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Objective.Hyperferritinemia is frequently accompanied by rapidly progressive (RP) interstitial lung disease (ILD) with polymyositis (PM)/dermatomyositis (DM). To clarify the mechanism of RP-ILD with hyperferritinemia, we investigated the associations between serum ferritin levels and various cytokines in patients with PM/DM.Methods.This retrospective study included 38 patients admitted to our hospital with PM/DM. Levels of serum ferritin and cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, TNF-α, IFN-α, IFN-γ, and IP-10) were measured. Disease activity was evaluated using the tool proposed by the International Myositis Assessment and Clinical Studies Group. We analyzed the associations between disease activity and levels of serum ferritin and cytokines.Results.The levels of serum ferritin, IL-8, IL-10, IL-18, and TNF-α, were significantly correlated with disease activity. In a multivariate analysis, IL-6(t=3.6,P=0.0010), IL-8(t=4.8,P<0.0001), and IL-10(t=5.7,P<0.0001)significantly contributed to serum ferritin levels. The levels of serum ferritin, IL-6, IL-8, and IL-10, were higher in the RP-ILD subset than in the non-ILD subset or the chronic ILD subset.Conclusion.IL-6, IL-8, and IL-10 are significant contributors to hyperferritinemia in PM/DM. The regulation of these cytokines might offer a possible treatment strategy for RP-ILD with PM/DM.

This is an electronic version of an article published in Amyloid 2009, Vol. 16, No. 3 : Pages 178-180. Amyloid is available online at: http://informahealthcare.com/doi/pdf/10.1080/13506120903090940, We report a patient with AH amyloidosis associated with lymphoplasmacytic leukemia that has remained in a stable state with a nephrotic syndrome for 17 months since the commencement of cyclic rituximab therapy aimed at suppression of pathogenetic gamma heavy chains. Free light chains in serum and CD20-positive cells in peripheral blood were useful as hematological markers in the patient. Rituximab might be a potent therapeutic option for AH amyloidosis associated with a B-cell lymphoproliferative disorder., Article, AMYLOID. 16(3):178-180 (2009)

We report a young female patient with Henoch-Schönlein purpura (HSP) nephritis complicated by reversible posterior leukoencephalopathy syndrome (RPLS). The patient suddenly showed generalized seizures and cortical blindness with severe hypertension due to renal insufficiency approximately 1 year after cessation of corticosteroid treatment for HSP nephritis. Magnetic resonance imaging (MRI) demonstrated bilateral abnormal signals mainly in the cerebellum and white matter of the occipital lobe. Clinical symptoms quickly improved in conjunction with disappearance of abnormal signals on brain MRI after starting control of hypertension and continuous hemodiafiltration with steroid pulse therapy and plasmapheresis. RPLS may be caused by vasculitis and also by hemodynamic change due to severe hypertension in HSP, particularly in patients with nephropathy. In such cases intensive treatment should be performed as soon as possible to avoid neurological sequelae.

The original publication is available at www.springerlink.com., Article, CLINICAL RHEUMATOLOGY. 26(1): 117-119 (2007)

Idiopathic inflammatory myopathies (IIMs) are a group of inflammatory muscle disorders of unknown etiology; these include polymyositis (PM), dermatomyositis (DM), and inclusion body myositis. Extra-muscular manifestations such as dermatitis, arthritis, interstitial lung disease (ILD), cardiomyopathy, and enteropathy are occasional complications in patients with PM/DM. Several myositis-specific autoantibodies (MSAs) have been discovered in IIMs; these can help predict clinical characteristics, response to treatment, and prognosis. For example, anti-aminoacyl-tRNA synthetase (ARS) antibodies, including Jo-1 antibody (Ab) and anti-melanoma differentiation-associated gene 5 (MDA-5) Ab, have been associated with the manifestation of ILD in PM and DM. Anti-MDA5 Ab-associated ILD has a 1-year survival rate of 50-60%; however, short-term prognosis is relatively good in anti-ARS Ab-associated ILD. Fatal outcome occurs remarkably often within the first 6 months of anti-MDA5 Ab-associated ILD. Therefore, intensive treatment should be administered to patients harboring anti-MDA-5 Ab or showing hyperferritinemia in ILD with DM. In addition, corticosteroid occasionally induces myopathy, which is an issue arising in PM/DM treatment. Some experts recommend combination therapy of corticosteroid and an immunosuppressive agent as a first-line treatment for myositis in PM/DM. Methotrexate and azathioprine are commonly used immunosuppressive agents for myositis in western countries. Immunosuppressive agents are steroid-sparing, serving to mitigate corticosteroid-related side effects, thus making combination therapy an effective treatment option. Preventing the progression of physical dysfunction is of prime importance to patients with PM/DM. Dermatologists, neurologists, and rheumatologists should therefore work together to care for these patients before muscular and extra-muscular involvement develop progressively and irreversibly.

Background The 16/6-idiotype (16/6-Id) of the human anti-DNA antibody was found to induce experimental lupus in naïve mice, manifested by production of autoantibodies, leukopenia and elevated inflammatory markers, as well as kidney and brain involvement. We assessed behavior and brain pathology of naive mice injected intra-cerebra-ventricularly (ICV) with the 16/6-Id antibody. Methods C3H female mice were injected ICV to the right hemisphere with the human 16/6-Id antibody or commercial human IgG antibodies (control). The mice were tested for depression by the forced swimming test (FST), locomotor and explorative activity by the staircase test, and cognitive functions were examined by the novel object recognition and Y-maze tests. Brain slices were stained for inflammatory processes. Results 16/6-Id injected mice were cognitively impaired as shown by significant differences in the preference for a new object in the novel object recognition test compared to controls (P = 0.012). Similarly, the preference for spatial novelty in the Y-maze test was significantly higher in the control group compared to the 16/6-Id-injected mice (42% vs. 9%, respectively, P = 0.065). Depression–like behavior and locomotor activity were not significantly different between the16/6-Id-injected and the control mice. Immunohistochemistry analysis revealed an increase in astrocytes and microglial activation in the hippocampus and amygdala, in the 16/6-Id injected group compared to the control. Conclusions Passive transfer of 16/6-Id antibodies directly into mice brain resulted in cognitive impairments and histological evidence for brain inflammation. These findings shed additional light on the diverse mosaic pathophysiology of neuropsychiatric lupus. See related Commentary article: http://www.biomedcentral.com/1741-7015/11/91

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 k-LCs, � -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 � -FLC levels were significantly correlated with the urinary proteincreatinine 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 � -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.

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).

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.

Objective.To determine the frequency of International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III or IV lupus nephritis in patients with systemic lupus erythematosus (SLE) without clinical renal involvement.Methods.We investigated the renal pathology of 195 patients with SLE, including 86 patients without clinical renal involvement.Results.Lupus nephritis other than class I was found in 58% of the patients without clinical renal involvement, and class III and IV nephritis was found in 15% of these patients. To reveal the predictive measures involved in class III or IV lupus nephritis, we explored the clinical measures in patients with SLE who did not have clinical renal involvement. Anti-dsDNA antibody titers were significantly higher (p = 0.0266) and C3 values were significantly lower (p = 0.0073) in patients with class III or IV lupus nephritis than in patients without class III or IV lupus nephritis. The sensitivity and specificity values were 77% and 73%, respectively, for cutoff levels of both 40 IU/ml for anti-dsDNA antibodies and 55 mg/dl for C3 (OR 8.8, p = 0.0011).Conclusion.The frequency of nephritis, including ISN/RPS class III and IV, was unexpectedly high in SLE patients without clinical renal involvement. ISN/RPS class III or IV lupus nephritis could be hidden in patients with SLE who present both a high titer of anti-dsDNA antibody and a low concentration of C3, even when they have clinically normal urinary findings and renal function.

Corticosteroid therapy is frequently associated with adverse psychiatric effects, including dysregulated mood psychosis and delirium. Recent reports have shown that the effects of short-term, high-dose corticosteroid therapy appear to be primarily associated with manic rather than depressive or psychotic symptoms, or delirium, while depressive symptoms may be more common and severe than manic symptoms during long-term corticosteroid therapy at relatively low dosages. Management includes tapering corticosteroids, with or without the addition of medications to treat acute psychiatric symptoms. Use of adjunctive psychotropic medications may be necessary, particularly if corticosteroids cannot be tapered or discontinued. However, little information is available on the treatment of corticosteroid-induced mood disorders (CIMDs). One controlled study suggested lithium therapy may prevent CIMDs. None of the 27 patients given open-label lithium developed CIMDs while receiving corticosteroids, whereas 6 (14%) of 44 retrospectively reviewed patients not receiving lithium developed CIMDs. One open-label trial on olanzapine has been conducted in 12 patients with multiple medical diagnoses. In several case reports/series, various classes of psychotropic medications, including second-generation antipsychotics (SGAs), e.g., olanzapine, risperidone, and quetiapine, have been successfully used to treat CIMDs, mainly for manic symptoms. Mood stabilizers, e.g., lithium, valproate, and carbamazepine, have also been used to treat CIMDs. Overall, these reports have had methodical limitations that complicate the assessment of the effects of psychotropic medications, namely multiple medical diagnoses, as well as the parallel effects of tapering the corticosteroids dosage during the study because of CIMDs dose

Background The risk for amenorrhea following treatment of systemic lupus erythematosus (SLE) patients with low-dose intravenous cyclophosphamide (IVCY) has not been fully explored. Our objective was to ascertain the incidence of amenorrhea following treatment with low-dose IVCY and the association between amenorrhea and the clinical parameters of SLE. Methods A case-control retrospective study of premenopausal women ≤ 45 years old who had been treated for SLE with low-dose IVCY (500 mg/body/pulse) plus high-dose glucocorticoids (0.8-1.0 mg/kg/day of prednisolone; IVCY group) or glucocorticoids alone (0.8-1.0 mg/kg/day of prednisolone; steroid group) in our hospital from 2000 through 2009 was conducted using a questionnaire survey and medical record review. Results Twenty-nine subjects in the IVCY group and 33 subjects in the steroid group returned the questionnaire. A multivariate analysis revealed that age at initiation of treatment ≥ 40 years old was significantly associated with amenorrhea [p = 0.009; odds ratio (OR) 10.2; 95% confidence interval (CI) 1.8-58.7]. IVCY treatment may display a trend for association with amenorrhea (p = 0.07; OR 2.9; 95% CI 0.9-9.4). Sustained amenorrhea developed in 4 subjects in the IVCY group and 1 subject in the steroid group; all of these patients were ≥ 40 years old. Menses resumed in all subjects < 40 years old, irrespective of treatment. Conclusions Although low-dose IVCY may increase the risk for amenorrhea, our data suggest that patients < 40 years old have a minimum risk for sustained amenorrhea with low-dose IVCY treatment. A higher risk for sustained amenorrhea following treatment with IVCY is a consideration for patients ≥ 40 years old.

Systemic sclerosis (SSc) is a chronic disease of unknown etiology that is characterized by multiple tissue fibrosis. Transforming Growth Factor-beta (TGF-β) 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-β 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.

Acute/subacute interstitial pneumonia (A/SIP) is an intractable and fatal complication of DM. Since a useful indicator predicting the complication of A/SIP has not been found, the aim of this study was to determine whether serum ferritin is a potential predictive indicator of the occurrence of A/SIP in 64 patients with DM.Of the total patients enrolled, 19 had A/SIP, 24 had chronic interstitial pneumonia and 21 were without interstitial lung disease (ILD). Clinical manifestations and laboratory data were obtained from medical records on admission.Serum ferritin levels were extremely high in patients with DM with A/SIP. It was significantly higher in DM with A/SIP than that in DM without A/SIP (median 790 vs 186 ng/ml; P0.0001). The cumulative survival rate for 6 months was 62.7% in patients with DM with A/SIP. Moreover, the cumulative survival rate was significantly (P = 0.016) lower in the group with ferritin levelsor =1500 ng/ml than the rate in the group with ferritin levels1500 ng/ml.Serum ferritin can be useful as a predictor of the occurrence of A/SIP and correlates with the prognosis of A/SIP in DM. The intensive treatment using combination therapy with various immunosuppressant agents should be chosen for patients with ILD with DM showing hyperferritinaemia, especially levels1500 ng/ml.

The aim of the present study was to evaluate whether the interferon-induced helicase (IFIH1) Ala946Thr (rs1990760 A>G) polymorphism is associated with susceptibility to systemic lupus erythematosus (SLE) and dermatomyositis (DM) or polymyositis (PM) in the Japanese population. The study population consisted of 243 SLE patients, 125 DM/PM patients, and 268 healthy controls from Japan. A Taqman single nucleotide polymorphism genotyping assay was designed for rs1990760 by Applied Biosystems. There were no significant differences between SLE and DM/PM patients and healthy controls regarding the frequency of each genotype and allele. However, the frequency of the AA genotype and the A allele tended to be higher in PM patients with interstitial lung disease (ILD). Additionally, when comparing the AA and AG + GG genotypes at rs1990760, the AA genotype was significantly more frequent in PM patients with ILD than in healthy controls [odds ratio, 3.23 (95% confidence interval, 1.06-9.81); P = 0.04] or in PM patients without ILD [odds ratio, 5.40 (95% confidence interval, 1.37-21.26); P = 0.027]. Our observations suggest that the G allele protects against the onset of ILD and that the AA genotype is a risk factor for lung injury in PM patients.

The objective of this study was to explore the association of single nucleotide polymorphisms (SNPs) of the CD244 gene with several clinical features of systemic lupus erythematosus (SLE). Two hundred and forty-three patients with SLE and 369 healthy controls were enrolled. Two SNPs (rs6682654 and rs3766379) in the CD244 gene were determined by allelic discrimination using a specific TaqMan probe. Only SNP rs3766379 was significantly associated with susceptibility to SLE [P = 0.009; odds ratio (OR) 1.28; 95% confidence interval (CI) 1.04-1.57]. The association was preferentially observed in subsets of SLE patients with nephritis and neuropsychiatric lupus. The frequency of the rs6682654 C allele was strongly associated with nephritis and neuropsychiatric lupus (P = 0.00065; OR 1.99; 95% CI 1.34-2.95, and P = 1.6 × 10(-7); OR 3.47; 95% CI 2.12-5.70, respectively), as was the frequency of the rs3766379 T allele (P = 0.0014; OR 1.86; 95% CI 1.27-2.71, and P = 2.6 × 10(-7); OR 3.15; 95% CI 2.00-4.96, respectively). In this study, an SNP of the CD244 gene was associated with susceptibility to SLE. There was a strikingly strong association in SLE patients with nephritis and neuropsychiatric lupus, suggesting that this genetic marker could predict involvement of those severe complications.

We investigated the expression of hepatocyte growth factor (HGF), which has mitogenic and anti-fibrotic activities, in muscle tissue of polymyositis/dermatomyositis (PM/DM) patients, as well as its functional roles in cultured myoblasts. Immunohistochemistry in muscle from PM/DM patients revealed that HGF was expressed predominantly on infiltrating mononuclear cells and that muscle cells expressed the receptor c-met. Cultured myoblasts produced HGF; which was increased by IL-1alpha but suppressed by TGF-beta and dexamethasone. Exogenous HGF induced myoblast proliferation and reduced procollagen type I production. Furthermore, HGF enhanced the gene expression of muscle regulatory factors MyoD and Myf5, while suppressing expression of fibrosis-related genes, connective tissue growth factor and alpha-smooth muscle actin. Although dexamethasone showed contrasting effects to HGF on the expression of these genes, co-treatment with HGF ameliorated the effects of dexamethasone. Taking the beneficial roles of HGF into consideration, administration of HGF might contribute to muscle regeneration in PM/DM especially under corticosteroid treatment.

Sympathetic storms (SyS) are characterized by hyperactivity of autonomic functions, resulting in episodes of hyperthermia, hypertension, tachycardia, and hyperhidrosis. We show here a patient with neuro-Behcet’s disease (NBD) complicated by SyS. Although SyS is well known to occur with brain tumors, trauma, and hydrocephalus, this is the first report to show that SyS is a manifestation of central nervous system involvement in a patient with NBD. High concentrations of norepinephrine (NE) and IL-8 in cerebrospinal fluid reflected the activity of SyS. The patient’s symptoms showed almost complete improvement after treatment with corticosteroids and intravenous cyclophosphamide. Also, the concentrations of NE and IL-8 were decreased to normal levels. An awareness of the potential for SyS and adequate immunosuppressant therapy are of importance when dealing with patients with NBD.

Lupus profundus is a rare lupus-specific skin lesion with skin biopsies exhibiting lobular lymphocytic infiltration and destruction of subcutaneous fat tissue. In this report, a CT scan was effective in demonstrating both the presence and the extent of inflammation of lupus profundus in two patients with systemic lupus erythematosus (SLE). Case 1 was a 30-year-old woman developing erythema with subcutaneous induration on the upper arms during the quiescent phase of SLE. A skin biopsy confirmed a diagnosis of lupus profundus. A CT scan of the right upper arm demonstrated a high density area (HDA) of the subcutis under the erythema: a finding consistent with lupus profundus. Case 2 was a 28-year-old woman recently diagnosed with SLE. She also developed a skin ulcer on the right hip. A CT scan of the hip revealed an HDA and lipoatrophy of the subcutis around the ulcer: these findings were compatible with lupus profundus. Treatment with high-dose prednisolone improved the illness in the both cases. A CT scan is a useful and convenient imaging modality for confirming the diagnosis of lupus profundus.

We report a patient with rheumatoid arthritis (RA) who showed bicytopenia with hyperferritinemia and hepatic dysfunction ascribable to hemophagocytic syndrome (HPS) 2 weeks after commencement of bucillamine. Pathology of the bone marrow showing infiltration of macrophages confirmed the diagnosis of HPS. On the basis of renal dysfunction with an increase in fibrin degradation products, disseminated intravascular coagulation was considered to be concurrent with HPS. Oral prednisolone and cyclosporine A were started right after cessation of bucillamine, and yielded complete normalization of hepatic and renal function and hematology. As there was neither disease activity of RA nor associated infection throughout the clinical course, bucillamine was suspected of being the cause of HPS in our patient. HPS is a very rare complication in RA, but should be actively considered when abnormalities in laboratory data, especially pancytopenia and hepatic dysfunction, quickly worsen.

We report an 85-year-old man with Hashimoto's encephalopathy (HE) who showed spontaneous complete remission. The autoantibody against the amino (NH2) terminal region of alpha-enolase was positive in our patient. Neuropsychological manifestations, such as personality change and progressive cognitive impairment, gradually improved over approximately 6 weeks after onset of disease without corticosteroid treatment in parallel with a decrease in the anti-thyroglobulin antibody in the cerebrospinal fluid. HE should be considered as a possible diagnosis even in elderly patients with neuropsychiatric symptoms, particularly when a previous history of thyroid disease is present.

Previously, we reported a case of localized plasma cell type Castleman's disease with severe hepatomegaly and reactive systemic AA amyloidosis. The amyloid deposits were demonstrated in both the hepatic tissue and in the gastric mucosa. Surgical resection of an isolated extra-hepatic tumor was performed. The laboratory findings, including SAA and IL-6, remained within normal limits and the patient's hepatomegaly subsequently showed regression. Nine years after the operation, no amyloid deposition was seen in the gastric mucosa and the patient's liver was of normal size. Our findings with long-term follow up in this case indicated that the cessation of SAA production was the probable cause of histopathological regression of AA amyloid deposits in this patient.

We report a patient with polymyalgia rheumatica (PMR) who showed a relapse soon after tapering of oral prednisolone. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were quickly normalized after the re-increase in oral prednisolone, and muscle pain and stiffness gradually improved in parallel with a decrease in serum amyloid A (SAA). Flow cytometry simultaneously demonstrated an increase in CD8 + CD25 + cells and a decrease in CD4 + CD25 + cells and CD4 + CD45RA + cells. When clinical symptoms remain with negative results for CRP and ESR even after the start of corticosteroid treatment, SAA might be a potent therapeutic marker for disease activity in PMR.

To investigate whether there is a correlation between subtypes of plasma cells in the bone marrow and the production of M-protein, flow cytometry and serum free light chain (FLC) analyses were carried out in 17 patients with primary systemic AL amyloidosis (mean age, 59.9+/-8.8 years) and controls with M-protein (MGUS controls, n=6) and without it (negative controls, n=9). The patients showed a significantly higher value in the serum predominant FLC:serum creatinine ratio (43.8+/-63.2) and CD38++ CD19- CD56+ subpopulation (monoclonal plasma cells) (2.57+/-5.35%) than either the negative (p

This is an electronic version of an article published in AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS. 13: 71(2006) [AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS] is available online at: http://www.informaworld.com/openurl?genre=article&issn=1350-6129&volume=13&issue=3&spage=71, Article, Amyloid-Journal of Protein Folding Disorders. 13(Suppl. 1): 45-45 (2006)

We report a patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who showed high titers of anti-sulfated glucuronyl paragloboside (SGPG) IgM antibody without M-protein in serum. The patient was resistant to corticosteroids and immunosuppressants, but after administration of rituximab, clinical symptoms improved and the patient remained in a stable state for approximately 10 months. Rituximab may be a potent therapeutic option for refractory cases of CIDP irrespective of detectable M-protein in either serum or urine.

We prospectively investigated therapeutic and adverse effects of tacrolimus in seven patients with myasthenia gravis (MG) who were resistant to conventional therapies or could not be treated with thymectomy because of complications. Within two months of initiation of tacrolimus all the patients subjectively showed improvement of clinical symptoms, while both the quantitative MG score for disease severity and MG-activities of daily living profile were significantly decreased (p < 0.05) 3 and 6 months after commencement compared with before. Nine months after initiation and later, MG temporarily exacerbated in two patients with rapid tapering of oral prednisolone and one non-thymectomized one. This drug is useful in the treatment of refractory patients with MG irrespective of thymectomy, particularly in the early phase after commencement. When tacrolimus is additionally used for treatment of MG, preceding drugs, particularly corticosteroids such as oral prednisolone, should be carefully tapered if necessary in order to prevent clinical exacerbation.

Neuropsychiatric symptoms are often seen in patients with systemic lupus erythematosus (SLE). To investigate the relationship between involvement of the nervous system and clinical factors, including autoantibodies and the activity of SLE, we retrospectively reviewed 25 patients with neuropsychiatric SLE (NPSLE, mean age: 35.2±12.2 years). As controls 37 SLE patients without neuropsychiatric manifestations (mean age: 31.8±15.8 years) were employed in this study. At the onset no significant differences were seen in any clinical factors between the patients and the controls except for serum antinuclear antibodies. In relapse, the patients with NPSLE showed significantly lower levels of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores without neuropsychiatric evaluation (p

We report a patient with rheumatoid arthritis (RA) who developed malignant lymphoma of the diffuse large B-cell type in the right submandibular region shortly after initiation of oral methotrexate (MTX). Despite cessation of MTX, the lymphadenopathy did not regress, and only reached complete remission after 3 courses of CHOP therapy followed by irradiation. In this patient highly active RA itself was considered to be the main cause of malignant lymphoma, and MTX might have contributed to the development by modifying the immune system. When RA is highly active, MTX should be used carefully because of the possible development of malignant lymphoma as well as other serious complications.

To investigate whether monoclonal plasma cells in the bone marrow are useful as a therapeutic marker in AL amyloidosis, serial flow cytometry was performed in five patients with this disorder before and after chemotherapy. Four patients were treated with 2 or 3 courses of VAD (vincristine, doxorubicin and dexamethazone) and subsequently with high-dose melphalan followed by auto-PBSCT. The remaining one patient was treated with two courses of VAD alone. Before treatment all patients exhibited a CD19- CD56+ subpopulation, which indicated monoclonal plasma cells, in varying degrees. After treatment all patients showed a decrease in monoclonal plasma cells in accordance with the disappearance of M-protein in serum and/or urine. In two patients treated with VAD followed by auto-PBSCT, polyclonal (CD19+ CD56-) and total plasma cells gradually increased in the follow-up study, while monoclonal plasma cells stayed at less than 0.3% nine months after treatment. No apparent correlation was found between altered maturation of plasma cells and disappearance of M-protein. With respect to easy detection of monoclonal plasma cells producing amyloidogenic M-protein, flow cytometry of bone marrow aspirates is useful and reliable in the follow-up of patients with AL amyloidosis and in the evaluation of the effects of chemotherapy.

We report a 46-year-old woman who extensively showed intracranial calcifications possibly due to neuropsychiatric systemic lupus erythematosus (NPSLE) and antiphospholipid syndrome (APS). She had been treated with oral prednisolone for SLE since age 15, and experienced two abortions due to APS at ages 28 and 35 respectively. After a convulsion attack due to NPSLE at age 30, she had been suffering from dysarthria and choreic movement in her extremities. On admission to our hospital brain CT demonstrated extensive and symmetrical calcifications bilaterally in basal ganglia, subcortical white matter of the frontal lobe and dentate nuclei. She was shown to have neither metabolic nor congenital disorders causing these intracranial abnormalities. In this patient both NPSLE and APS, therefore, might have contributed to the remarkable intracranial calcifications in a long clinical course.

A 74-year-old woman who had developed numbness in both hands was diagnosed as having bilateral carpal and right cubital tunnel syndrome and underwent bilateral carpal and right cubital tunnel release. Transthyretin immunoreactive amyloid deposits were seen on specimens and were also detected in gastric, duodenal and ileal mucosal biopsies. The transthyretin gene analysis showed no mutation. This is a rare case of senile systemic amyloidosis presenting as carpal tunnel syndrome.

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) is similar to polymyalgia rheumatica (PMR) in that it shows arthralgia attributable to tenosynovitis and muscle pain, occurring most commonly in the elderly, and shows a good response to corticosteroid treatment.1–4 The aetiologies of RS3PE and PMR are still unknown, but they are sometimes associated with neoplastic, other rheumatic, or infectious diseases.5,6 Here, we report clinical findings in four patients with RS3PE or PMR, or both, after infection with Mycoplasma pneumoniae . Increases in inflammatory reactions were seen in all patients, and the final diagnoses were RS3PE alone in patients 1 and 4, RS3PE associated with PMR in patient 2, and PMR alone in patient 3 (table 1).7,8 None of the …

Background Systemic sclerosis (SSc) is a multisystem disorder of connective tissue characterized by excessive accumulation of extracellular matrix in the skin and various internal organs. Some clinical studies have shown that autoantibodies and genetic polymorphisms could reflect clinical manifestations of SSc. IL12RB2 genetic variants have been associated with multiple autoimmune disorders. In 2012, Bossini-Castillo et al. revealed the association of an IL12RB2 genetic variant with SSc in Caucasian populations. Objectives In this study we explored the association of a single nucleotide polymorphism (SNP) of the IL12RB2 gene with susceptibility to SSc in the Japanese population. Methods Four hundred thirty-five patients with SSc, 46 patients with SLE and 322 healthy controls (HC) were enrolled in this study. Three SNPs (rs1495965, rs924080, and rs3790567) in the IL12RB2 gene were determined by allelic discrimination with the use of each specific TaqMan probe. In patients with SSc, the number of female and male was three hundred eighty-nine and forty-six. The frequencies of the patients with diffuse cutaneous type were 47%, interstitial lung disease were 55%, and anti-topoisomerase I positivity were 33%. Results Only a SNP (rs1495965) was significantly associated with susceptibility to SSc in the Japanese population. At rs1495965, the C allele showed a significantly higher frequency in patients with SScthan that in controls ( P = 0.0060; odds ratio, 1.34; 95% confidence interval, 1.1-1.7). In this study, we didn’t support an association of IL12RB2 rs924080 and rs3790567 with SSc, as previously reported in Caucasian populations. In contrast, any significant associations of SLE with the SNPs were observed in the present study. In particular, the clinical subsets of SSc showed a more significant association between the C allele and diffuse cutaneous SSc (dcSSc, P = 0.0015) and the presence of interstitial lung disease (ILD, P = 0.0022), the presence of anti-topoisomerase antibody (Topo, P = 0.00039). We showed the significant association between a SNP in the IL12RB2 gene and susceptibility to SSc in the Japanese population, especially in the presence of dcSSc, ILD, and Topo. However, the SNP we found as a susceptibility gene in the present study was different from the SNP previously reported in the Caucasian population. Conclusions The IL12RB2 gene was one of susceptibility-genes in patients with SSc. Our results strongly suggest that this SNP may be a powerful indicator for the severity of skin and lung involvement in patients with SSc. References Rueda B, Broen J, Simeon C, et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum Mol Genet 2009;18:2071-7 Dieude P, Guedj M, Wipff J, et al. Association between the IRF5 re2004640 functional polymorphism and systemic sclerosis: a new perspective for pulmonary fibrosis. Arthritis Rheum 2009;60:225-33 Mizuki N, Meguro A, Ota M, et al. Genome-wide association studies identify IL23R-IL12RB2 and IL-10 as Behcet’s disease susceptibility loci. Nat Genet 2010; 42:703-706 Bossini-Castillo L, Martin JE, Broen J, et al. A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. Hum Mol Genet 2012;21:926-933 Disclosure of Interest None Declared

Background The complication of interstitial lung disease (ILD) is associated with the anti-aminoacyl tRNA synthetase (aaRS) antibody or the anti-melanoma differentiation-associated gene 5 (MDA5) antibody in polymyositis (PM)/dermatomyositis (DM). Anti-MDA5 antibody is associated with clinically amyopathic DM and fatal outcome due to rapidly progressive (RP) ILD in Asia. The frequency of fatal outcome is 40-50% in RP-ILD with anti-MDA5 antibody. The pathophysiology of ILD has remained unknown sufficiently in PM/DM. Objectives The aim of the present study was to investigate and compare the cytokine profiles in PM/DM with ILD and without ILD, to clarify the differences between anti-MDA5 antibody-positive ILD and anti-aaRS antibody-positive ILD, and to analyze the predictive factor for the prognosis of ILD in PM/DM. Methods Fifty PM/DM patients were enrolled in this study. These patients were divided into two subsets, PM/DM without ILD and PM/DM with ILD, which included 17 and 33 patients, respectively. Moreover, 16 healthy controls (HCs) were also enrolled. Serum cytokines were measured by multiplex assay in all subjects. The levels of each cytokine were analyzed in PM/DM with ILD or without ILD. We also compared the differences between anti-MDA5 antibody-positive ILD subset and anti-aaRS antibody positive-ILD subset in PM/DM. Results The levels of IL-6, IL-8, IL-10, IL-12, TNF-α, IFN-α, IFN-γ and IP-10 were significantly higher in the PM/DM without ILD subset than in HCs. No significant differences were found in IL-1β, IL-2, IL-4, IL-13 or IL-17 between these subsets. Moreover, the following were significantly higher in the PM/DM with ILD subset than the PM/DM without ILD subset: IL-4 (P = 0.004), IL-6 (P = 0.03), IL-8 (P = 0.03), IL-10 (P = 0.01), TNF-α (P = 0.0002) and IP-10 (P = 0.011). A multivariate analysis demonstrated that TNF-α was the cytokine most associated with ILD. Moreover, the frequencies of the complication with RP-ILD was 80% and 17% in anti- MDA5 antibody-positive ILD and anti-aaRS antibody-positive ILD, respectively. The levels of IL-8 and IFN-α were higher in anti-MDA5 subset than anti-aaRS subset. The fatal outcome due to ILD was found in the 40% of anti-MDA5 subset, although the improvement of ILD was revealed in all patients with the anti-aaRS antibody. IL-8 levels were higher in PM/DM patients with the fatal outcome due to progressive ILD than those with the improvement of ILD. Conclusions Inflammatory cytokines, including IL-6, IL-8, TNF-α, IFN and IP-10, were involved in the pathophysiology of PM/DM. TNF-α was mainly associated with ILD in PM/DM. IL-8 and IFN-α could be closely associated with the pathophysiology of ILD in anti-MDA5 antibody-positive DM. Serum IL-8 levels might be a possible predictor for the prognosis in ILD with PM/DM. Disclosure of Interest None Declared