Anti-Mi-2 and Anti-TIF1-γ Double-Positive Juvenile Dermatomyositis Treated under Diagnosis of Chronic Eczema: A Case Report.

Myositis-specific autoantibodies are relevant factors that define the disease phenotype of dermatomyositis (DM). Anti-Mi-2 antibody-positive DM patients may present with the typical skin lesions and prominent myositis. On the other hand, adult DM patients with anti-TIF-γ antibody seem to be associated with internal malignancy. Here, we report a rare case of juvenile dermatomyositis (JDM) exhibiting anti-Mi-2 and anti-transcriptional intermediary factor-1 gamma (TIF1-γ) antibodies, with no internal malignancy. A 16-year-old female Japanese patient under treatment with a 2-year history of chronic eczematous lesions was admitted to our department with elevated levels of muscle enzymes. Characteristic skin changes, such as Gottron's papules of the hand, heliotrope rash of the eyelids, and poikiloderma-like legions and diffuse pigmentation on the back, were observed. Histologically, the patient's skin was characterized by the presence of lymphocytic vascular inflammation and endothelial swelling, which are consistent with DM. Severe symmetric proximal muscle weakness, elevated serum muscle enzymes and the presence of anti-TIF1-γ and Mi-2 antibodies were noted. The diagnosis of JDM was made according to the European League Against Rheumatism (EULAR) diagnostic criteria. A high dose of corticosteroids and following intravenous cyclophosphamide treatment (750 mg three times) resulted in an improvement in clinical manifestations and functional outcomes, and recurrence did not occur. Estimation of autoantibodies may serve as an ancillary tool in delineating and defining distinct clinical phenotypes in JDM.

Total Hip Joint Replacement in a Patient with Colchicine-Resistant Familial Mediterranean Fever under Canakinumab Treatment.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent episodes of fever and serositis. Periodic febrile attack can be managed with biologic medication in colchicine-resistant FMF patients, however, no reports or guidelines exist regarding the postoperative management of elective joint surgery in these patients. Although it is not clear how FMF attacks are triggered, they may be precipitated by stress including anesthesia or surgery. This study reports the case of a 51-year-old FMF patient who received total hip replacement under canakinumab (a specific interleukin-1ß monoclonal antibody) treatment. He had highly active FMF, which was resistant to colchicine; however, his recurrent febrile attack with serositis was successfully controlled with canakinumab. Four months later from the start of canakinumab treatment, his hip osteoarthritis was required for total hip replacement (THR) because of the traumatic fracture. THR was successfully done and FMF attack was not occurred after this elective surgery. Discontinuation of canakinumab 3 weeks before surgery and resumption 6 weeks after led to favorable outcome without complications. This case addresses the differential management concerning stopping and restating of canakinumab in the perioperative setting in contrast to the other biologics such as tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) blocking agents. This case report suggests that canakinumab may represent a safe and effective therapy for the colchicine-resistant FMF, even in the patients requiring THR therapy.

Immunoglobulin A Vasculitis in a Japanese Patient with Complete Familial Mediterranean Fever Carrying MEFV Exon 10 Mutation.

Immunoglobulin A (IgA) vasculitis is a systemic small-vessel vasculitis involving the skin, kidney, joints, and gastrointestinal tract. Familial Mediterranean fever (FMF) is the most common autoinflammatory disease characterized by periodic fever, peritonitis, pleuritis, or arthritis. It is well known that FMF may coexist with vasculitis, especially small and medium vessel vasculitis. Here we present a Japanese male patient with FMF who later developed IgA vasculitis and a relapsing disease course. A 51-year-old Japanese male was referred because of upper abdominal pain, arthralgia, and bilateral purpura of the lower limbs. He fulfilled the criteria for IgA vasculitis, which was successfully treated by corticosteroid and immunosuppressive therapy. He had a medical history of periodic fever since the age of 10 years old. The Mediterranean fever (MEFV) gene analysis revealed that he was heterozygous for M694I and E148Q mutations. Colchicine therapy resolved his periodic febrile attacks. To our knowledge, coexistence of FMF with IgA vasculitis has not been reported in East Asia, including Japan. Our case suggests that MEFV gene exon 10 mutations could be related to the development of IgA vasculitis and affects its clinical course.

IL-35 inhibits human osteoclastogenesis from monocytes induced by receptor-activator of NF-κB ligand.

IL-35 is known as a regulatory cytokine produced by regulatory T cells. It has also been reported that IL-35 suppresses the proliferation of Th17 cells, which is involved in the pathogenesis of many autoimmune diseases. However, in rheumatoid arthritis patients, the role of IL-35 is controversial, and the role of IL-35 in bone metabolism has not been clarified. We investigated the effect of IL-35 on human osteoclast differentiation and activation. We first evaluated the effect of rhIL-35 on human osteoclastogenesis from monocytes cultured alone, induced by soluble-RANKL. We also examined the role of IL-35 on the bone-resorption function of mature osteoclasts. Furthermore, we analysed the molecular mechanism of IL-35 function in monocytes or pre-osteoclasts using RT-PCR. rhIL-35 significantly inhibited human osteoclastogenesis in a dose-dependent manner. In addition, rhIL-35 also significantly decreased the area of pit formation by mature osteoclasts. rhIL-35 significantly decreased mRNA expression of RANK in monocytes and RANK and FOS in pre-osteoclasts. Our current findings suggest that IL-35 inhibits osteoclastogenesis and osteoclast activation by inhibiting both RANK and FOS. IL-35 also has an inhibitory effect on osteoclastic-bone resorption, suggesting that IL-35 may have a therapeutic potential for RA.

A novel peptide from TCTA protein inhibits proliferation of fibroblast-like synoviocytes of rheumatoid arthritis patients.

BACKGROUND: We have demonstrated that a peptide, which we named 'Peptide A', derived from the extracellular domain of T-cell leukemia translocation-associated gene (TCTA) protein, inhibited human osteoclastogenesis. OBJECTIVE: In the current study, we examined whether this peptide inhibits the proliferation of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) or not. MATERIAL AND METHODS: Fibroblast-like synoviocytes obtained from five RA patients were cultured in the absence or presence of 1, 5, 10 µg/ml of peptide. We used 29-mer scrambled peptide as a control. RESULTS: The peptide inhibited the proliferation of RA FLS dose-dependently. On the other hand, the scrambled peptide showed no inhibition. CONCLUSIONS: The peptide inhibits both human osteoclastogenesis and the proliferation of RA FLS. Thus, the peptide may be used for the therapy of both osteoporosis and synovitis of RA patients. This is the first report of the new peptide we discovered, which inhibits both osteoclastogenesis and synovitis. Thus, this new peptide could be a new drug for patients with both osteoporosis and RA.

Successful Treatment of Ultrasound-confirmed Synovitis in Anti-MDA5 Antibody-positive Clinically Amyopathic Dermatomyositis with Corticosteroid Therapy.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive clinically amyopathic dermatomyositis (CADM) is a subtype of dermatomyositis without severe myositis but with characteristic cutaneous manifestations and severe interstitial lung disease. Joint symptoms can occur in patients with anti-MDA5 antibody-positive CADM. However, the treatment strategy and utility of ultrasound for treating joint symptoms remain unknown. We herein report an 85-year-old man with anti-MDA5 antibody-positive CADM who presented with ultrasound-confirmed synovitis that improved with medium-dose corticosteroid therapy.

Voltage-dependent anion channels (VDACs, porin) expressed in the plasma membrane regulate the differentiation and function of human osteoclasts.

Fewer molecules have been identified on human than murine osteoclasts, the former differing from murine osteoclasts in many ways. We show that voltage-dependent anion channels (VDACs, porin) are expressed in the plasma membrane of human osteoclasts. A search for novel proteins expressed in the plasma membrane of human osteoclasts identified VDAC. Anti-VDAC antibodies inhibited human osteoclastogenesis in vitro. VDAC expression was detected in membranes by immunoelectron microscopy and immunocytochemical double staining. The VDAC protein functions as a Cl(-) channel. VDACs regulate bone resorption, which show using Osteologic™ plates. The epitope of the antibody lay within a 10-amino acid sequence in the VDAC. The findings suggest that the VDAC is, at least partly, a novel Cl(-) channel regulating the differentiation and function of human osteoclasts. VDACs may play a crucial role in acidifying the resorption lacunae between osteoclasts and bone. Inhibitors of VDACs could be used to treat diseases involving increased resorption, such as osteoporosis, rheumatoid arthritis, and Paget's disease.

Tacrolimus potently inhibits human osteoclastogenesis induced by IL-17 from human monocytes alone and suppresses human Th17 differentiation.

Tacrolimus (FK506, Prograf®) is an orally available, T cell specific and anti-inflammatory agent that has been proposed as a therapeutic drug in rheumatoid arthritis (RA) patients. It has been known that T cells have a critical role in the pathogenesis of RA. Recent studies suggest that Th17 cells, which mainly produce IL-17, are involved in many autoimmune inflammatory disease including RA. The present study was undertaken to assess the effect of tacrolimus on IL-17-induced human osteoclastogenesis and human Th17 differentiation. Human CD14(+) monocytes were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and IL-17. From day 4, tacrolimus was added to these cultures. Osteoclasts were immunohistologically stained for vitronectin receptor 10days later. IL-17 production from activated T cells stimulated with IL-23 was measured by enzyme-linked immunosorbent assay (ELISA). Th17 differentiation from naïve T cells was assayed by flow cytometry. Tacrolimus potently inhibited IL-17-induced osteoclastogenesis from human monocytes and osteoclast activation. Addition of tacrolimus also reduced production of IL-17 in human activated T cells stimulated with IL-23. Interestingly, the population of human IL-17(+)IFN-γ(-) CD4 T cells or IL-17(+)TNF-α(+) CD4 T cells were decreased by adding of tacrolimus. The present study demonstrates that the inhibitory effect of tacrolimus on IL-17-induced osteoclastogenesis from human monocytes. Tacrolimus also inhibited expression of IL-17 or TNF-α by reducing the proportion of Th17, suggesting that therapeutic effect on Th17-associated disease such as RA, inflammatory bowel disease, multiple sclerosis, psoriasis, or allograft rejection.

The role of T-cell leukemia translocation-associated gene protein in human tumorigenesis and osteoclastogenesis.

Synovial tissues of patients with rheumatoid arthritis (RA) include factors regulating bone resorption, such as receptor activator NF-κB ligand (RANKL), TNF-α, IL-6, IL-17, and IFN-γ. However, in addition to these cytokines, other factors expressed in synovial tissues may play a role in regulating bone resorption. In 2009, we demonstrated that novel peptides from T-cell leukemia translocation-associated gene (TCTA) protein expressed in synovial tissues from patients with RA inhibit human osteoclastogenesis, preventing cellular fusion via the interaction between TCTA protein and a putative counterpart molecule. Only a few studies on the role of TCTA protein have been reported. Genomic Southern blots demonstrated a reduced TCTA signal in three of four small cell lung cancer cell lines, suggesting the loss of one of the two copies of the gene. In the current paper, we reviewed the roles of TCTA protein in lung cancer cell lines and human osteoclastogenesis.

Role of osteoclasts and interleukin-17 in the pathogenesis of rheumatoid arthritis: crucial 'human osteoclastology'.

Many papers have reported that osteoclasts play an important role in the pathogenesis of rheumatoid arthritis (RA); however, when we started to investigate the pathogenesis of RA, the roles of osteoclasts were not highlighted in RA bone resorption. In recent years, the number of articles on the roles of osteoclasts and interleukin (IL)-17 in the pathogenesis of RA has increased exponentially. In this review article, we describe our articles on the roles of osteoclasts and IL-17 in joint destruction in RA, from 1990 to 2011, and highlight a novel term, 'human osteoclastology', which we have used since 2008.

Presence of anti-transcriptional intermediary factor-1 gamma antibodies in a dermatomyositis patient with retroperitoneal cancer of unknown primary site.

A 71-year-old woman with dermatomyositis (DM) received glucocorticoid steroid (GCS) and tacrolimus treatment. Relapse of skin symptoms was observed after tapering the GCS dose, and the patient tested positive for anti-transcriptional intermediary factor-1 gamma (TIF1-γ) antibody. Examinations for malignancy were repeatedly performed. However, no obvious findings indicative of a tumour were observed. Two years after, a retroperitoneal tumour was detected and pathologically diagnosed as poorly differentiated adenocarcinoma. The patient developed intestinal and biliary obstruction and eventually died of sepsis. Herein, we report the presence of anti-TIF1-γ antibodies in a DM patient with cancer of unknown primary site.

Association between inflammatory cytokines and immune-checkpoint molecule in rheumatoid arthritis.

BACKGROUND: Anti-citrullinated peptide antibodies (ACPA) and inflammatory cytokines play important roles in the development of rheumatoid arthritis (RA). T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is an immune-checkpoint molecule involved in inhibitory signaling. Galectin-9 (Gal-9) mediated ligation of TIM-3 induces the amelioration of autoimmune diseases. TIM-3 is expressed in synovial osteoclasts and involved in the rheumatoid bone destruction. The aim of this study was to investigate the relationships between inflammatory cytokines and immune-checkpoint molecules in RA patients. METHODS: Serum levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), soluble TIM-3 (sTIM-3) and Gal-9 were determined by ELISA. Patients were stratified into two groups based on ACPA titers: low-medium ACPA (ACPA <200 U/mL) and high ACPA (ACPA ≥200 U/mL). Serum levels of cytokines or immune-checkpoint molecules were evaluated between RA patients with low-medium ACPA titers and high ACPA titers. RESULTS: Elevated serum levels of inflammatory cytokines were correlated with DAS28-ESR in RA patients. Although serum levels of sTIM-3 were elevated in RA patients, significant correlations between sTIM-3 and cytokines (IL-6 or TNF-α) were observed exclusively in RA patients with low-medium ACPA titers (<200 U/mL). Serum levels of IL-6 and TNF-α levels were significantly correlated with elevated Gal-9 levels regardless of ACPA status. A significant correlation between IL-6 and Gal-9 was observed in RA patients without advanced joint damage. Conversely, a significant correlation between TNF-α and Gal-9 was observed in RA patients with advanced joint damage. CONCLUSIONS: Our data indicated that there are positive correlations between circulating inflammatory cytokines and checkpoint molecules in RA patients and these interactions can be modulated by ACPA status or joint damage stage.

Cold-inducible RNA-binding protein (CIRP) potentiates uric acid-induced IL-1ß production.

BACKGROUND: Gout is an autoinflammatory disease driven by interleukin-1 (IL-1) induction in response to uric acid crystals. IL-1ß production is dependent on inflammasome activation, which requires a priming signal, followed by an activating signal. The cold-inducible RNA-binding protein (CIRP) has been recently identified as a damage-associated molecular pattern (DAMP). In this study, we evaluated the roles of CIRP in monosodium urate (MSU)-mediated IL-1ß secretion using human neutrophils. METHODS: Human neutrophils were stimulated by MSU in the presence or absence of CIRP priming to determine NLRP3 inflammasome activation and subsequent caspase-1 activation and IL-1ß production. Cellular supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA) to determine the presence of IL-1ß or caspase-1 (p20). The cellular supernatants and lysates were also analyzed by immunoblotting using anti-cleaved IL-1ß or anti-cleaved caspase-1 antibodies. RESULTS: Neither CIRP nor MSU stimulation alone induced sufficient IL-1ß secretion from neutrophils. However, MSU stimulation induced IL-1ß secretion from CIRP-primed neutrophils in a dose-dependent manner. This MSU-induced IL-1ß secretion from CIRP-primed neutrophils was accompanied by the induction of cleaved IL-1ß (p17), which was inhibited by the pretreatment of MCC950, a specific inhibitor for NLRP3. Furthermore, cleaved caspase-1 was induced in the cellular lysates of CIRP/MSU-treated neutrophils. Additionally, CIRP stimulation induced the protein expression of pro-IL-1ß in neutrophils. CONCLUSIONS: Our data indicate that CIRP, an endogenous stress molecule, triggers uric acid-induced mature IL-1ß induction as a priming stimulus for NLRP3 inflammasome in human neutrophils. We propose that CIRP acts as an important proinflammatory stimulant that primes and activates inflammasome and pro-IL-1ß processing in response to uric acid in innate immune cells.

Clinical relevance for circulating cold-inducible RNA-binding protein (CIRP) in patients with adult-onset Still's disease.

BACKGROUND: Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease in which danger-associated molecular patterns (DAMPs)-mediated inflammasome activation seems to be involved in the disease pathogenesis. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that respond to cellular stress and has been identified as a DAMP that triggers the inflammatory response. The aim of this study is to investigate the clinical significance of serum CIRP levels in AOSD. METHODS: Serum samples were obtained from 44 patients with active AOSD or 50 patients with rheumatoid arthritis (RA), 20 patients with systemic lupus erythematosus (SLE), and 15 healthy control patients (HCs). Serum levels of CIRP and IL-18 were determined using enzyme-linked immunosorbent assay. Results were compared among AOSD patients, RA patients, SLE patients and HCs. Results were also analyzed according to the clinical features of AOSD. RESULTS: Serum CIRP levels were significantly higher in AOSD patients compared with RA patients (median: 9.6 ng/mL, IQR [5.7-14.4] versus 3.2 ng/mL, IQR [1.9-3.8]; p < 0.001) and with HCs (2.8 ng/mL, [IQR; 1.4-4.9], p < 0.001). There was a significant positive correlation between serum CIRP levels and AOSD disease activity score (Pouchot's score r = 0.45, p = 0.003) as well as between AOSD-specific biomarkers ferritin and IL-18. However, there was no significant difference in the serum CIRP levels among AOSD patients with three different disease phenotypes. CONCLUSIONS: These results suggest that CIRP may play a significant role in the pathophysiology of AOSD and could be a potential biomarker for monitoring the disease activity of AOSD.

Familial Mediterranean fever phenotype progression into anti-cyclic citrullinated peptide antibody-positive rheumatoid arthritis:a case report.

Familial Mediterranean fever (FMF) is caused by dysfunction of the MEFV gene product, pyrin. Here we report a case of FMF phenotype which developed into rheumatoid arthritis (RA), based on a positive result for anti-cyclic citrullinated peptide (CCP) antibody (Ab). A 42-year-old woman presented to our clinic with more than 6 months of intermittent arthralgia in the wrists, feet, and fingers associated with menstruation. No fever was reported and there was no family history of FMF or other autoimmune diseases. Laboratory tests revealed elevated C-reactive protein (CRP) and rheumatoid factor (RF). Tests for autoantibodies including anti-CCP Ab, antinuclear Ab, and anti-DNA Ab were all negative. Genetic analysis identified an R304R homozygous mutation in MEFV; however, the pathological significance is unclear because this mutation does not cause amino acid substitution. We diagnosed incomplete FMF phenotype despite the lack of fever due to periodic arthritis, lack of autoantibodies, and complete resolution of arthritis following colchicine treatment within a day. Several months later, increased stiffness and arthralgia persistently occurred in finger joints on both sides. Ultrasonography revealed synovitis at the metacarpophalangeal and metatarsophalangeal joints. Laboratory analysis revealed the patient to be positive for anti-CCP Ab. Therefore, we finally diagnosed RA. Her arthritis diminished following administration of methotrexate and salazosulfapyridine. We consider the possibility that pyrin dysfunction may have affected the acquired immunity, contributing to the onset of RA as an autoimmune disease. This is an interesting case of equivalent FMF progressing into RA and will be valuable to raise awareness of a continuum from autoinflammatory to autoimmune disease.

IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-alpha antibody: a novel mechanism of osteoclastogenesis by IL-17.

IL-17 is a proinflammatory cytokine crucial for osteoclastic bone resorption in the presence of osteoblasts or synoviocytes in rheumatoid arthritis. However, the role of IL-17 in osteoclastogenesis from human monocytes alone remains unclear. Here, we investigated the role of IL-17 in osteoclastogenesis from human monocytes alone and the direct effect of infliximab on the osteoclastogenesis induced by IL-17. Human peripheral blood mononuclear cells (PBMC) were cultured for 3 days with M-CSF. After non-adherent cells were removed, IL-17 was added with either infliximab or osteoprotegerin (OPG). Seven days later, adherent cells were stained for vitronectin receptor. On the other hand, CD11b-positive monocytes purified from PBMC were also cultured and stained as described above. CD11b-positive cells were cultured with TNF-alpha and receptor activator of NF-kappaB ligand (RANKL). In the cultures of both adherent cells and CD11b-positive cells, IL-17 dose-dependently induced osteoclastogenesis in the absence of soluble-RANKL. OPG or infliximab inhibited IL-17-induced osteoclastogenesis. Interestingly, in the culture of CD11b-positive cells, the osteoclastogenesis was more potently inhibited by infliximab than by OPG. TNF-alpha and RANKL synergistically induced osteoclastogenesis. The present study clearly demonstrated the novel mechanism by which IL-17 directly induces osteoclastogenesis from human monocytes alone. In addition, infliximab potently inhibits the osteoclastogenesis directly induced by IL-17.

Radiographic repair in three Japanese patients with rheumatoid arthritis treated with bucillamine.

Bucillamine (Bc) is a cysteine derivative with two SH groups, and a homolog of D-penicillamine, a disease-modifying antirheumatic drug (DMARD) widely used in Japan. However, it remains unclear whether Bc repairs bone erosion in patients with RA. Here, we treated three RA patients with Bc who subsequently showed radiographic repair of erosions and cysts.

[Serum markers of synovitis and bone metabolism in rheumatoid arthritis].

Matrix metalloproteinase-3 (MMP-3) is a useful marker to evaluate the prognosis of joint destruction in rheumatoid arthritis (RA) . The role of MMP-3 in immune cells, however, remains to be elucidated in the pathogenesis of RA. On the other hand, biologic therapies, including tumor necrosis factor alpha (TNF-alpha) -blocking therapy, has been shown to reduce disease activity measures and joint damage progression ; however, the effects of biologic therapies on systemic osteoporosis remain to be elucidated in RA. In this article, we reviewed the literature on these issues after describing our hypothesis of the pathogenesis of synovitis in RA.

[Effects of biologic therapies on systemic osteoporosis in patients with rheumatoid arthritis].

Biologic therapies including tumor necrosis factor alpha (TNF-alpha)-blocking therapy have been shown to reduce disease activity measures and joint damage progression. However, effects of biologic therapies on systemic osteoporosis remain to be elucidated in patients with rheumatoid arthritis (RA). In this review article, we reviewed the literature on the issue after we described our hypothesis on the pathogenesis of synovitis in patients with RA.

Associations between HLA-DRB1, RANK, RANKL, OPG, and IL-17 genotypes and disease severity phenotypes in Japanese patients with early rheumatoid arthritis.

We examined associations between human leukocyte antigen DRB1 (HLA-DRB1) shared epitope (SE), receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL), osteoprotegerin (OPG), and interleukin 17 (IL-17) genotypes with age of disease onset and radiographic progression in Japanese patients with early rheumatoid arthritis (RA). HLA-DRB1 genotypes were evaluated in 123 patients with early RA (98 female, 25 male) within 1 year of symptom onset. In 72 patients, radiographic progression over a 2-year period was evaluated using Larsen's methods, and genotypes of three polymorphic sites in RANK, five sites in RANKL, two sites in OPG, and three sites in IL-17 were determined by direct polymerase chain reaction sequencing. Possession of an SE allele was significantly associated with earlier disease onset in females (median 46.9 vs 51.9 years in SE- patients; P = 0.04). Single nucleotide polymorphisms (SNPs) in RANKL (rs2277438, P = 0.028) and IL-17 (rs3804513, P = 0.049) were significantly associated with radiographic progression at 2 years. RANKL-G-, SE- patients (n = 12) had significantly less joint damage than did RANKL-G+, SE- patients (n = 11; P = 0.0038), RANKL-G-, SE+ patients (n = 21; P = 0.0018) and RANKL-G+, SE+ patients (n = 28; P = 0.0024). In Japanese RA patients, HLA-DRB1 SE alleles are associated with disease onset at an earlier age, as has been observed in Caucasian RA patients. In addition, SNPs in RANKL and IL-17 may be associated with radiographic progression in Japanese patients with early RA.