Michael H. Weisman

X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome.

More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female‐predominant diseases (systemic lupus erythematosus [SLE], primary Sjögrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls.

Omega-3 fatty acids are associated with a lower prevalence of autoantibodies in shared epitope-positive subjects at risk for rheumatoid arthritis

Objectives Previously, we found that omega-3 fatty acids (n-3 FAs) were inversely associated with anti-cyclic citrullinated peptide (anti-CCP) positivity in participants at risk for future rheumatoid arthritis (RA). We investigated whether n-3 FAs were also associated with rheumatoid factor (RF) positivity and whether these associations were modified by shared epitope (SE) positivity. Methods The Studies of the Etiology of RA (SERA) cohort includes RA-free participants who are at increased risk for RA. We conducted a nested case–control study (n=136) to determine the association between RF and anti-CCP2 positivity and n-3 FA percentage in erythrocyte membranes (n-3 FA% in red blood cells (RBCs)). Additionally, in the baseline visit of the SERA cohort (n=2166), we evaluated the association between reported n-3 FA supplement use and prevalence of RF and anti-CCP2. We assessed SE positivity as an effect modifier. Results In the case–control study, increasing n-3 FA% in RBCs was inversely associated with RF positivity in SE-positive participants (OR 0.27, 95% CI 0.10 to 0.79), but not SE-negative participants. Similar associations were seen with anti-CCP positivity in SE-positive participants (OR 0.42, 95% CI 0.20 to 0.89), but not SE-negative participants. In the SERA cohort at baseline, n-3 FA supplement use was associated with a lower prevalence of RF positivity in SE-positive participants (OR 0.32, 95% CI 0.12 to 0.82), but not SE-negative participants; similar but non-significant trends were observed with anti-CCP2. Conclusions The potential protective effect of n-3 FAs on RA-related autoimmunity may be most pronounced in those who exhibit HLA class II genetic susceptibility to RA.

Combined role of vitamin D status and CYP24A1 in the transition to systemic lupus erythematosus

Objective We examined whether measures of vitamin D were associated with transitioning to systemic lupus erythematosus (SLE) in individuals at risk for SLE. Methods 436 individuals who reported having a relative with SLE but who did not have SLE themselves were evaluated at baseline and again an average of 6.3 (±3.9) years later. Fifty-six individuals transitioned to SLE (≥4 cumulative American College of Rheumatology criteria). 25-Hydroxyvitamin D (25[OH]D) levels were measured by ELISA. Six single-nucleotide polymorphisms in four vitamin D genes were genotyped. Generalised estimating equations, adjusting for correlation within families, were used to test associations between the vitamin D variables and the outcome of transitioning to SLE. Results Mean baseline 25[OH]D levels (p=0.42) and vitamin D supplementation (p=0.65) were not different between those who did and did not transition to SLE. Vitamin D deficiency (25[OH]D <20 ng/mL) was greater in those who transitioned compared with those who did not transition to SLE (46% vs 33%, p=0.05). The association between 25[OH]D and SLE was modified by CYP24A1 rs4809959, where for each additional minor allele increased 25[OH]D was associated with decreased SLE risk: zero minor alleles (adjusted OR: 1.03, CI 0.98 to 1.09), one minor allele (adjusted OR: 1.01, CI 0.97 to 1.05) and two minor alleles (adjusted OR: 0.91, CI 0.84 to 0.98). Similarly, vitamin D deficiency significantly increased the risk of transitioning to SLE in those with two minor alleles at rs4809959 (adjusted OR: 4.90, CI 1.33 to 18.04). Conclusions Vitamin D status and CYP24A1 may have a combined role in the transition to SLE in individuals at increased genetic risk for SLE.

Previous diagnosis of Sjögren's Syndrome as rheumatoid arthritis or systemic lupus erythematosus

OBJECTIVE The diagnosis of SS is often difficult and many patients are symptomatic for years with other diagnoses before confirmation of SS. Our aim was to determine whether overlapping clinical and serologic features with RA and SLE may in part drive the misdiagnoses. METHODS A total of 1175 sicca patients were evaluated in a multidisciplinary clinic and classified as having SS based on the American-European Consensus Group Criteria. They were interrogated for a past history of suspicion or diagnosis of RA, SLE or SSc. These diseases were confirmed or ruled out by applying the corresponding classification criteria if the patients responded affirmatively. RESULTS Of these, 524 (44.6%) subjects reported previous diagnosis or suspicion of RA, SLE or SSc, which was confirmed in 130 (24.8%) but excluded in 394 (75.2%) subjects. Of those previously diagnosed with another illness, 183 (34.9%) met the criteria for primary SS. RF was present in 70/191 patients with previous diagnosis of RA compared with 445/845 without a prior RA diagnosis (P = 3.38E-05), while 128/146 with a diagnosis of SLE had positive ANA compared with 622/881 without the diagnosis (P = 8.77E-06). Age also influenced former diagnoses: people with suspected RA were older than those without the diagnosis (P = 5.89E-06), while patients with SLE suspicion were younger (P = 0.0003). Interestingly, the previous diagnoses did not significantly delay a final classification of SS. CONCLUSION Among subjects classified as SS, the presence of a positive ANA or RF was associated with a previous, apparently erroneous diagnosis of SLE or RA, respectively.

Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome

Primary Sjögrens syndrome (pSS) has a strong female bias. We evaluated an X chromosome dose effect by analyzing 47,XXY (Klinefelters syndrome, 1 in 500 live male births) among subjects with pSS. 47,XXY was determined by examination of fluorescence intensity of single nucleotide polymorphisms from the X and Y chromosomes. Among 136 pSS men there were 4 with 47,XXY. This was significantly different from healthy controls (1 of 1254 had 47,XXY, p=0.0012 by Fishers exact test) as well men with rheumatoid arthritis (0 of 363 with 47,XXY), but not different compared to men with systemic lupus erythematosus (SLE) (4 of 136 versus 8 of 306, Fishers exact test p=NS). These results are consistent with the hypothesis that the number of X chromosomes is critical for the female bias of pSS, a property that may be shared with SLE but not RA.

Associations of Smoking and Age With Inflammatory Joint Signs Among Unaffected First-Degree Relatives of Rheumatoid Arthritis Patients: Results From Studies of the Etiology of Rheumatoid Arthritis.

To examine whether genetic, environmental, and serologic rheumatoid arthritis (RA) risk factors are associated with inflammatory joint signs in a cohort of first‐degree relatives (FDRs) of RA patients.

Brief Report: Patients With Primary Sjögren's Syndrome Who Are Positive for Autoantibodies to Tripartite Motif-Containing Protein 38 Show Greater Disease Severity.

Autoantibodies reactive with Ro52 (tripartite motif−containing protein 21 [TRIM21]) are detected in 70% of patients with primary Sjögrens syndrome (SS). TRIM21 belongs to a 34‐member C‐IV family of TRIM proteins. Although autoantibodies against other TRIM proteins within the C‐IV family have been detected in the sera of patients with primary SS, their clinical relevance remains unclear. This study was undertaken to investigate the frequency of anti‐TRIM38 in patients with primary SS and evaluate its association with various clinical measures of the disease.

Infection, malignancy, switching, biosimilars, antibody formation, drug survival and withdrawal, and dose reduction: what have we learned over the last year about tumor necrosis factor inhibitors in rheumatoid arthritis?

Purpose of reviewThis article reviews the most current studies investigating the use of tumor necrosis factor inhibitors (TNFis) in the treatment of rheumatoid arthritis. Recent findingsStudies over the past year have clarified that suppressing TNF with monoclonal antibodies does increase infection risk, yet coupled with reduction in disease activity and less use of corticosteroids as a consequence, the overall risk to the population is balanced. With caution (provided by some recent studies) TNFi agents can be reduced (dosage intervals lengthened) and maintain benefit. Biosimilars, not surprisingly, are going to be therapeutically identical to the innovator, and not more of a risk for causing antibodies to interfere with benefit. Uncertainty remains about when and how to make the switch. SummaryTNFi agents have made their powerful impact on management of patients with rheumatoid arthritis, but questions remain: what is their true infection and malignancy risk in the evolving populations using these drugs today; are we able to maintain their benefit with a reduced schedule (and presumed less cost) and yet recapture their benefit if we guess wrong; are biosimilars just as good, or even better with less cost; are there data to inform us about how to achieve successful switching among different mechanism of action TNFi agents? Finally, are we going to face the specter of cost containment causing change from innovator to biosimilars over which we have no control?

Trends in functional disability and determinants of clinically meaningful change over time in Hispanics with Rheumatoid arthritis in the United States

To identify determinants of clinically meaningful change in functional disability in low‐income Hispanic patients with established rheumatoid arthritis (RA) in the US.

Patient-Reported Outcomes in Rheumatic Diseases

Barton and Katz have assembled an issue that will be a standard reference for the near future. Their experts show clearly the value of patient-reported outcomes (PROs) in SLE precisely because the disease is extraordinarily complex, and hence, patient input is especially relevant. Similar issues are in play for psoriatic arthritis, since what patients think is important may vary widely from physician assessment. Nowhere could the impact of disease be more potentially devastating than in systemic sclerosis, where patient experience must be paramount. Juvenile arthritis is a special case because of the need to understand the patients, parents, and parent-proxy perspective approach to appraisals of health care decision-making. A very thoughtful article describing the issues of literacy and English proficiency on health outcomes gives some important insights into the challenges of health care disparities. The impact of patient-reported outcomes in the arena of quality assessment is discussed, keeping in mind the challenges posed in the United States by the variability of information technology infrastructures and the diversity of our patient populations. Clearly, the burden of fibromyalgia and knee OA are best captured by PROs, and for rheumatoid arthritis, the PRO has had an almost unchallenged high-ranking status as a meaningful assessment of the impact of this disease. In recent years, PROs are becoming an important aspect of axial spondyloarthritis following the lead of our European colleagues, who have used quite rigorous methodologies to categorize the patient experience with this common chronic disease. PROMIS, or patient-reported outcomes measurement information system, standardizes the collection of universally relevant domains of health and disease into one instrument that can capture outcomes across diseases and clinical settings—a major research advance that is bearing fruit as we speak.