Prevalence and Significance of the Presence of Anti-transglutaminase and Anti-endomysium Antibodies in Patients with Early Inflammatory Joint Disease

Dougados M., Serrand C., Alonso S., Berenbaum F., Claudepierre P., Combe B., Gossec L., Witrand A.R., Saraux A., Wendling D., Querré T.L., Molto A.

This study aimed to evaluate the 10-year clinical outcome of patients with recent-onset axial spondyloarthritis (axSpA). The DESIR cohort is an inception cohort of axSpA patients. The diagnosis and management of patients were based on the decision of the treating rheumatologist. Both complete cases and imputed data analyses were conducted. Of the 708 enrolled patients, 45 were excluded due to a change in the baseline diagnosis, 3 patients died, and 300 were lost to follow-up over the 10 years. In the completer population, one patient required bilateral total hip replacement, and 56 patients received a pension due to invalidity. The prevalence of main extra-musculoskeletal features increased from baseline to year 10: psoriasis from 18% to 30%, acute anterior uveitis from 10% to 18%, and inflammatory bowel disease from 5% to 10%. The most frequent comorbidity was hypertension, with an increase from 5% to 15% from baseline to year 10. In the imputed data analysis the estimated proportions of patients with an acceptable status at year 10 were 70% [95% CI: 63; 77] for acceptable PASS, 43% [95% CI: 37; 49] for BASDAI < 3, and 48% [95% CI: 41; 56] for ASDAS < 2.1. These findings suggest that despite a quite favorable 10-year outcome exists for severe outcomes, a large proportion of patients present with an important disease burden reflected by patient-reported outcomes. This information can be valuable for providing patients with information at the time of diagnosis.

Beydon M., McCoy S., Nguyen Y., Sumida T., Mariette X., Seror R.

Sjögren syndrome is a phenotypically varied autoimmune disorder that can occur alone in primary Sjögren syndrome or in association with other connective tissue diseases (CTDs), including rheumatoid arthritis, systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The estimation of the prevalence and incidence of Sjögren syndrome varies depending on diagnostic criteria and study design, making it difficult to estimate geographical and temporal trends. Nonetheless, disease phenotype is influenced by geographical origin, which is a risk factor for systemic activity. Whether mortality in primary Sjögren syndrome is increased compared with that of the general population is not yet known, but extra-glandular manifestations, in particular lymphomas, are clear risk factors for mortality. In CTDs associated with Sjögren syndrome, lymphoma risk seems higher than that of patients with CTD alone, and there is potentially lower disease activity in SLE with Sjögren syndrome and in SSc with Sjögren syndrome than in SLE or SSc alone. In this epidemiological Review, the authors summarize the available evidence relating to the prevalence, incidence, risk factors and mortality associated with the autoimmune disorder Sjögren syndrome, with or without the co-occurrence of other connective tissue diseases.

Catassi C., Verdu E.F., Bai J.C., Lionetti E.

Coeliac disease is an autoimmune disorder that primarily affects the small intestine, and is caused by the ingestion of gluten in genetically susceptible individuals. Prevalence in the general population ranges from 0·5% to 2%, with an average of about 1%. The development of the coeliac enteropathy depends on a complex immune response to gluten proteins, including both adaptive and innate mechanisms. Clinical presentation of coeliac disease is highly variable and includes classical and non-classical gastrointestinal symptoms, extraintestinal manifestations, and subclinical cases. The disease is associated with a risk of complications, such as osteoporosis and intestinal lymphoma. Diagnosis of coeliac disease requires a positive serology (IgA anti-transglutaminase 2 and anti-endomysial antibodies) and villous atrophy on small-intestinal biopsy. Treatment involves a gluten-free diet; however, owing to the high psychosocial burden of such a diet, research into alternative pharmacological treatments is currently very active.

Naddei R., Di Gennaro S., Guarino A., Troncone R., Alessio M., Discepolo V.

A higher prevalence of celiac disease (CD) has been reported in patients with juvenile idiopathic arthritis (JIA) compared to the general population. Factors related to the increased risk of co-occurrence and associated disease course have not been fully elucidated. Aims of this study were to determine the prevalence of CD in a large Southern Italian cohort of children with JIA, describe their clinical features and disease course and investigate risk factors associated with their co-occurrence. Demographic, clinical and laboratory data of all patients with JIA admitted to our Pediatric Rheumatology Unit from January 2001 to June 2019, who underwent CD screening, were retrospectively extracted from clinical charts and analyzed. Eight of 329 JIA patients were diagnosed with CD, resulting in a prevalence higher than the general Italian population (2.4% vs 0.93%, p < 0.05). Familiarity for autoimmunity was reported by 87.5% patients with JIA and CD compared to 45.8% of those without CD (p < 0.05). 87.5% patients with JIA and CD required both a conventional Disease Modifying Anti-Rheumatic Drug (DMARD) and a biological DMARD over time compared to 36.4% of those without CD (p < 0.05). A higher CD prevalence was found in a large JIA cohort, supporting the need for CD screening in all JIA children, especially those with a family history of autoimmunity, found to be associated with the co-occurrence of the two diseases. This is clinically relevant since patients with CD and JIA more often required a step-up therapy, suggesting a more severe JIA clinical course.

Daien C., Czernichow S., Letarouilly J., Nguyen Y., Sanchez P., Sigaux J., Beauvais C., Desouches S., Le Puillandre R., Rigalleau V., Rivière P., Romon M., Semerano L., Seror R., Sfedj S., et. al.

This article presents the 1st set of dietary recommendations of the French Society for Rheumatology for patients suffering from chronic inflammatory rheumatic diseases (IRD) made by a working group consisting of 12 rheumatology experts, 3 physician nutrition specialists, 1 internal medicine specialist, 1 registered dietician and 3 representatives from patient associations. This group relied on a systematic literature review and on expert opinions, while taking into consideration not only the joint effects of diet in IRD but also the extra-articular ones. Eight general principles and nine recommendations were established. The general principles emphasize that nutritional advice is not a substitute for pharmacological treatment of IRD and that it is an integral part of the patients' overall care, which could help the patient actively participate in their care. The recommendations propose supporting weight loss in subjects who are overweight or obese, a Mediterranean-type diet and supplementation in polyunsaturated fatty acids, mainly omega-3. Conversely, gluten-free diets (in the absence of celiac disease), vegetarian/vegan diets, fasting and elimination of dairy products should not be proposed. Supplementation with vitamins or trace elements is not indicated for controlling chronic IRD activity, while the use of probiotics or spices is not recommended given the limited or disparate data.

Schulz C., Fuehner S., Schlüter B., Fobker M., Sengler C., Klotsche J., Niewerth M., Minden K., Foell D.

An association of different autoimmune diseases is suspected. In juvenile idiopathic arthritis (JIA), only few and partially conflicting data on the co-existence of other autoimmune disorders are available. The prevalence of autoantibodies in patients with JIA in Germany is not known. Samples from 499 patients (median age at time of blood collection 11 years, median disease duration 4.4 years) in the prospective, multicenter inception cohort of children newly diagnosed with JIA (ICON-JIA) were analysed for the presence of anti-thyroid antibodies, celiac disease-specific antibodies (anti-tTG IgA, anti-tTG IgG), and connective tissue disease-associated antibodies (CTD-screen). A total of 76 (15.2%) patients had either clinically diagnosed autoimmune comorbidity or elevated autoantibodies. Of 21 patients with clinical autoimmune comorbidity, only 8 were also serologically positive at the time of testing, while 55 patients had autoantibodies without clinical diagnosis. Thus, 63 patients (12.6%) had at least one elevated autoantibody. Antibodies against thyroglobulin were found in 3% and against thyreoperoxidase in 4% of the samples. TSH receptor antibodies could not be detected in any of the 499 patients. Tissue transglutaminase antibodies were elevated in 0.4% of the patients. A positive screen for CTD-specific antinuclear antibodies was found in 7%, but only rarely specific antibodies (anti-dsDNA 1.4%, anti-SS-A and -SS-B 0.2% each, anti-CENP-B 0.4%) were confirmed. In our study, a specific correlation between JIA and other autoimmune phenomena could not be confirmed. The lack of well-matched control groups makes interpretation challenging. Further data need to corroborate the suspected increased risk of developing other autoimmune phenomena in JIA patients.

Combe B., Rincheval N., Berenbaum F., Boumier P., Cantagrel A., Dieude P., Dougados M., Fautrel B., Flipo R., Goupille P., Mariette X., Saraux A., Schaeverbeke T., Sibilia J., Vittecoq O., et. al.

Abstract Objective To report the 10-year outcome of an inception cohort of patients with early rheumatoid arthritis (RA), the ESPOIR cohort, and predictors of outcome. Methods From 2003 to 2005, 813 patients were included if they had early arthritis (&lt;6 months) with a high probability of RA and had never been prescribed DMARDs. Multivariate analysis was used to evaluate predictors of outcome. Results In total, 521 (64.1%) RA patients were followed up for 10 years; 35 (4.3%) died, which appears to be similar to the French general population. Overall, 480 (92.1%) patients received a DMARD; 174 (33.4%) received at least one biologic DMARD, 13.6% within 2 years. At year 10, 273 (52.4%) patients were in DAS28 remission, 40.1% in sustained remission, 14.1% in drug-free remission, 39.7% in CDAI remission. Half of the patients achieved a health assessment questionnaire-disability index (HAQ-DI) &lt; 0.5. SF-36 physical component and pain were well controlled. Structural progression was weak, with a mean change from baseline in modified Sharp score of 11.0  (17.9). Only 34 (6.5%) patients required major joint surgery. A substantial number of patients showed new comorbidities over 10 years. Positivity for anti-citrullinated peptides antibodies (ACPA) was confirmed as a robust predictor of long-term outcome. Conclusions We report a very mild 10-year outcome of a large cohort of patients with early RA diagnosed in the early 2000s, which was much better than results for a previous cohort of patients who were recruited in 1993. This current favourable outcome may be related to more intensive care for real-life patients.

Smolen J.S., Aletaha D., McInnes I.B.

Rheumatoid arthritis is a chronic inflammatory joint disease, which can cause cartilage and bone damage as well as disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use of conventional, biological, and newz non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favourable, many still do not respond to current therapies. Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with unmet needs of patients with rheumatoid arthritis.

Lerner A., Matthias T.

Rheumatoid arthritis (RA) and celiac disease (CD) belong to the autoimmune disease family. Despite being separate entities they share multiple aspects. Epidemiologically they share comparable incidence environmental influences, associated antibodies and a recent incidental surge. They differ in their HLA pre-dispositions and specific predictive and diagnostic biomarkers. At the clinical level, celiac disease exhibits extra-intestinal rheumatic manifestations and RA gastrointestinal ones. Small bowel pathology exists in rheumatic patients. A trend towards responsiveness to a gluten free diet has been observed, ameliorating celiac rheumatic manifestations, whereas dietary interventions for rheumatoid arthritis remain controversial. Pathophysiologically, both diseases are mediated by endogenous enzymes in the target organs. The infectious, dysbiotic and increased intestinal permeability theories, as drivers of the autoimmune cascade, apply to both diseases. Contrary to their specific HLA pre-disposition, the diseases share multiple non-HLA loci. Those genes are crucial for activation and regulation of adaptive and innate immunity. Recently, light was shed on the interaction between host genetics and microbiota composition in relation to CD and RA susceptibility, connecting bugs and us and autoimmunity. A better understanding of the above mentioned similarities in the gut-joint inter-relationship, may elucidate additional facets in the mosaic of autoimmunity, relating CD to RA.

Iqbal T., Zaidi M.A., Wells G.A., Karsh J.

Background and Aim To evaluate presence of sero-negative spondyloarthritis (SpA) in celiac disease (CD) patients, and whether compliance with a gluten free diet (GFD) improved arthritis manifestations in these patients. Methods We undertook a prospective, questionnaire based, cross-sectional cohort study to evaluate the presence or absence of SpA simultaneously in both CD and non-CD cohorts. Results 356/590 (60.3%) patients with CD participated in this study. 99% had diagnosis confirmed by a diagnostic test (79% small bowel biopsy, 19.8% blood test, 3.9% stool test). Approximately 131 (37%) cases of arthritis were reported in CD patients. Of the 6/356 CD patients with seronegative spondyloarthritides, four had sacroiliitis, two ankylosing spondylitis, and one psoriatic arthritis, compared to one ankylosing spondylitis and five psoriatic arthritis in non-CD. Osteoarthritis (89 vs 59, P = 0.93) was the most common diagnosis reported by respondents. More CD patients with diarrhea (94%) and anemia (81%) improved on GFD, compared to arthritis symptoms (30%). Autoimmune thyroiditis (10.6% vs 0.4%), insulin dependent diabetes mellitus (IDDM) (2.2% vs 1.7%), systemic Lupus erythematosus (SLE) (1.1% vs 0), and psoriasis (12.9% vs 5.5%) occurred more frequently in CD patients. The prevalence of Crohn's disease, ulcerative colitis, Sjogren's syndrome, primary biliary cirrhosis, and primary sclerosing cholangitis was around 1% each. Univariate Logistic regression analysis showed ≤ high school education (odds ratio [OR] 2.01, P < 0.003), age ≥ 60 years (OR 4.13, P < 0.001), and osteoporosis (OR 2.78, P < 0.001) to be significantly associated with report of arthritis in CD patients. Conclusion We did not find a high rate of SpA in CD patients. In contrast, increased rates of autoimmune thyroiditis, SLE, IDDM, and psoriasis were seen in CD.

Stolwijk C., Boonen A., van Tubergen A., Reveille J.D.

Spondyloarthritis (SpA) represents a group of interrelated diseases with common clinical features and a close association with HLA-B27. Reports of incidence and prevalence of diseases vary depending on methodological differences between studies, the case definition used to classify disease, and the prevalence of HLA-B27 in the population studied. Newly proposed criteria for axial SpA and peripheral SpA present a new approach to facilitate classification of the SpA into 2 main subtypes and the criteria allow earlier detection of patents with inflammatory back pain. These criteria were developed for use in a (specialized) clinical setting and not for large epidemiologic studies.

Dougados M., Baeten D.

Spondyloarthritis is a group of several related but phenotypically distinct disorders: psoriatic arthritis, arthritis related to inflammatory bowel disease, reactive arthritis, a subgroup of juvenile idiopathic arthritis, and ankylosing spondylitis (the prototypic and best studied subtype). The past decade yielded major advances in the recognition of spondyloarthritis as an entity, the classification of the disease, and understanding of the genetic and pathophysiological mechanisms of disease-related inflammation and tissue damage. In parallel, new clinical and imaging outcomes have allowed the assessment of various therapeutic modalities. Blockers of tumour necrosis factor are a major therapeutic advance, but the exact roles of physiotherapy, and treatment with non-steroidal anti-inflammatory drugs and other biological treatments are unknown. The major challenges with direct relevance for clinical practice for the next decade are the development of techniques for early diagnosis, therapeutic modulation of structural damage, and, ultimately, induction of long-term, drug-free remission.

Lindqvist U., Rudsander Å., Boström Å., Nilsson B., Michaëlsson G.

To find out whether patients with psoriatic arthritis (PsoA) have an increased prevalence of antibodies to gliadin (AGA) and of coeliac disease.One hundred and fourteen PsoA patients with skin disease of 20+/-13 yr and joint disease of 11+/-10 yr duration answered a questionnaire concerning their medical history and underwent clinical examination, including radiology. Serum IgA AGA and IgG AGA, IgA antibodies to endomysium and immunoglobulins, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration were determined.Five of the 114 patients (4.4%) had coeliac disease. After exclusion of these five patients, the mean IgA AGA concentration was significantly higher (P=0.0005) than that in a reference group. None of the patients had IgA antibodies to endomysium. The mean serum IgA concentration was significantly increased and IgM decreased. Patients with a high concentration of IgA AGA had significantly higher ESR and CRP and a longer duration of morning stiffness than those with a low AGA concentration.Patients with PsoA have an increased prevalence of raised serum IgA AGA and of coeliac disease. Patients with raised IgA AGA seem to have more pronounced inflammation than those with a low IgA AGA concentration.