTS: In the elderly-onset group, compared with the younger-onset group, typical skin rashes were less frequent (21.3% vs 58.9%, respectively; p < .0001), whereas pleuritis (27.7% vs 7.4%, respectively; p = .0011) and disseminated intravascular coagulation (19.1% vs 2.1%, respectively; p = .0004) were more frequent, and serum ferritin levels were higher (median 12,700 ng/ml vs 2526 ng/ml, respectively; p < .0001). Overall survival and AOSD-related survival were reduced (p = .0006 and p = .0023, respectively) and drug-free remission was less frequent (p = .0035) in the elderly-onset group compared with the younger-onset group. CONCLUSIONS: Our results demonstrated that elderly-onset AOSD patients had several characteristics that differed from younger-onset AOSD patients, including less typical skin lesions, more AOSD-related complications, higher ferritin levels, and poorer prognoses.

Are the 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome applicable to patients with adult-onset Still's disease?

The objectives of this study are to determine whether the 2016 European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organization classification criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (SJIA) can be used to identify MAS in patients with adult-onset Still's disease (AOSD). Using laboratory data from 76 AOSD patients with and without MAS, we analyzed the ability of the collective and individual constitutive elements of the 2016 MAS in SJIA criteria and additional laboratory measures to discriminate between AOSD patients with (n = 16) and without (n = 60) MAS. Cutoff values to determine the sensitivity, specificity, and predictive values were calculated from receiver operating characteristic curves, and modified classification criteria for MAS in AOSD were evaluated. The 2016 MAS in SJIA classification criteria had an overall sensitivity of 100%, specificity of 70.0%, positive predictive value of 47.1%, and negative predictive value of 100% to discriminate between AOSD patients with and without MAS based on laboratory data. Among the individual criteria, the sensitivity of triglycerides (46.7%) and the specificity of ferritin (15.0%) for MAS in AOSD were particularly low. The sensitivity and specificity for classifying MAS in AOSD patients were increased to 100 and 93%, respectively, by excluding triglycerides and changing the cutoff values for other criteria in the 2016 MAS in SJIA classification. The 2016 classification criteria for MAS in SJIA had higher sensitivity but lower specificity to identify MAS in AOSD patients compared with SJIA patients.

Successful golimumab therapy in four patients with refractory Takayasu's arteritis.

Recent studies suggested that anti-TNF-α biological therapies are effective in treating Takayasu's arteritis (TA) refractory to conventional immunosuppressive therapy. However, the efficacy of golimumab (GLM) for TA therapy is unknown. We report four women with TA who were successfully treated with GLM. GLM was prescribed as induction therapy for three patients and as maintenance therapy for one patient. GLM showed therapeutic value and might be useful, together with other anti-TNF-α agents, in treating TA.

The balance between Foxp3 and Ror-γt expression in peripheral blood is altered by tocilizumab and abatacept in patients with rheumatoid arthritis.

BACKGROUND: The balance between Th17 cells and regulatory T (Treg) cells has been shown to play an important role in the development of rheumatoid arthritis (RA). Recent studies have shown that treatment with abatacept (ABT) or tocilizumab (TCZ) affects Th17 and Treg cell populations. Although not unanimously accepted, several reports have shown that Treg cells are decreased by ABT and increased by TCZ, and that Th17 cells are decreased by TCZ. To further investigate the effects of ABT and TCZ on the skewing of T cell populations, we analyzed the expression of master regulators genes of helper T cell lineages following ABT/TCZ treatment of RA patients. METHODS: Ten patients treated with ABT and 10 patients treated with TCZ were enrolled. Total RNA was extracted from peripheral blood cells at baseline, and after 12 and 24 weeks of therapy. The expression levels of T-bet, GATA3, Foxp3 and Ror-γt were semi-quantified using real-time PCR. The relative expression levels were expressed as the ratios of two genes (T-bet/GATA3, Foxp3/GATA3, Foxp3/T-bet, Foxp3/Ror-γt, Ror-γt/T-bet, Ror-γt/GATA3), and the changes in these ratios with treatment were determined. RESULTS: The Foxp3/Ror-γt ratio was decreased after ABT therapy (0.67 ± 0.16 at 24 weeks, P = 0.0034) but was increased after TCZ therapy (2.00 ± 1.03 at 24 weeks, P = 0.0013). In addition, the Ror-γt/GATA3 ratio was decreased after TCZ therapy (0.78 ± 0.37 at 24 weeks, P = 0.0008). Except for these ratios, no significant skewing in the expression of these factors was detected. No significant relationship between clinical response to the treatment and change in the ratios of these factors was determined. CONCLUSION: Treatment with TCZ or ABT differently affected the balance between Foxp3 and Ror-γt expression in the peripheral blood of patients with RA.

Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice.

OBJECTIVE: Interferon regulatory factor 5 (IRF-5) is a transcription factor that mediates intracellular signals activated by engagement of Toll-like receptors (TLRs). IRF5 polymorphisms are associated with an increased or decreased risk of systemic lupus erythematosus (SLE) in various human populations, but the precise role of IRF5 in SLE development is not fully understood. This study was undertaken to examine the role of IRF5 in the development of murine lupus. METHODS: We crossed gene-targeted IRF5-deficient (IRF5(-/-) ) mice with MRL/MpJ-lpr/lpr (MRL/lpr) mice and examined the progeny for survival, glomerulonephritis, autoantibody levels, immune system cell populations, and dendritic cell function. RESULTS: IRF5(-/-) MRL/lpr mice survived longer than control IRF5(+/+) MRL/lpr mice and displayed only very mild glomerulonephritis. Autoantibodies to SLE-related nuclear antigens were lower in IRF5(-/-) MRL/lpr mouse serum, and numbers of activated CD4+ T cells were reduced in the spleen. Splenic DCs from IRF5(-/-) MRL/lpr mice produced lower levels of inflammatory cytokines when treated in vitro with TLR-7 or TLR-9 ligands or immune complexes. Interferon-α production in response to CpG was also decreased. CONCLUSION: Our results show that IRF5 is a crucial driver of lupus development in mice, and indicate that IRF5 may be an attractive new target for therapeutic intervention to control disease in SLE patients.

RP105-negative B cells in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem disease characterized by B cells producing autoantibodies against nuclear proteins and DNA, especially anti-double-strand DNA (dsDNA) antibodies. RP105 (CD180), the toll-like receptor- (TLR-) associated molecule, is expressed on normal B cells. However, RP105-negative B cells increase in peripheral blood from patients with active SLE. RP105 may regulate B-cell activation, and RP105-negative B cells produce autoantibodies and take part in pathophysiology of SLE. It is possible that targeting RP105-negative B cells is one of the treatments of SLE. In this paper, we discuss the RP105 biology and clinical significance in SLE.

Phenotyping of P105-negative B cell subsets in patients with systemic lupus erythematosus.

This study aimed to investigate phenotype of RP105(-) B cell subsets in patients with systemic lupus erythematosus (SLE). Flow cytometry was used for phenotyping RP105-negaive B cell subsets. Based on CD19, RP105, and CD138 expression, RP105(-) B cells consist of at least 5 subsets of late B cells, including CD19(+)RP105(int), CD19(+) RP105(-), CD19(low) RP105(-) CD138(-), CD19(low) RP105(-)CD138(int), and CD19(low) RP105(-) CD138(++) B cells. Especially, CD19(+)RP105(int) and CD19(low) RP105(-)CD138(int) B cells are significantly larger than other RP105(-) B cell subsets in SLE. By comparison of RP105(-) B cell subsets between patients with SLE and normal subjects, these subsets were detectable even in normal subjects, but the percentages of RP105(-) B cell subsets were significantly larger in SLE. The phenotypic analysis of RP105(-) B cell subsets suggests dysregulation of later B cell subsets in SLE and may provide new insights into understanding regulation of B cells in human SLE.

Erythema nodosum-like lesions in Behçet's disease: a clinicopathological study of 26 cases.

The histopathological features of erythema nodosum-like lesions remain controversial with regard to whether they resemble those of conventional erythema nodosum. We reviewed the clinicopathological features of erythema nodosum-like lesions in 26 patients with Behçet's disease and evaluated the clinical characteristics of Behçet's disease in these patients. The results suggest that: (i) the clinico-pathological features of 27% of the erythema nodosum-like lesions in Behçet's disease are indistinguishable from those of conventional erythema nodosum; (ii) the other 73% of the erythema nodosum-like lesions are histopathologically characterized by the presence of vasculitis (venulitis or phlebitis); (iii) the clinical features of erythema nodosum-like lesions with vasculitis show heterogeneity; (iv) the presence of the erythema nodosum type lesion may be an indicator of the mildness of Behçet's disease; and (v) the presence of severe vasculitis, especially phlebitis, in erythema nodosum-like lesions may be an indicator of the involvement of the gastrointestinal tract in Behçet's disease.

Therapeutic response of patients with adult Still's disease to biologic agents: multicenter results in Japan.

OBJECTIVE: The efficacy of biologics in treating adult Still's disease (ASD) is suggested, but the information is still lacking and the validation is insufficient. To determine the efficacy of several biologic agents in refractory ASD in Japan, a multicenter survey was performed. METHOD: Clinical data on 16 ASD patients who had been treated with at least 1 of the biological agents (total 24 occasions) were collected retrospectively. RESULTS: Infliximab was used in 9 cases, etanercept in 4, and tocilizumab in 11. Half of the patients that had been treated initially with infliximab or etanercept were changed to another biologics. Tocilizumab was effective in cases switched from another 2 drugs. Tocilizumab showed efficacy in treating both systemic and arthritic symptoms and showed apparent steroid-sparing effect and the highest continuation rate. CONCLUSION: Tocilizumab may be a promising biologic agent in refractory ASD.

Functional disturbance of the stress-adaptation system in patients with scleroderma.

There have been several reports indicating the association between recent stress experiences and the onset or the exacerbation of rheumatic diseases, although few such reports exist in patients with scleroderma (SSc). The present study was performed to elucidate whether there were any functional disturbances in the neuro-endocrine-immune system as a homeostatic system upon stress in SSc patients. Various serum levels of stress-related hormones and cytokines were examined before and after a mental calculation stress test, and a basal questionnaire study of sense of coherence (SOC, which is related to the ability to cope with stress), recent stress experiences, and quality of life (QOL) was performed in 17 SSc patients and in 38 healthy volunteers. Physical QOL state was impaired in patients, but there were no differences in recent stress experiences and SOC scores between patients and controls. Basal serum cortisol levels were similar in patients and controls, but increased levels of proinflammatory cytokine and noradrenalin were seen in SSc patients. Characteristically, contrary to the control group, whose cortisol levels increased significantly following the mental calculation stress test, no significant increase was observed in the patients when post-test cortisol levels were compared to pre-test levels, suggesting a defect in the normal cortisol response upon stress in SSc patients. The present results suggest that there may be impaired function of the neuro-endocrine-immune system upon stress in SSc patients.

Immediate Effect of Baricitinib on Arthritis and Biological Disease-Modifying Antirheumatic Drug-Induced Psoriasis-Like Skin Lesions in Two Patients with Rheumatoid Arthritis.

Biological disease-modifying antirheumatic drugs (bDMARDs) are very effective for treating rheumatoid arthritis (RA). However, they sometimes induce adverse events such as psoriasis-like skin lesions. We describe psoriasis-like skin lesions that developed simultaneously with an RA flare in patient 1 during treatment with abatacept and in patient 2 soon after starting certolizumab pegol. The skin lesions persisted in patient 2 despite stopping certolizumab. Baricitinib was initiated because of RA flare and resulted in immediate beneficial effects on arthritis as well as skin lesions. The RA went into remission in both patients, and the psoriasis-like skin lesions disappeared within four weeks (patient 1) and three months (patient 2).

Autoantibody-producing RP105(-) B cells, from patients with systemic lupus erythematosus, showed more preferential expression of BCMA compared with BAFF-R than normal subjects.

OBJECTIVE: B cells lacking RP105 produce autoantibodies in patients with SLE. Expression of B-cell activating factor (BAFF) binding receptors (BBRs) and survival of RP105(-) B cells from SLE patients were examined. METHODS: Detection of difference of gene expression between RP105(-) and RP105(+) B cells was done by DNA microarrays. Surface expression was confirmed by flow cytometry. The contribution of BAFF, a proliferation-inducing ligand (APRIL) and monomers/trimers of sCD40L to survival of RP105(-) and RP105(+) B cells was examined. RESULTS: Gene expression of B-cell maturation antigen (BCMA) was different among BBRs in RP105(-) and RP105(+) B cells in SLE. Preferential expression of BCMA on RP105(-) B cells was confirmed compared with RP105(+) B cells by flow cytometry, although BAFF receptor (BAFF-R) expression on RP105(-) B cells was significantly lower. Additionally, relative ratios of BCMA/BAFF-R expression on RP105(-) B cells were increased significantly in SLE patients compared with normal subjects. Stimulation by sCD40L decreased the number of surviving RP105(-) and RP105(+) B cells in vitro. RP105(+) B cells were not rescued from sCD40L-induced cell death by BAFF and/or APRIL. In contrast, either BAFF or APRIL maintained the survival of RP105(-) B cells due to avoidance of cell death. Activated RP105(-) B cells reduced BAFF-R and increased BCMA levels. CONCLUSIONS: RP105(-) B cells from SLE patients showed more preferential expression of BCMA compared with BAFF-R than normal subjects, and were possibly regulated by BAFF/APRIL. Our results provide a new insight of BCMA and their ligands in B cells from SLE patients.

[A case of cutaneous Mycobacterium nonchromogenicum infection suggesting sarcoidosis association].

A 67-year-old man clinically diagnosed a year earlier with sarcoidosis based on low-grade fever, lymphadenopathy, trunk skin rash, and histopathological skin tests was admitted for newly developing subcutaneous nodules on the trunk and arms and fever of 38 degrees C. Although initially suspected of recurrent sarcoidosis, he was diagnosed with Mycobacterium chromogenicum infection isolated from skin lesion culture. Combined clarithromycin of 800 mg/day, ethambutol of 750 mg/day, and embiomycin of 0.5 g/day was started, after which fever declined and WBC count and CRP decreased to normal in a week. One month later, skin lesions had disappeared. This case is interesting considering the association of nontuberculous mycobacterial infection with sarcoidosis.

[A case of visceral larva migrans due to Toxocara canis showing varied manifestations].

A 21-year-old woman admitted for a low-grade fever, dry cough, polyarthralgia, and general fatigue was found to have elevateal accustomed to eating raw meat and cattle liver peripheral blood eosinophil counts and serum IgE. Chest X-ray imaging and computed tomography (CT) showed multiple small nodules in both lung fields. A multiple dot-ELISA assay of her serum showed that she had visceral larva migrans caused by Ascaris suum or Toxocara canis. Following treatment with albendazole, she developed myelopathy and was again admitted. A cerebrospinal fluid examination showed increased eosionophils and significant antibody elevation against T. canis. Her disease was considered to have entered the central nervous system, one of the target organs of visceral larva migrans. She was successfully treated with dietylcarbamazine and has shown no reccurrence. This case showed the different manifestations of visceral larva migrans and the rising incidence of this disease in Japan raises concerns about associated of diet.

Effectiveness of Certolizumab Pegol in Treating Rheumatoid Arthritis Patients with Persistent Inflamed Residual Mono- or Oligosynovitis Resistant to Prior TNF-α Inhibitors.

We report four cases of successful treatment with certolizumab pegol (CZP) of rheumatoid arthritis (RA) patients with persistent inflamed residual mono- or oligosynovitis resistant to prior TNF-α inhibitors. Although the patients were in a moderate disease activity, a low activity, or a remission of RA, they sustained inflammatory mono-/oligoarthritis even after treatment with prior TNF inhibitors. They were then all treated with CZP and observed in a serial ultrasonography. In all cases, the positive power Doppler signals in the joint have disappeared promptly and all of the patients were able to retain remission in the long term. The treatment of CZP to the refractory mono-/oligoarthritis of inflammatory synovitis in RA patients has not been previously described. The cases suggest that it may be associated with the feature of CZP, possible effective penetration into the site of inflammation.

[A case of idiopathic fibrosing mediastinitis presented with bilateral pleural effusion].

A case is reported of a 56-year-old male who presented with bilateral pleural effusion as an initial manifestation of idiopathic fibrosing mediastinitis. The patient showed shortness of breath with severe loss of vital capacity and weight loss. A mediastinal mass surrounding the thoracic aorta and bilateral pleuritis was identified by the chest CT scan. The mass extended, along the abdominal aorta, to the upper portion of retroperitoneum. Laboratory data showed elevated levels of C-reactive protein (CRP), erythrocyte sedimentation ratio (ESR), and IgG. Biopsy of the mediastinal and the pleural mass showed adipose tissue and fibrosis with mild perivascular inflammatory infiltration. A diagnosis of idiopathic fibrosing mediastinitis was made, and 40 mg/day of prednisolone was administered. Although CRP and ESR was normalized, the mass size and vital capacity were almost unchanged.

[BCMA and autoantibody-producing RP105 B cells; possible new targets of B cell therapy in systemic lupus erythematosus].

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease with multiple organ disorders. Although the prognosis of SLE has been recently improved, corticosteroid and immunosuppressive agents are still main treatment used in medical practice. Refractory disease and complications by the conventional drugs still remain. RP105 (CD180) is one of the toll-like receptor associated molecules. The molecule is expressed on mature B cells. Significantly increased population of RP105-negative [RP105(-)] B cells is found in SLE. RP105(-) B cells belong to highly activated and differentiated late B cells and produce autoantibodies including anti-dsDNA antibodies. RP105(-) B cells are further divided into at least 5 subsets that include novel human B cell subsets. In active SLE, subset 1 (activated B cells) and 3 (early-plasmablasts) are significantly increased compared to inactive SLE patients. Especially, subset 3 RP105(-) B cells may play an important role in pathophysiology of SLE. RP105(-) B cells from active SLE patients express preferentially BCMA (B-cell maturation antigen) compared to BAFF-R (B-cell activating factor-receptor) than normal subjects and other autoimmune diseases. In SLE, it is suggested that BAFF/APRIL (a proliferation-inducing ligand) maintain chronic activation and survival of RP105(-) B cells. The increased RP105(-) B cells may reflect the breaking of tolerance checkpoint for autoreactive B cells and finally affect autoimmunity in SLE. For the B cell therapy, especially targeting of autoantibody-producing B cells, including subset 3 of RP105(-) B cells, BCMA and RP105(-) B cell itself may be an ideal target.