Disease progression in relation to pre-onset parity among women with rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) often ameliorates during pregnancy and flares postpartum, but the relationship of pregnancy and childbirth to RA prognosis is unclear. We examined RA severity for association with parity prior to RA onset and asked whether time from birth (latency) and/or the mother's HLA genotype influenced results. METHODS: A cohort study was conducted of 222 women previously identified in a prospective study of newly diagnosed RA, who returned for follow-up evaluation a median of 8 years later. Stratified analyses using Mantel-Haenszel methods were conducted to evaluate 5 RA severity measures based on hand and wrist radiographs, physical exams, and Health Assessment Questionnaires for association with parity. RESULTS: Overall, we observed little evidence of altered risk of progression to severe RA in relation to pre-onset parity, adjusting for RA onset age and time to follow-up. Stratifying parous women who had only live births by latency (<15 years/15+ years) showed no difference in risk of severe RA compared to nulligravid women. Live birth deliveries were significantly protective for women with 0 but not for those with 1 or 2 copies of the RA risk-associated HLA-DRB1 shared epitope sequence for erosion score (RR 0.26 95% CI 0.09-0.89) and joint count (RR 0.28 95% CI 0.09-0.87). CONCLUSION: We observed little evidence of difference in severe RA by pre-onset parity overall. However, among women not predisposed to RA by possessing the risk-associated HLA genotype, parous women who had only live births had lower risk of progression to severe RA as measured by erosion score and joint count.

Adverse pregnancy outcomes and risk of subsequent rheumatoid arthritis.

OBJECTIVE: Pregnancy and reproductive outcomes have been associated with altered risk of some autoimmune diseases, including rheumatoid arthritis (RA). We sought to determine whether prior pregnancy resulting in a low birth weight (LBW) infant or preterm birth is associated with a risk of subsequent RA in the mother. METHODS: We conducted an analysis of RA risk in parous women from a population-based prospective study of newly diagnosed cases of RA and age-matched healthy controls. The primary outcome measure was disease status (RA versus control), with exposures of prior preterm birth and prior delivery of an infant with LBW (≤2,500 gm), very low birth weight (VLBW; ≤1,500 gm), or extremely low birth weight (ELBW; ≤1,000 gm). A preplanned analysis including only rheumatoid factor (RF)-positive RA cases was also conducted. RESULTS: A total of 202 RA cases and 1,102 controls were analyzed. Prior delivery of an infant with ELBW was associated with RA in the mother (relative risk [RR] 3.7 [95% confidence interval (95% CI) 1.0-13.2]). Prior VLBW (RR 4.0 [95% CI 1.3-11.4]) and ELBW (RR 5.5 [95% CI 1.4-22.5]) infants were associated with RF-positive RA. Prior LBW deliveries and preterm births were more common among RA cases than controls, but the differences were not statistically significant. CONCLUSION: Compared to those with uncomplicated pregnancies, women with a prior VLBW or ELBW delivery had a higher risk of RA, particularly RF-positive RA. This association may reflect common risk factors for pregnancy complications and RA. Alternatively, complicated pregnancy itself may confer risk of subsequent RA.

A multi-centre, blinded, randomised, placebo-controlled, laboratory-based study of MQX-503, a novel topical gel formulation of nitroglycerine, in patients with Raynaud phenomenon.

OBJECTIVE: MQX-503 is a novel nitroglycerine preparation designed to absorb quickly and allow local vasodilatation in the skin. We examined the efficacy and tolerability of this medication in Raynaud phenomenon (RP) in a laboratory-based study. METHODS: In this multi-centre, double-blind, randomised, placebo-controlled, cross-over study, subjects were treated with 0.5% or 1.25% nitroglycerine or placebo gel. Subjects received each dose twice in a randomised order. Each study session consisted of baseline laser Doppler measurements, study gel application and 5 min of cold chamber exposure (-20°C). Blood flow (BF) was measured at the end of exposure and for the next 120 min at set intervals. Other outcome measures included achievement of baseline BF; the time to achieve 50% and 70% baseline skin temperature (ST); and pain, tingling and numbness scores. RESULTS: 37 subjects completed 214 treatment periods. Time to achieve baseline BF was significantly shorter in the two treated groups (HR=1.77 and 2.02 for 0.5% and 1.25% vs placebo, respectively). The proportion of subjects achieving baseline BF was 45.8% for placebo, 66.2% for 0.5% and 69% for 1.25% (p=0.01 and p=0.002 for 0.5% and 1.25% vs placebo, respectively). No meaningful differences were seen in ST or pain/numbness/tingling scores. Treatment was well tolerated with no serious adverse events. CONCLUSIONS: Treatment with MQX-503 caused a significant improvement in skin BF compared with placebo. Data from this proof of concept study suggest benefit of MQX-503 in subjects with RP.

Parity and HLA alleles in risk of rheumatoid arthritis.

Specific HLA II alleles are associated with rheumatoid arthritis (RA) risk and others with protection. Risk-associated alleles encode similar amino acid sequences from 70 through 74 of HLA-DRß1 (QKRAA, QRRAA, RRRAA), referred to as the "shared epitope" (SE) and protective alleles encode DERAA at the same location. Fetal-maternal cell exchange results in long-term microchimerism i.e. harboring small numbers of genetically disparate cells. Women with RA who lack the SE were recently found to harbor microchimerism with the SE more often than healthy women. This finding raises the question whether microchimerism with DERAA confers benefit against RA and is underscored by the observation that overall parity reduces RA risk. While there is currently no test for microchimerism with DERAA, we conducted studies to ask whether parity benefits women at risk for RA, either because they have the SE or lack the protective DERAA sequence. HLA genotyping was conducted for 310 RA and 571 healthy women. Parity was associated with reduced RA risk in women aged <45 years (RR 0.53, 95% CI 0.34-0.82) and further analyses examined this group. RA risk reduction with parity was greater among women with the SE than SE-negative women (RR 0.42, 95%CI 0.22-0.79 vs. RR 0.79, 0.38-1.64). Among women without DERAA, RA risk was significantly reduced with parity (RR 0.44, 95% CI 0.26-0.74) but not among DERAA-positive women (RR 0.95 95% CI 0.34-2.65). In summary, results indicate the effect of parity varied according to a woman's HLA-genotype, and women at increased risk of RA benefited most.

Does pregnancy provide vaccine-like protection against rheumatoid arthritis?

OBJECTIVE: Previous studies have evaluated the correlation between rheumatoid arthritis (RA) risk and pregnancy history, with conflicting results. Fetal cells acquired during pregnancy provide a potential explanation for modulation of RA risk by pregnancy. The present study was undertaken to examine the effect of parity on RA risk. METHODS: We examined parity and RA risk using results from a population-based prospective study in Seattle, Washington and the surrounding area and compared women who were recently diagnosed as having RA (n = 310) with controls (n = 1,418). We also evaluated the distribution of parity in cases according to HLA genotype. RESULTS: We found a significant reduction of RA risk associated with parity (relative risk [RR] 0.61 [95% confidence interval 0.43-0.86], P = 0.005). RA risk reduction in parous women was strongest among those who were younger. Most striking was that RA risk reduction correlated with the time that had elapsed since the last time a woman had given birth. RA risk was lowest among women whose last birth occurred 1-5 years previously (RR 0.29), with risk reduction lessening progressively as the time since the last birth increased (for those 5-15 years since last birth, RR 0.51; for those >15 years, RR 0.76), compared with nulliparous women (P for trend = 0.007). No correlation was observed between RA risk and either age at the time a woman first gave birth or a woman's total number of births. Among cases with the highest genetic risk of RA (i.e., those with 2 copies of RA-associated HLA alleles), a significant underrepresentation of parous women versus nulliparous women was observed (P = 0.02). CONCLUSION: In the present study, there was a significantly lower risk of RA in parous women that was strongly correlated with the time elapsed since a woman had last given birth. While the explanation for our findings is not known, HLA-disparate fetal microchimerism can persist many years after a birth and could confer temporary protection against RA.

Nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs, including COX-2 selective drugs, are often used for acute and chronic musculoskeletal pain,including osteoarthritis, trauma, overuse syndromes, and compression fractures. Although these medications are often well tolerated in the young and otherwise healthy patient, the chronic use of these medications can lead to multiple medical problems, most commonly related to the gastrointestinal tract. Recently, concerns about cardiovascular adverse effects have been raised, particularly in the COX-2 drugs. Dosing and duration of therapy should be adjusted for comorbidities. CBC and renal and hepatic function should be checked at intervals of 3 to 6 months, depending on the patient.