GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

Association of elevated serum carbohydrate antigen 19-9 levels with extensive interstitial lung disease in patients with systemic sclerosis: A cross-sectional study.

AIM: To assess the usefulness of carbohydrate antigen 19-9 (CA19-9) as a biomarker for systemic sclerosis-associated interstitial lung disease (SSc-ILD), using serum samples and clinical parameters of patients with SSc. METHODS: Patients with SSc admitted to Tokyo Women's Medical University Hospital between 2010 and 2021 and those who underwent chest computed tomography (CT) were included. Patients were diagnosed with ILD based on chest CT findings, and SSc-ILD was categorized as either a limited or extensive disease based on chest CT and pulmonary function test findings. Serum CA19-9 levels were measured in 56 patients with SSc and in 32 healthy individuals. Additionally, we evaluated the difference in serum CA19-9 levels between the groups, the correlation with ILD area and pulmonary function, and discriminative performance to diagnose extensive ILD. RESULTS: Of the 56 patients with SSc, 40 (71.4%) had ILD, and 17 (30.4%) were classified as having extensive disease. Serum CA19-9 levels were significantly elevated in patients with extensive disease compared to those with limited disease (median [interquartile range]: 25.7 U/mL [10.1-50.8] vs. 8.8 U/mL [4.5-17.6], p = .02) and correlated with ILD area (r = .30, p = .02). There was no significant correlation between serum CA19-9 level and pulmonary function. The cutoff of CA19-9 for the diagnosis of the extensive disease was determined to be 19.8 U/mL, with a sensitivity of 64% and specificity of 82% and an area under the curve of 0.74 (95% confidence interval 0.58-0.90). CONCLUSION: The serum CA19-9 level may be a useful marker for identifying patients with SSc-ILD with extensive disease.

Antifibrotic effect of apremilast in systemic sclerosis dermal fibroblasts and bleomycin-induced mouse model.

Phosphodiesterase (PDE) 4 inhibitors have been reported to suppress the progression of dermal fibrosis in patients with systemic sclerosis (SSc); however, the precise mechanisms remain to be elucidated. Therefore, we conducted experiments focusing on the antifibrotic and anti-inflammatory effects of apremilast using dermal fibroblasts derived from patients with SSc and an SSc mouse model. Dermal fibroblasts derived from healthy controls and patients with SSc were incubated with apremilast in the presence or absence of 10 ng/ml transforming growth factor (TGF)-ß1 for the measurement of intracellular cAMP levels and evaluation of mRNA and protein expression. A bleomycin-induced dermal fibrosis mouse model was used to evaluate the inhibitory effects of apremilast on the progression of dermal fibrosis. Intracellular cAMP levels were significantly reduced in dermal fibroblasts derived from patients with SSc compared with those derived from healthy controls. Apremilast reduced the mRNA expression of profibrotic markers and the protein expression of type I collagen and Cellular Communication Network Factor 2 (CCN2) in dermal fibroblasts. Additionally, apremilast inhibited the progression of dermal fibrosis in mice, partly by acting on T cells. These results suggest that apremilast may be a potential candidate for treating dermal fibrosis in SSc.

Secondary spontaneous pneumothorax in a patient with resistant Mycobacterium abscessus infection and systemic sclerosis-associated interstitial lung disease: A case report.

Mycobacterium abscessus subsp. abscessus (MABA) is refractory and sometimes fatal especially in an immunocompromised patient. Also, MABA-associated pneumothorax is an extremely rare complication. We report a case of MABA pulmonary infection complicated pneumothorax treated successfully. A 69-year-old Japanese female with immunosuppressed systemic sclerosis-associated interstitial lung disease experienced left-sided secondary spontaneous pneumothorax. MABA was detected in the pleural effusion and blood culture. Microbial sensitivity test showed the MABA was sensitive to only amikacin, sitafloxacin, and clofazimine. Combination therapy with these antibiotics including azithromycin achieved remission within three weeks. In the treatment of MABA infection, compliance with microbial sensitivity test is crucial.

Characteristics of Japanese patients with systemic sclerosis complicated with calcinosis.

AIM: Calcinosis is often observed in systemic sclerosis (SSc), but its pathogenesis remains unclear. The aim of the present study was to explore the association of clinical features with calcinosis in patients with SSc. METHODS: A retrospective cohort study was performed analyzing 416 SSc patients from our SSc database. We examined the clinical features with relation to calcinosis and SSc. RESULTS: Calcinosis was observed in 24.0% of patients with SSc. The group with calcinosis comprised more female patients (P < 0.05) and diffuse cutaneous types (P < 0.001) than the group without calcinosis. Complications of Raynaud's phenomenon (P < 0.05), nail fold bleeding (NFB) (P < 0.001), peripheral bone resorption (P < 0.001), myositis (P < 0.001), and pulmonary hypertension (P < 0.05) were more frequently observed in patients with calcinosis compared with those without calcinosis. The group with calcinosis had a higher modified Rodnan total skin-thickness score (mRSS) than the group without calcinosis (P < 0.001). The factors that affected calcinosis in multivariable analysis were peripheral bone resorption (partial correlation coefficient 0.46, 34%), anti-Scl-70 antibody (partial correlation coefficient 0.29, 20%), diffuse type (partial correlation coefficient 0.34, 16%) and NFB (partial correlation coefficient 0.23, 11.2%). CONCLUSIONS: Calcinosis in SSc is associated with Raynaud's phenomenon, NFB, and pulmonary hypertension, so peripheral circulatory insufficiency seems to be one of the causes of calcinosis. Furthermore, as it is related to mRSS and the diffuse cutaneous type, common factors related to skin fibrosis are considered to be involved.

Single nucleotide polymorphisms of the HIF1A gene are associated with susceptibility to pulmonary arterial hypertension in systemic sclerosis and contribute to SSc-PAH disease severity.

AIM: Hypoxia-inducible factor (HIF)1α is induced by endothelial cells under hypoxic conditions, suggesting that HIF1α may be involved in vascular impairment in patients with systemic sclerosis (SSc). The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) of the HIF1A gene are associated with susceptibility to SSc and its complications, including pulmonary arterial hypertension (PAH). METHOD: This study involved 182 Japanese SSc patients (discovery cohort) and 178 healthy controls. Four SNPs (rs11549465, rs11549467, rs1957757, and rs12434438) of the HIF1A gene were genotyped using specific TaqMan probes. We also employed another SSc cohort (N = 135) to validate the significant results of SNPs found in the discovery SSc cohort. RESULTS: The frequencies of the four SNPs did not show any significant differences between the SSc and healthy control groups. The AA genotype at rs12434438 was significantly higher in SSc patients with PAH than in those without PAH (P = .012). These results were validated using another SSc cohort (N = 135, P = .006). Moreover, the AA genotype was significantly associated with the severity of PAH. CONCLUSION: Although HIF1A gene polymorphisms were not associated with susceptibility to SSc, the AA genotype at rs12434438 was associated with a subset of SSc patients with severe PAH, suggesting that the rs12434438 SNP may contribute to the development of PAH with SSc.

Antifibrotic effects of 2-carba cyclic phosphatidic acid (2ccPA) in systemic sclerosis: contribution to the novel treatment.

BACKGROUND: Cyclic phosphatidic acid (cPA) has an inhibitory effect on the autotaxin (ATX)/lysophosphatidic acid (LPA) axis, which has been implicated to play an important role in the progression of fibrosis in systemic sclerosis (SSc). The purpose of this study is to assess the antifibrotic activity of cPA for the treatment of SSc using SSc skin fibroblasts and an animal model of bleomycin-induced skin fibrosis. METHODS: We used a chemically stable derivative of cPA (2ccPA). First, we investigated the effect of 2ccPA on extracellular matrix (ECM) expression in skin fibroblasts. Next, the effect of 2ccPA on the intracellular cAMP levels was determined to investigate the mechanisms of the antifibrotic activity of 2ccPA. Finally, we administered 2ccPA to bleomycin-induced SSc model mice to evaluate whether 2ccPA prevented the progression of skin fibrosis. RESULTS: 2ccPA decreased ECM expression in SSc skin fibroblasts and TGF-ß1-treated healthy skin fibroblasts without LPA stimulation. 2ccPA increased the intracellular cAMP levels in skin fibroblasts, suggesting that the antifibrotic effect of 2ccPA was the consequence of the increase in the intracellular cAMP levels. Administration of 2ccPA also ameliorated the progression of bleomycin-induced skin fibrosis in mice. CONCLUSIONS: Our data indicated that 2ccPA had inhibitory effects on the progression of skin fibrosis by abrogating ECM production from activated skin fibroblasts. These cells were repressed, at least in part, by increased intracellular cAMP levels. 2ccPA may be able to be used to treat fibrotic lesions in SSc.

Sildenafil attenuates the fibrotic phenotype of skin fibroblasts in patients with systemic sclerosis.

Systemic sclerosis (SSc) is a multi-organ fibrotic disease that affects the skin and various internal organs. Therapeutic strategies for tissue fibrosis have not been established; however, aberrantly activated fibroblasts in affected lesions are key targets for modulating fibrosis. Recently, increased intracellular cyclic GMP (cGMP) levels were demonstrated to improve fibrosis levels in various diseases. The purpose of this study was to assess the anti-fibrotic properties of cGMP in cultured fibroblasts from patients with SSc. The phosphodiesterase (PDE) 5 inhibitor sildenafil increased the intracellular cGMP levels in skin fibroblasts in a dose-dependent manner. Sildenafil treatment also significantly decreased the expression of several pro-fibrotic factors that were upregulated by TGF-ß1 treatment in SSc skin fibroblasts. These inhibitory effects occurred via non-canonical TGF-ß signaling. Our findings revealed that sildenafil might be a novel strategy to treat tissue fibrosis and vasculopathy in SSc.

Cytokine profiles in polymyositis and dermatomyositis complicated by rapidly progressive or chronic interstitial lung disease.

OBJECTIVE: PM and DM are often complicated by interstitial lung disease (ILD). In this study we aimed to evaluate various serum cytokines in patients with PM/DM with ILD so as to clarify the differences in pathophysiology between anti-melanoma differentiation-associated gene 5 antibody-associated ILD (anti-MDA5-ILD) and anti-aminoacyl tRNA synthetase antibody-associated ILD (anti-ARS-ILD). METHODS: We evaluated the serum cytokine profiles of 38 patients with PM/DM and compared the cytokine profiles of the non-ILD and ILD subsets as well as the anti-MDA5-ILD and anti-ARS-ILD subsets. RESULTS: The myositis intention-to-treat activity index score, which indicates whole disease activity, significantly correlated with serum IL-6, IL-8, TNF-α and IP-10. These cytokine levels were significantly higher in the ILD subset than the non-ILD subset and were lower in the ILD subset following treatment. By multivariate analysis, TNF-α was the most significant cytokine [P = 0.0006, odds ratio (OR) 1.4, CI 1.1, 2.2] associated with PM/DM with ILD. IL-8 levels were significantly higher in anti-MDA5-ILD than in anti-ARS-ILD, although IL-6, TNF-α and IP-10 levels were high in both subsets. IL-8 was the most significant cytokine (P = 0.0006, OR 1.5, CI 1.1, 3.0) associated with anti-MDA5-ILD by multivariate analysis. Moreover, the ratio of IL-4 to IFN-γ was lower in anti-MDA5-ILD than in anti-ARS-ILD. CONCLUSION: IL-6, IL-8, TNF-α and IP-10 are associated with global disease activity in PM/DM. These cytokine levels were high, especially in the ILD subset. Serum IL-8 levels and the balance between IL-4 and IFN-γ may contribute to the differences in pathophysiology between anti-ARS-ILD and anti-MDA5-ILD.

Clinical manifestations of Adult-onset Still's disease presenting with erosive arthritis: Association with low levels of ferritin and Interleukin-18.

Objective: Adult-onset Still's disease (AOSD) is a clinical entity with heterogeneous etiology. We have encountered patients with AOSD who had severe polyarthritis and who fulfilled the classification criteria for rheumatoid arthritis (RA); however, most patients with AOSD typically exhibit mild arthritis. In this study, we proposed two clinical subsets of AOSD and investigated the clinically significant characteristics of the two subtypes. Methods: We retrospectively analyzed 71 consecutive patients with AOSD. We reviewed the medical records of all patients who were followed up for more than 2 years. We classified all the patients with AOSD into the following 2 subsets: an RA subtype for patients who met the criteria for RA according to the American College of Rheumatology and a non-RA subtype for patients who did not meet the criteria for RA. Results: Our results indicated that the non-RA subtype was accompanied by severe inflammatory complications, including pleuritis and hemophagocytic syndrome. In addition, the serum ferritin and serum IL-18 levels were significantly higher in patients with the non-RA subtype than in those with the RA subtype. Interestingly, only 1 patient with the RA subtype had anti-CCP antibodies, and 1 non-RA subtype patient had rheumatoid factor. These findings distinguish these patients from patients with true RA. Conclusions: There were two subsets of patients with AOSD in the examined population. Patients with high levels of IL-18 or ferritin presented with severe systemic inflammatory disorders (the non-RA subtype), and patients with low levels of IL-18 or ferritin developed severe arthritis (RA subtype).

Ghrelin attenuates collagen production in lesional fibroblasts from patients with systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterized by thickening of the skin and tissue fibrosis of the internal organs. Ghrelin is primarily described as a gut hormone, and many studies currently indicate that ghrelin has protective effects in different organs, including the heart, pancreas, lung and liver, resulting from its anti-fibrotic properties. We found decreased levels of ghrelin in the plasma from patients with SSc compared with those from healthy controls. In skin fibroblast cultures, recombinant ghrelin diminished the production of collagen type I. In addition, the mRNA levels of COL1A2 and TGFB genes were significantly decreased by the stimulation of ghrelin. We showed that ghrelin may exert anti-fibrotic effects in the skin fibroblasts from patients with SSc. Because the plasma levels of ghrelin are low in SSc, the administration of ghrelin could be a new strategy for the treatment of SSc.

Urinary free light chain is a potential biomarker for ISN/RPS class III/IV lupus nephritis.

OBJECTIVES: To evaluate the use of urinary free light chains (FLCs) as a biomarker for proliferative LN and the potential association between the intensity of plasma cell infiltration of the kidney and urinary FLC levels in LN. METHODS: Forty-three SLE patients were consecutively enrolled in the study. These patients were divided into an International Society of Nephrology and Renal Pathology Society (ISN/RPS) class III/IV LN subset (n = 18) and an ISN/RPS class I/II/V (class non-III/IV) LN subset (n = 25). The expression of κ-LCs, λ-LCs, CD19 and CD138 in kidney specimens was also evaluated with immunohistochemical staining. To measure FLC levels before and after treatment, an additional six patients with class III/IV LN were consecutively enrolled. RESULTS: Urinary FLCs were significantly higher in the class III/IV LN subset than in the class non-III/IV LN subset. Urinary λ-FLC levels were significantly correlated with the urinary protein-creatinine ratio in the class III/IV LN subset (rs = 0.67, P < 0.01). Moreover, the LC-secreting CD19(-)/CD138(+) cell counts in the kidney specimens were higher in the class III/IV LN subset than in the class non-III/IV LN subset. Total urinary FLC levels were correlated with the numbers of CD138(+) cells in the kidney (r = 0.71, P = 0.03). Following treatment, urinary λ-FLCs could not be detected in any of the patients. CONCLUSION: The intensity of plasma cell infiltration of the kidney is associated with urinary FLC levels. Urinary FLCs are potentially useful biomarkers in ISN/RPS class III/IV LN or proliferative LN.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in Japan: a review of the literature.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory syndrome that is characterized by recurrent episodes of fever attacks associated with rashes, abdominal pain, myalgia, conjunctivitis, chest pain, and arthralgia. Some patients have severe abdominal pain leading to abdominal surgery. Most reported cases of TRAPS involve patients of European ancestry, but there have been nine reports of patients with TRAPS in Japan. Here, we review these nine case reports. Reported TNFRSF1A gene mutations in these nine index patients were C70S, T61I, C70G, C30Y, C30R, N101K, and N25D. Fever (100 %) was seen in all 23 cases. Most patients developed rash (erythema) (84.6 %) and arthralgia (73.3 %), and half suffered from myalgia (54.5 %) and abdominal pain (50.0 %). Although one-half of the patients suffered from abdominal pain, none underwent surgery. In contrast, only a small percentage of patients suffered from chest pain (20.0 %), conjunctivitis (20.0 %), and headache (10.0 %). Almost all cases (95.7 %) concerned patients whose relatives suffered from periodic fever. These findings suggest that the clinical features of Japanese TRAPS patients may be milder than those of patients in Western countries.

Brief report: Association of HLA-DRB1*0101/*0405 with susceptibility to anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis in the Japanese population.

OBJECTIVE: The complication of interstitial lung disease (ILD) in polymyositis/dermatomyositis (PM/DM) is associated with anti-aminoacyl-transfer RNA synthetase (anti-aaRS) antibody or anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody positivity. Anti-MDA-5 antibody is associated with clinically amyopathic DM and fatal outcome due to rapidly progressive ILD in Asian populations. The association between genetic factors and anti-MDA-5 antibody-positive DM is unclear. This study was undertaken to investigate the HLA-DRB1 genotype in patients with anti-MDA-5 antibody-positive DM. METHODS: We examined genetic differences among 17 patients with anti-MDA-5 antibody-positive DM, 33 patients with anti-aaRS antibody-positive PM/DM, 33 patients with PM/DM without anti-aaRS antibody or ILD, and 265 healthy controls. RESULTS: The frequencies of HLA-DRB1*0101 and DRB1*0405 were 29% and 71%, respectively, in patients with anti-MDA-5 antibody-positive DM, which were higher than the frequencies in healthy controls (10% and 25%, respectively). Among the 17 patients with anti-MDA-5 antibody-positive DM, 16 (94%) harbored either the DRB1*0101 or DRB1*0405 allele. The combined frequency of the DRB1*0101 allele and the DRB1*0405 allele was significantly higher in patients with anti-MDA-5 antibody-positive DM than in patients with PM/DM without anti-aaRS antibody or ILD, with an odds ratio (OR) of 42.7 (95% confidence interval [95% CI] 4.9-370.2) (P = 1.1 × 10(-5)), or in patients with anti-aaRS antibody-positive PM/DM (OR 13.3 [95% CI 1.6-112.6], P = 4.5 × 10(-3)). CONCLUSION: Our findings indicate that HLA-DRB1*0101/*0405 is associated with susceptibility to anti-MDA-5 antibody-positive DM in the Japanese population.

Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVE: The aim of this study was to investigate the precise clinical characteristics and to analyse the association between the anti-MDA5 antibody (anti-MDA5ab) titre and disease status in patients with anti-MDA5ab-positive DM. METHODS: Twenty-seven patients who presented with DM and were positive for the anti-MDA5ab were enrolled. The association between the clinical manifestations and the clinical parameters, including the anti-MDA5ab, was analysed. RESULTS: The complication of rapidly progressive interstitial lung disease (RP-ILD) occurred in 20 (74%) patients. The frequencies of fatal outcome, relapse and malignancy were 33, 4 and 4%, respectively. Remarkably, a fatal outcome occurred within the first 6 months. Compared with six non-RP-ILD patients, elderly age at onset, severely involved pulmonary function and high levels of serum ferritin were present in 20 RP-ILD patients with anti-MDA5ab. Alveolar-arterial oxygen difference (AaDO(2)) ≥32 mmHg and ferritin ≥828 ng/ml at admission were poor prognostic factors in RP-ILD patients with anti-MDA5ab-positive DM. The median value of the anti-MDA5ab titre on admission was higher in patients who later died than in those who survived. The efficacy of treatment was indicated by the anti-MDA5ab, ferritin and IL-18 concentrations. The decline index of the anti-MDA5ab titre after treatment was lower in the subset of patients who died than in the subset of patients who lived. Sustained high levels of anti-MDA5ab, ferritin and IL-18 were present in the patients who died. CONCLUSION: Anti-MDA5ab titre and ferritin and IL-18 concentrations are useful for the evaluation of the response to treatment and the status of ILD in patients with anti-MAD5ab-positive DM.

Activation of the activin A-ALK-Smad pathway in systemic sclerosis.

Systemic sclerosis (SSc) is a chronic disease of unknown etiology that is characterized by multiple tissue fibrosis. Transforming Growth Factor-beta (TGF-ß) is thought to be the most important mediator that induces fibrosis. However, the molecular mechanisms by which fibrosis is induced have not been fully elucidated. In this study, the role of activin, a member of the TGF-ß superfamily, was investigated in the pathogenesis of fibrosis in SSc. Serum activin A levels in patients with SSc were measured by ELISA, and the expression of the activin receptor type IB (ACVRIB/ALK4) and the activity of the signaling pathway via ACVRIB/ALK4 were investigated using western blotting. To evaluate a potential therapeutic strategy for SSc, we also attenuated the ACVRIB/ALK4 pathway using an inhibitor. Serum activin A levels were significantly higher in SSc patients than in normal controls. Activin A and ACVRIB/ALK4 expression were also higher in cultured SSc fibroblasts. Activin A stimulation induced phosphorylation of Smad2/3 and CTGF expression in SSc fibroblasts. Procollagen production and Col1α mRNA also increased upon stimulation by activin A. The basal level of Smad2/3 phosphorylation was higher in cultured SSc fibroblasts than in control cells, and treatment with the ALK4/5 inhibitor SB431542 prevented phosphorylation of Smad2/3 and CTGF expression. Furthermore, production of collagen was also induced by activin A. Activin A-ACVRIB/ALK4-Smad-dependent collagen production was augmented in SSc fibroblasts, suggesting the involvement of this signaling mechanism in SSc. Inhibition of the activin A-ACVRIB/ALK4-Smad pathway would be a new approach for the treatment of SSc.

Efficacy and safety of intravenous cyclophosphamide pulse therapy with oral prednisolone in the treatment of interstitial lung disease with systemic sclerosis: 4-year follow-up.

Interstitial lung disease (ILD) is a noteworthy condition in the treatment of systemic sclerosis (SSc) because of its associated mortality and morbidity; however, the efficacy of various treatments for ILD has been controversial in previous reports. In this study, we examined the efficacy and safety of intravenous cyclophosphamide (IVCY) pulse therapy with prednisolone (PSL) for the treatment of ILD with SSc. A total of 121 patients with SSc were screened and evaluated for ILD, using high-resolution computed tomography of the chest, pulmonary function testing, and bronchoalveolar lavage. Thirteen patients with active ILD were enrolled in this study. The treatment protocol for ILD was 0.4 g/m(2) of body surface area of IVCY monthly plus 0.8 mg/kg of body weight of PSL daily. Two to six doses of IVCY were administered, depending on the remission of ILD. Initial PSL doses were maintained for a month and then gradually tapered to 10 mg daily. An activity index of ILD showed improvements in all patients in the 12 months after the initial intervention; however, four patients experienced recurrence of ILD after 24 months, and one additional patient had recurrence of ILD after 36 months. Seven patients reached the 48-month point with no recurrence of ILD. This long observational study for 48 months showed the efficacy of IVCY with PSL for active alveolitis in the first year. However, because five patients had recurrence of ILD more than 1 year after the treatment, it would be necessary to consider maintenance therapy for ILD beyond 1 year.

Clinical manifestations of neurological involvement in primary Sjögren's syndrome.

The aim of this study was to evaluate neurological manifestations of primary Sjögren's syndrome (pSS) and investigate the etiology and pathogenesis of peripheral and central nervous complications in pSS. Thirty-two patients with pSS were enrolled in the present study, 20 of whom had neurological involvement plus sicca symptoms. The clinical features were evaluated by neurological examinations including nerve conduction study, magnetic resonance imaging, cerebrospinal fluid, and electroencephalogram. The frequency of fever was significantly higher (P = 0.006) in pSS with neurological involvement than in pSS without neurological involvement. There was no statistical significance in other factors between the two groups. Peripheral nervous system (PNS), central nervous system (CNS), and both PNS and CNS involvements were revealed in 14, 3, and 3 patients, respectively. Optic neuritis and trigeminal neuralgia were revealed frequently in cranial neuropathy. Anti-aquaporin 4 antibody was detected in one patient with optic neuritis. Of the nine patients with polyneuropathy, eight patients presented pure sensory neuropathy including small fiber neuropathy (SFN). pSS with SFN appeared to have no clinically abnormal features, including muscle weakness and decreasing deep tendon reflex. Skin biopsy revealed epidermal nerve fiber degenerated in one pSS patient with pure sensory neuropathy who was diagnosed as having SFN. Our observations suggest that a number of mechanisms can be attributed to neurological involvements in pSS rather than just the mechanisms previously described (i.e., vasculitis and ganglioneuronitis). Presumably, specific autoantibodies may directly induce injury of the nervous system.

Interleukin-18 is a key mediator in dermatomyositis: potential contribution to development of interstitial lung disease.

OBJECTIVE: To determine whether IL-18 is involved in the inflammation of DM and PM. METHODS: Thirty-three patients with DM were enrolled in this study, including 25 with interstitial lung disease (ILD). In addition, 16 patients with PM were enrolled, including 6 with ILD. All patients were admitted to our hospital as a result of their condition requiring treatment, and clinical laboratory data including serum IL-18 were recorded on admission. RESULTS: Serum IL-18 was significantly (P < 0.0001) higher in both DM and PM patients than in healthy controls (n = 30). Serum ferritin and IL-18 were significantly (P = 0.003 and 0.0044, respectively) higher in DM than in PM patients. Additionally, ferritin and IL-18 were significantly (P = 0.023 and 0.034, respectively) higher in DM patients with ILD than in DM patients without ILD. Significant positive correlations were found between creatine kinase (CK) and ferritin (r(s) = 0.39, P = 0.024); CK and IL-18 (r(s) = 0.48, P = 0.005); and IL-18 and ferritin (r(s) = 0.54, P = 0.0012) in the DM group as a whole. These findings were different for the DM plus ILD subgroup: significant positive correlations were found between CK and ferritin (r(s) = 0.40, P = 0.047); CK and IL-18 (r(s) = 0.63, P = 0.0008); and IL-18 and ferritin (r(s) = 0.41, P = 0.042). CONCLUSION: Serum IL-18 was strikingly elevated in patients with DM and was associated particularly with disease activity and ILD complication in DM.