Muriel Elhai

Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies

OBJECTIVE SSc is known as the most severe connective tissue disorder, and to be associated with a high mortality risk. Some improvements in therapy for SSc have been achieved in recent years and some preliminary data have suggested an improvement in patient survival. Thus, we set out to determine whether mortality rate in SSc patients has decreased over the past 40 years through a meta-analysis of cohort studies. METHODS We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to June 2010. All cohort studies reporting on SSc mortality were analysed. We then calculated pooled standardized mortality ratios (SMRs) of SSc mortality and calculated their changes over time using meta-regression analysis. RESULTS Nine studies were included, corresponding to a total of 2691 SSc patients. The pooled SMR was 3.53 [95% CI 3.03, 4.11, P < 0.0001; I(2 )= 93%, P(het) = 0.001]. Mid-cohort year ranged from 1977 to 1995 (before 1980: two studies; 1980-90: five studies; and after 1990: two studies): adjusted meta-regression analysis did not show significant change in SMR over time (P = 0.523). Among 732 deaths, heart involvement was the most frequent cause of deaths (29%) followed by lung involvement. CONCLUSION Our results confirm that SSc is a devastating condition as reflected by a pooled SMR of 3.5. Additionally, SMR has not significantly changed over the past 40 years. Further studies are needed to assess the effect of the most recent available therapies on mortality in SSc.

Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study

Objective To evaluate the safety and effectiveness of tocilizumab and abatacept in systemic sclerosis (SSc)-polyarthritis or SSc-myopathy. Methods 20 patients with SSc with refractory polyarthritis and seven with refractory myopathy from the EUSTAR (EULAR Scleroderma Trials and Research) network were included: 15 patients received tocilizumab and 12 patients abatacept. All patients with SSc-myopathy received abatacept. Clinical and biological assessments were made at the start of treatment and at the last infusion. Results After 5 months, tocilizumab induced a significant improvement in the 28-joint count Disease Activity Score and its components, with 10/15 patients achieving a EULAR good response. Treatment was stopped in two patients because of inefficacy. After 11 months’ treatment of patients with abatacept, joint parameters improved significantly, with 6/11 patients fulfilling EULAR good-response criteria. Abatacept did not improve muscle outcome measures in SSc-myopathy. No significant change was seen for skin or lung fibrosis in the different groups. Both treatments were well tolerated. Conclusions In this observational study, tocilizumab and abatacept appeared to be safe and effective on joints, in patients with refractory SSc. No trend for any change of fibrotic lesions was seen but this may relate to the exposure time and inclusion criteria. Larger studies with longer follow-up are warranted to further determine the safety and effectiveness of these drugs in SSc.

Ultrasonographic hand features in systemic sclerosis and correlates with clinical, biologic, and radiographic findings

To investigate ultrasonographic (US) hand features in systemic sclerosis (SSc) patients and their relationship with clinical, biologic, and radiographic data.

Abatacept for refractory juvenile idiopathic arthritis–associated uveitis: Two new cases. Comment on the article by Zulian et al

We read with great interest the article by Zulian et al, published recently in Arthritis Care & Research, which reported the efficacy of abatacept treatment for refractory juvenile idiopathic arthritis (JIA)–associated uveitis (Zulian F, Balzarin M, Falcini F, Martini G, Alessio M, Cimaz R, et al. Abatacept for severe anti–tumor necrosis factor refractory juvenile idiopathic arthritis–related uveitis. Arthritis Care Res [Hoboken] 2010;62:821–5). Seven patients with JIA-related uveitis refractory to diseasemodifying antirheumatic drugs (DMARDS) and at least 2 anti–tumor necrosis factor (anti-TNF ) agents, were treated with abatacept with sustained improvement and good tolerance (6 of the 7 patients). Herein, we report 2 new cases of JIA-related uveitis refractory to immunosuppressive drugs and anti-TNF agents and treated with abatacept with efficacy. The first patient is an 11-year-old girl with an oligoarticular JIA, antinuclear antibody–positive, and recurrent unilateral anterior uveitis. Her disease was diagnosed when she was 3 years old, and the uveitis remained active despite topical steroids, cycloplegic ophthalmic drops, and methotrexate (MTX; 0.4 mg/kg/week). Etanercept (12.5 mg/week) was administered from 2004 to 2006 with articular improvement but uveitis relapses. Adalimumab (20 mg/2 weeks) was tried during 4 months in 2008 and stopped for inefficiency. In November 2008, a severe ocular and arthritis flare occurred with a high level of biologic inflammatory parameters (erythrocyte sedimentation rate [ESR] 39 mm/hour, C-reactive protein [CRP] level 6.9 mg/ dl). The child’s height was 2 SDs below the normal target for her age. Abatacept infusions were started at 10 mg/kg and given at weeks 0, 2, and 4, and every 4 weeks thereafter. Ocular complications were present at baseline: band keratopathy with decreased visual acuity (3/10 in her right eye) and unilateral posterior synechiae. After 1 infusion, pain and synovitis disappeared. No uveitis flare occurred. At 16 months, JIA was still inactive. The ophthalmologic examination did not reveal any sign of anterior chamber inflammation. Symptomatic drugs (steroids and cycloplegic ophthalmic drops) could be stopped. Unfortunately, the pre-existing complication (band keratopathy) limited the complete recovery, and the visual acuity was unchanged. The height increased to 1 SD below the target. ESR and CRP values decreased and remained in the normal range (Figure 1). Abatacept infusions continued to be given every 7 weeks. The second patient is a 9-year-old girl diagnosed at age 3 years as having an oligoarticular JIA-related uveitis. Her ocular disease remained active despite topical steroids, cycloplegic ophthalmic drops, systemic steroids, MTX (12.5 mg/week) from 2004 to 2009, and azathioprine during 2 months in 2009. She was treated with etanercept (12.5 mg/week) from October 2005 to August 2006 and switched to adalimumab (15 mg/2 weeks) because of worsening of uveitis. Adalimumab was stopped in July 2007 because of inefficiency. Infliximab was tried from July 2007 to May 2008 without improvement. In June 2009, uveitis and arthritis flare occurred with systemic inflammation (ESR 57 mm/hour, CRP level 45 mg/dl). Abatacept infusions were given at a dosage of 10 mg/kg at weeks 0, 2, and 4, and every 4 weeks thereafter. Sight-threatening ocular complications were present: posterior synechiae, cataract, posterior vitreal detachment, and cystoid macular edema with decreased visual acuity (5/10 in the right eye and 4/10 in the left eye). Her height was 1 SD below the normal target. After the fifth infusion, the JIA became inactive with no pain, no joint swelling, and no uveitis flare. After 10 months, sustained benefit was noted with abatacept infusions every 6 weeks. The ophthalmologic examination revealed no sign of anterior chamber inflammation. The visual acuity had improved at 10/10 in her right eye and 7/10 in her left eye, and posterior vitreal detachment had disappeared. However, symptomatic drugs could not be decreased. There was catch-up growth. Changes in ESR and CRP values with time are shown in Figure 1. No infusion reactions or other drug-related adverse events occurred in the 2 patients. Figure 1. Changes in C-reactive protein (CRP; mg/dl) level and erythrocyte sedimentation rate (VS; mm/hour) with abatacept treatment in the two patients. Arthritis Care & Research Vol. 63, No. 2, February 2011, pp 307–310

Independent Replication and Metaanalysis of Association Studies Establish TNFSF4 as a Susceptibility Gene Preferentially Associated with the Subset of Anticentromere-positive Patients with Systemic Sclerosis

Objective. Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk. Methods. Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and metaanalysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry. Results. Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12–1.66)], with significant intra-cohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15–1.54) and TT genotype p = 0.00046; OR 2.02 (1.36–2.98)]. Conclusion. We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype.

IgG4-related skin disease successfully treated by thalidomide: a report of 2 cases with emphasis on pathological aspects.

IMPORTANCE In IgG4-related disease (IgG4-RD), skin involvement is rare and associated especially with systemic disease. We report 2 cases of isolated skin IgG4-RD successfully treated with thalidomide and investigated their phenotypic characteristics. OBSERVATIONS Two men had cephalic nodules. Skin biopsies revealed dense lymphocytic infiltrates with numerous plasma cells and fibrosis. IgG4-RD was confirmed by very high IgG4+ to IgG+ plasma cells ratios of 76% (patient 1) and 100% (patient 2). The serum IgG4 level was normal. There was no other organ involvement. Thalidomide therapy was introduced. After 6 months, lesions were in remission. Patient 1 required long-term, low-dose thalidomide, whereas patient 2 stopped treatment and showed no relapse. Immunostaining revealed numerous FoxP3+ cells in the interfollicular areas, which decreased with treatment in patient 2, and numerous follicular helper T lymphocytes (TFH) within the follicular germinal centers. There were numerous mast cells; some stained for interleukin (IL)-6, and expression of phospho-Smad2/3 was demonstrated. CONCLUSIONS AND RELEVANCE IgG4-RD may be skin limited. Cutaneous infiltrates comprise numerous FoxP3+ cells that may interact with mast cells to produce IL-6 and stimulate fibrosis synthesis via the transforming growth factor β/phospho-Smad2/3 pathway. The role of TFH cells remains to be studied. IgG4-RD should be added to the causes of cutaneous pseudolymphomas. Thalidomide could be considered as a therapeutic option in IgG4-RD.

Radiological cervical spine involvement in young adults with polyarticular juvenile idiopathic arthritis

OBJECTIVES Radiological cervical spine involvement in JIA has already been assessed with a large range of prevalence (5-80%), but most studies were performed a long time ago, in symptomatic JIA and without differentiating subsets of JIA. We set out to describe structural cervical spine involvement in young adults with polyarticular JIA (pJIA) regardless of the cervical symptoms and to compare lesions with those observed in adult RA. METHODS All consecutive pJIAs followed in a transition programme were included. Standard radiographs of the cervical spine, hands, feet and hip were analysed by two independent radiologists blinded to the diagnosis. An RA control group (<55 years), matched for sex and disease duration, was recruited. RESULTS Fifty-seven pJIA and 58 RA patients were included. Radiographs showed cervical lesions in 65% of pJIA and 67% of RA patients. In total, 51% of pJIA with radiographic abnormalities had no clinical symptoms. In pJIA, the most frequent structural lesions were anterior atlantoaxial subluxation (33%), erosion of the odontoid process (19%), C1-C2 arthritis (17%) and apophyseal joint arthritis (16%). Cervical lesions in pJIA were similar to those in RA except for ankylosis and hypotrophia (P < 0.05). The presence of cervical lesions correlated with a more severe disease. CONCLUSION Structural cervical spine involvement is common in pJIA persisting into adulthood, frequently asymptomatic and associated with a more severe disease. We suggest that radiographic assessment of the cervical spine should be done systematically at onset of the disease and regularly during its course regardless of clinical symptoms.

Critical role of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of inflammation-driven dermal fibrosis in a mouse model of systemic sclerosis

Objective To investigate the contribution of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of dermal fibrosis on gene inactivation and targeted molecular strategies. Methods Human skin expression of DNAM-1 was determined by immunohistochemistry. Mice deficient for DNAM-1 (dnam1−/−) and wild-type controls (dnam1+/+) were injected with bleomycin or NaCl. Infiltrating leucocytes, T cells, B cells and monocytes were quantified and inflammatory cytokines were measured in lesional skin of dnam1−/− and dnam1+/+ mice. The anti-fibrotic potential of a DNAM-1 neutralising monoclonal antibody (mAb) was evaluated in the mouse model of bleomycin-induced dermal fibrosis. Results Overexpression of DNAM-1 was detected in the skin of patients with SSc (systemic sclerosis). Dnam1−/− mice were protected from bleomycin-induced dermal fibrosis with reduction of dermal thickening (75±5%, p=0.03), hydroxyproline content (46±8%, p=0.04) and myofibroblast counts (39±5%, p=0.01). Moreover, the number of T cells was significantly decreased in lesional skin of dnam1−/− mice (69±15%, p=0.0007). Dnam1−/− mice also displayed decreased levels of TNF-α and IL-6 in lesional skin. Consistent with the gene inactivation strategy, treatment of mice with DNAM-1 neutralising mAb prevented dermal fibrosis induced by bleomycin with reduction of dermal thickness (64±6%, p=0.002), hydroxyproline content (61±8%, p=0.004) and myofibroblast counts (83±12%, p=0.002). Conclusions An inactivation gene strategy showed that DNAM-1 exerts profibrotic effects by controlling T cell activation and cytokine release. A molecular targeted strategy confirmed that DNAM-1 neutralising mAb has potent antifibrotic properties, supporting the hypothesis that inhibition of DNAM-1 might be a promising new approach for the treatment of SSc and potentially other related fibrotic diseases.

Hand and wrist involvement in systemic sclerosis: US features.

PURPOSE To characterize ultrasonographic (US) features in the hand of patients with systemic sclerosis (SSc) and to evaluate the sensitivity of US in the detection of calcinosis and acroosteolysis. MATERIALS AND METHODS The local ethics committee approved this study, and oral informed consent was obtained. A total of 44 consecutive patients with SSc (34 women; mean age, 56.1 years ± 12.1 [standard deviation]; 10 men; mean age, 45.0 years ± 14.0) and 30 healthy control subjects (20 women; mean age, 46.3 years ± 12.1; 10 men; mean age, 39.6 years ± 10.8) were included between October 2010 and December 2011. Bilateral US, including Doppler assessment of the wrists, hands, and fingers, was performed, and presence of synovitis, tenosynovitis with or without a layered appearance, calcifications, acroosteolysis, and distal vascularization was recorded. Radiography of both hands was performed to assess for acroosteolysis and calcinosis. Frequency of US features, sensitivity of US for calcinosis and acroosteolysis, and respective confidence intervals were calculated. RESULTS Synovitis was found in 17 patients (39%). Tenosynovitis was found in 12 patients (27%), and it had a layered pattern in 15 (41%) of 37 cases. Calcinosis was found in 17 patients (39%) with US, with a sensitivity of 89%. Acroosteolysis was found in nine (20%) patients with US and in 10 (23%) patients with radiography, with 90% sensitivity for US. Distal vascularization was detected in 26 patients (59%) and 30 control subjects (100%) and was in contact with the acroosteolysis bed in seven (78%) of nine patients with SSc. CONCLUSION US can be used to assess features of SSc, including synovitis, tenosynovitis, calcinosis, acroosteolysis, and distal vascularization and is sensitive for calcinosis and acroosteolysis detection. A layered pattern (similar to the appearance of an artichoke heart) of tenosynovitis was seen commonly. Online supplemental material is available for this article.

Mapping and predicting mortality from systemic sclerosis

Objectives To determine the causes of death and risk factors in systemic sclerosis (SSc). Methods Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. Results We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. Conclusion Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.