A CD40 variant is associated with systemic bone loss among patients with rheumatoid arthritis.

OBJECTIVES: Little is known about genes predisposing to systemic bone loss (SBL) in rheumatoid arthritis (RA). Therefore, we examined the association between SBL and variants of genes playing a critical role in both immune response and bone homeostasis among patients with RA. METHODS: IRAK-1 rs3027898, IRAK-2 rs3844283, IRAK-2 rs708035, IFIH1 rs1990760, CD40 rs48104850, TNFAIP3 rs2230926, and miR146-a rs2910164 were genotyped in 176 adult RA patients. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA). RESULTS: Low BMD was observed in 116 (65.9%) patients. Among them, 60 (34.1%) had low femoral neck (FN) Z score, 72 (40.9%) had low total femur (TF) Z score, and 105 (59.6%) had low lumbar spine (LS) Z score. Among all the SNPs assessed, only CD40 rs4810485 was found to be associated with reduced TF Z score with the CD40 rs4810485 T allele protecting against reduced TF Z score (OR = 0.40, 95% CI = 0.23-0.68, p = 0.0005). This association was confirmed in the multivariate logistic regression analysis (OR = 0.31, 95% CI = 0.16-0.59, p = 3.84 × 10-4). Moreover, median FN BMD was reduced among RA patients with CD40 rs4810485 GG genotype compared to RA patients harbouring CD40 rs4810485 TT and GT genotypes (0.788 ± 0.136 versus 0.826 ± 0.146 g/cm2, p = 0.001). IRAK-1 rs3027898, IRAK-2 rs3844283, rs708035, IFIH rs1990760, TNFAIP3 rs2230926, and miR146-a rs2910164 were not found to be associated with SBL. CONCLUSION: This study for the first time ever demonstrated an association between a CD40 genetic variant and SBL among patients with RA. KEY POINTS: • CD40 rs4810485 GG genotype is associated with decreased BMD among patients with RA. • CD40 rs4810485 might serve as a genetic marker for SBL in RA. • CD40 genetic variations might be integrated in future development of more effective therapeutic interventions for prevention of SBL in RA.

Asymptomatic vertebral fracture in Tunisian post-menopausal women at risk: prevalence and risk factors.

Data are still scarce regarding the prevalence and the associated factors of vertebral fractures (VF) in the North Africa and the Middle East region. In this study, VF were common in at risk Tunisian women with a prevalence of 26.19%. Lower total hip T-score, having severe back pain, and being physically inactive were independently associated with VF. INTRODUCTION: Vertebral fractures are related to a marked increase in morbidity and mortality and they are associated with a definite risk of subsequent fracture. Nevertheless, they remain underdiagnosed and little is known about their epidemiology in the African countries. In this first Tunisian study, we aimed to assess the prevalence and the associated factors of asymptomatic VF among at risk Tunisian post-menopausal women. METHODS: In this cross-sectional study, we included post-menopausal women without a previous diagnosis of VF and who were referred for bone mineral density (BMD) measurement. Each participant had had an extensive medical history investigation, a BMD assessment, and a vertebral fracture assessment (VFA) scan using a dual energy X-ray absorptiometry. VF were defined using Genant semi-quantitative method. RESULTS: Two hundred and ten post-menopausal women were included. The overall prevalence of VF was 26.19% and 9.52% of our participants had multiple VF. The prevalence of VF was significantly higher in older participants, those having a history of prior severe fragility fracture, or having at least one intrinsic fall. The percentage of low bone mineral density and osteoporosis were significantly higher in women with VF. After binary logistic regression analysis, severe back pain (OR = 3.016; 95% CI 1.304-6.974), regular physical activity (OR = 0.065; 95% CI 0.02-0.213), and total hip T-score (OR = 0.56; 95% CI 0.383-0.820) were independently associated with VF. CONCLUSION: VF are very prevalent among at risk Tunisian post-menopausal women and their incorporation in a clinical and densitometric tool might identify more effectively subsequent fracture.

Ultrasound remission in patients with rheumatoid arthritis in clinical remission.

OBJECTIVES: The aim of the study was to assess ultrasound (US) remission in patients with rheumatoid arthritis (RA) in clinical remission using different definitions. MATERIAL AND METHODS: This was a cross-sectional study including patients with RA in clinical remission defined by disease activity score (DAS28)-erythrocyte rate (ESR) ≤ 2.6 for at least 6 months. Each patient underwent B-mode and power Doppler (PD) assessments of 42 joints and 20 tendons. B-mode and PD signal for synovitis and tenosynovitis (TS) were defined and graded semi-quantitatively (0-3) according to the outcome measures in rheumatology clinical trials (OMERACT). Several different definitions of US remission were examined: the absence of synovial hypertrophy (SH), TS on B-mode and PD signal, the absence of SH and PD signal, a grade ≤ 1 of SH and the absence of PD, a grade ≤ 1 of SH and PD, the absence of PD, or a grade of PD ≤ 1. The DAS28, clinical disease activity index (CDAI), simple disease activity index (SDAI), and the Boolean American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria were compared. RESULTS: Thirty-seven patients were enrolled. The rate of remission according to the different composite indices was 70.2% for the SDAI, 64.8% for the CDAI, and 54% for the ACR/EULAR Boolean criteria. Synovial hypertrophy and TS in B-mode were detected in 94.6% and 40.5% of patients, respectively. Synovitis with PD signal was found in 59.5% and 13.5% of patients had TS with PD, respectively. Ultrasound remission at joints and tendons was found in 5.4-62.2% of patients. For the other remission criteria: CDAI, SDAI, and ACR/EULAR Boolean criteria, 7.7-60% of patients showed US remission at joints and tendons. CONCLUSIONS: Clinical remission, even classified by strict composite indices, does not seem to be the closest method to the concept of absence of inflammatory activity; hence the interest of integrating US in assessing remission in practice.

[Drug-induced vasculitis]. / Vascularites médicamenteuses : à propos d'une série de 13 cas.

INTRODUCTION: Drug-induced vasculitis is reported in almost 10-20 % of vasculitis. Several drugs may be incriminated in their occurrence. Our study aimed to study the epidemiological, clinical, histopathological and evolutionary characteristics of drug-indced vasculitis from a series of cases and to specify the different drugs involved. METHODS: We conducted a retrospective study during the period from January 2006 to December 2015 from the cases notified to the regional pharmacovigilance center of Sousse, Tunisia. The diagnosis was established according to the criteria proposed by the group of the American college of rheumatology (ACR). RESULTS: Our study included thirteen cases of drug-induced vasculitis over a ten-year period, with an mean incidence of 1.3 new cases per year. Mean age of patients was 40.84 years. The mean delay from the treatment onset was 14.46 days with extremes ranging from 5 days to six weeks. Most patients had pure skin involvement. Association with other extracutaneous complaints was present in five cases. Cutaneous biopsy was performed in all patients showing a pathological pattern of leukocytoclastic vasculitis, associated with fibrinoid necrosis, extravasation of red blood cells and allergic capillaritis. The outcome was favorable for all patients. The offending drugs in our series were amoxicillin, pristinamycin, rifampicin, fluconazole, metformin, glimepiride, phenobarbital, gabapentin, fenofibrate, ibuprofen, allopurinol, rituximab and tinzaparin. CONCLUSION: Anamnestic, clinical, biological and histopathological findings allow the early recognition of drug-induced vasculitis. Adequate treatment prevents systemic spreading and a worse prognosis.

A TRAF6 genetic variant is associated with low bone mineral density in rheumatoid arthritis.

OBJECTIVES: This study was aimed to investigate the association of the single nucleotide polymorphism of tumor necrosis factor receptor associated factor 6 (TRAF6), rs540386, with low bone mineral density (BMD) among patients with rheumatoid arthritis (RA). METHODS: TRAF6 rs540386 genotyping was performed by mutagenically separated PCR in a cohort of 188 (23 men, 165 women, median age, 56.2 years) adult RA patients and 224 age and gender-matched controls. BMD was measured using dual-energy X-ray absorptiometry (DXA) (Lunar Prodigy advance scans, GE Healthcare, USA). RESULTS: Among the RA patients, 64 (55 women, 9 men) had low BMD comprising of 57 patients with osteoporosis and 7 with osteopenia. Whereas TRAF6 rs540386 was not associated with RA susceptibility, it was however found to be a risk factor for reduced lumbar spine Z-score in the recessive model (OR = 3.34, 95% CI = (1.01-11.00), p = 0.038). This association was confirmed further in the multivariate logistic regression analysis taking into account several potential confounding factors (OR = 3.34 (1.01-11.00), p = 0.048). In addition, mean total femur Z-score was found to be reduced in TT patients when compared to CC + CT patients (- 1.30 ± 1.32 versus - 0.60 ± 1.05, p = 0.034). No association between TRAF6 rs540386 and local bone damage was observed. CONCLUSIONS: This study for the first time ever demonstrated an association between a genetic variant of TRAF6 and low BMD among patients with RA. Further investigations are needed to elucidate the exact role of this variant.

Atypical form of Adult-onset Still's Disease with Distal Interphalangeal Joints Involvement.

BACKGROUND: A distal interphalangeal (DIP) joint involvement in the adult-onset Still's disease (AOSD) has been described in some publications but is rarely reported to be severe. We report severe DIP joints damages in a young patient with AOSD. CASE REPORT: A 22 years old patient presented to our department complaining of inflammatory joints pain associated with prolonged fever and cutaneous rash. Physical examination identified polyarthritis and hepatosplenomegaly but no lymphadenopathies. After an extensive screening for neoplastic, infectious or hematologic diseases, the patient was finally diagnosed with AOSD. Treatment based on corticosteroids was then initiated with a good response on systemic signs. However, the patient continued to have recurrent arthritis affecting wrists and proximal interphalangeal joints. A Few years later, he developed a severe and disabling DIP arthritis with signs of joint destruction on conventional radiographs and MRI. Despite the initiation of methotrexate with optimal dosage, the patient continued to have polyarticular flares. The combination of methotrexate and sulfasalazine was responsible for drug-induced hepatotoxicity and this treatment was stopped. Anti-TNFα treatment was then indicated as general signs improved but severe joints damage persisted. Unfortunately, and due to healthcare system considerations, the patient was not able to benefit from TNFα inhibitors, and remained on methotrexate treatment only. Conculsion: The distal destructive arthritis during AOSD is rare and controversial. Our patient had a severe form with resistance to conventional therapies.

IRAK2 is associated with susceptibility to rheumatoid arthritis.

This study was performed to investigate the association of the single nucleotide polymorphisms of interleukin-1 receptor-associated kinase 2 (IRAK2) rs3844283 and rs708035 with rheumatoid arthritis (RA). IRAK2 rs3844283 and rs708035genotyping was determined by mutagenically separated PCR with specifically designed primers in a cohort of 222 (30 men, 192 women, mean age 49 years) adult RA patients and 224 matched controls. IRAK2 rs3844283 C allele was detected in 66% of RA patients and 74% of controls. The CC genotype was the most frequent genotype in both RA patients (45.5%) and the controls (56.3%). The G allele was found to be associated with RA susceptibility (OR = 1.47, 95% CI = 1.10-1.96, p = 0.008). The GG genotype was found to be associated with RA in the co-dominant and the dominant models (OR = 2.03, 95% CI = 1.08-3.81, p = 0.042 and OR = 1.54, 95% CI = 1.06-2.23, p = 0.023, respectively). IRAK2 rs708035 was found not to be in the Hardy-Weinberg equilibrium. The hyperfunctional IRAK2 rs708035 A allele was more frequent in RA patients than in controls (69.9 versus 62.2%, respectively, p = 0.015). Moreover, IRAK2 rs708035 and IRAK2 rs3844283 were in linkage disequilibrium and the GA haplotype was significantly more frequent in RA patients than in controls (p = 0.034). This study for the first time ever reports the association of IRAK2 rs3844283, IRAK2 rs708035, and the corresponding haplotypes with RA. Functional studies are recommended to elucidate the risk posed by the GA haplotype for the development of RA.

Micro RNA-146a But Not IRAK1 is Associated with Rheumatoid Arthritis in the Tunisian Population.

BACKGROUND: Rheumatoid arthritis (RA) is characterized by the production of an array of proinflammatory cytokines through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Interleukin-1 receptor (IL-1R) and Toll-like receptors contain a common cytoplasmic motif the Toll/IL-1R (TIR) homology domain. This motif is required for NF-κB activation. IL-1R-associated kinase 1 (IRAK1) is a key adapter molecule recruited during the signaling cascade of the TIR. Its gene expression is regulated by the micro-RNA (miR)-146a. OBJECTIVE: We investigated the role of IRAK1 single-nucleotide polymorphism (SNP) rs3027898 (IRAK1 rs3027898) and miR-146a SNP rs2910164 (miR-146a rs2910164) in Tunisian patients with RA and their association with C reactive protein (CRP), rheumatoid factor (RF), anticyclic citrullinated peptide (anti-CCP) antibodies, and erosion. PATIENTS AND METHODS: In a cohort of 172 adult RA patients and 224 matched controls, IRAK1 rs3027898 genotyping was determined by mutagenically separated polymerase chain reaction (MS-PCR) with newly designed primers, and miR-146a rs2910164 genotyping was determined by fragment length polymorphism PCR-restriction (RFLP-PCR). RESULTS: The IRAK1 rs3027898 A allele was detected in 67% of RA patients and 70% of controls indicating that it is not associated with RA in codominant, dominant, or recessive models even after stratification by age and gender. The miR-146a rs2910164 G allele was detected in 76% of RA patients and 68% of controls, thus the C allele confers some protection based on a dominant model [CC+GC (odds ratio (95% confidence interval) = 0.6 (0.3-0.9), p = 0.03)]. No association with CRP, RF, anti-CCP, or erosion was found for either SNPs. CONCLUSION: The IRAK1 rs3027898 was not associated with RA, whereas C allele of miR-146a rs2910164 was found to be protective. Functional studies are required to investigate the exact role of miR-146a rs2910164 during RA.

Crusted Norwegian scabies, an opportunistic infection, with tocilizumab in rheumatoid arthritis.

BACKGROUND: Crusted Norwegian scabies is an extremely rare hyperkeratotic variant of scabies infestation. We report herein a case of crusted scabies in a woman with severe rheumatoid arthritis (RA) treated by tocilizumab (TCZ), a monoclonal antibody blocking the interleukin-6 receptor. OBSERVATION: An 80-year-old female with severe RA developed erythroderma followed by hyperkeratosis, widespread scaling over the trunk, arms, hands and limbs, and crusted lesions on her scalp. She was on TCZ (8 mg/kg per month) with prednisone (20 mg/d). Several hypotheses were evoked (i.e., vasculitis, psoriasis or paraneoplasic syndrome) but a microscopic examination of the skin surprisingly demonstrated numerous scabies mites and eggs leading to the diagnosis of crusted (Norwegian) scabies. After repeated use of ivermectin and application of topical piperonyl butoxide cream, scabies disappeared. However, there had been outbreak of scabies among two individuals in the staff and two patients. TCZ was stopped after four infusions because of a severe infectious pneumonia and failure. CONCLUSION: Crusted scabies should be evoked in case of pruritus or erythroderma occurring under TCZ therapy and it may be explained by the interleukin-6 blockade.