Lack of Interferon and Proinflammatory Cyto/chemokines in Serologically Active Clinically Quiescent Systemic Lupus Erythematosus.

OBJECTIVE: Serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE) remain clinically quiescent for prolonged periods despite anti-dsDNA antibodies and/or low complements, indicating the presence of immune complexes. The immune mechanisms leading to this quiescence are unknown. However, in addition to activating complement, immune complex uptake by various cells leads to the production of interferon (IFN)-α and other proinflammatory factors that are also involved in tissue damage. Here we investigate whether production of these factors is reduced in SACQ patients. METHODS: The levels of 5 IFN-induced genes and 19 cyto/chemokines were measured in SACQ patients and were compared with those in serologically and clinically active (SACA) and serologically and clinically quiescent (SQCQ) patients. SACQ and SQCQ were defined as ≥ 2 years without clinical activity, with/without persistent serologic activity, respectively, and off corticosteroids/immunosuppressives. SACA was defined as disease activity compelling immunosuppression. Levels of OAS1, IFIT1, MX1, LY6E, and ISG15 were measured by quantitative real-time polymerase chain reaction (PCR) and a composite score (IFN-5) derived from this. Plasma cyto/chemokines were measured by Luminex assay. Nonparametric univariate and logistic regression analyses were conducted. RESULTS: There were no differences in gene expression or cyto/chemokine levels between SACQ and SQCQ patients. The SACQ IFN-5 score was significantly lower than that of SACA (p = 0.003) and was driven by SACQ status, not by autoantibody profile or disease duration. Levels of granulocyte-macrophage colony-stimulating factor, interleukin (IL) 6, IL-10, IFN-γ-inducible protein 10, monocyte chemoattractant protein 1, and tumor necrosis factor-α were significantly lower in SACQ than SACA. CONCLUSION: The levels of proinflammatory factors in SACQ mirror those of SQCQ patients, indicating reduced production of these factors despite the presence of immune complexes.

Anti-dsDNA and Antichromatin Antibody Isotypes in Serologically Active Clinically Quiescent Systemic Lupus Erythematosus.

OBJECTIVE: Serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE) are clinically quiescent despite serologic activity. Since studies suggest that antichromatin antibodies are more sensitive than anti-dsDNA antibodies in detecting active SLE, and that immunoglobulin (Ig) G, in particular complement-fixing subclasses, may be more pathogenic than IgM, we investigated the levels of anti-dsDNA and antichromatin isotypes in SACQ patients as compared to non-SACQ patients with SLE. METHODS: Levels of IgM, IgA, IgG, and IgG1-4 antichromatin and anti-dsDNA were measured by ELISA. SACQ was defined as ≥ 2 years with the SLE Disease Activity Index 2000 (SLEDAI-2K) at 2 or 4 from serologic activity, during which patients could be taking antimalarials, but not corticosteroids or immunosuppressives. Unselected non-SACQ patients with SLE were used as comparators. SACQ patient serum samples were further stratified based on subsequent development of flare, defined as clinical SLEDAI-2K ≥ 1 and/or treatment initiation. Nonparametric statistics were used, and generalized estimating equations were applied to account for multiple samples in the same patient. RESULTS: SACQ patients' complement-fixing antichromatin and anti-dsDNA IgG subclasses were significantly higher than those of non-SACQ patients. When the sample drawn latest in a SACQ period was analyzed, there was no difference between antichromatin or anti-dsDNA isotype or IgG subclass levels between patients who flared and those who remained SACQ, nor were consistent trends seen when samples were examined during SACQ and flare in the same patient. CONCLUSION: The SACQ phenotype does not arise from a lack of pathogenic anti-dsDNA and/or antichromatin autoantibodies. Neither increases in antichromatin nor anti-dsDNA isotype or IgG subclass levels were predictive of or coincident with flare in SACQ patients.

Prolonged clinical remission in patients with systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is typically a relapsing/remitting disease. However, some patients experience prolonged remission. These patients may provide further insights into SLE pathophysiology. In this study we characterize their clinical course. METHODS: Prolonged remission was defined as Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) = 0, = 2, or = 4 (based on serology) for ≥ 5 consecutive years, with visits ≤ 18 months apart. The patients could be taking antimalarials, but not corticosteroids or immunosuppressives. Flare was defined as clinical activity on SLEDAI-2K, or by corticosteroid/immunosuppressive initiation. Each patient's preremission course was classified as monophasic, relapsing/remitting, or chronic active. These patients were compared to matched SLE controls and patients achieving remission on medications. RESULTS: A total of 38/1613 (2.4%) patients achieved prolonged remission while taking no medications. The mean duration was 11.5 ± 6.4 years. Twenty-seven patients (71.0%) had relapsing/remitting disease, 11 (28.9%) had monophasic illness, and none had chronic active disease prior to remission. They differed from matched controls in ethnicity, disease activity at first visit, and cumulative organ damage. There were 34/1613 patients (2.1%) who achieved prolonged remission while taking steroids and/or immunosuppressives, with mean duration 8.5 ± 2.9 years. Twelve patients (35.3%) experienced disease flare. They were younger at diagnosis, with more disease activity prior to remission than patients taking no medications. CONCLUSION: Prolonged remission is an infrequent outcome among patients and is preceded by an atypically monophasic clinical course in a significant minority. Those taking medications represent a heterogeneous group: those who will tolerate eventual taper, and those whose disease activity was merely suppressed by ongoing immunosuppression. Prolonged remission may reflect unique pathophysiologic mechanisms, and warrants further investigation.

Non-biologic disease-modifying antirheumatic drugs (DMARDs) improve pain in inflammatory arthritis (IA): a systematic literature review of randomized controlled trials.

Evidence supports early use of non-biologic DMARDs to prevent irreversible damage in inflammatory arthritides, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and possibly ankylosing spondylitis (AS). However, there is a paucity of data exploring their effects on pain as a primary outcome in these conditions. This systematic literature review investigated the effect of non-biologic DMARDs on pain levels in IA and examined whether disease duration impacted efficacy. We searched Medline, Embase, Cochrane Central, and Cochrane Database of Systematic Reviews, abstracts from the 2008 to 2010 American College of Rheumatology annual congresses, and citation lists of retrieved publications. Only randomized, double-blind controlled trials were analyzed. Quality was assessed with the Risk of Bias tool. Descriptive statistics were used in meta-analysis. 9,860 articles were identified, with 33 eligible for inclusion: 8 in AS, 6 in PsA, 9 in early RA (ERA), and 10 in established RA. In ERA and established RA, all studies of DMARDs (monotherapy and combination therapies) consistently revealed statistically significant reductions in pain except three oral gold studies. In AS, sulfasalazine studies showed significant pain reduction, whereas use of other DMARDs did not. In PsA, 5 of 6 studies reported VAS-pain improvement. From the studies included, we were unable to assess the influence of disease duration on pain outcomes in these rheumatic conditions. DMARDs improve pain in early and established RA. Sulfasalazine may improve pain in AS and PsA. Further study is needed to assess the relationship between disease duration and DMARD efficacy in reducing pain in these conditions.

Outcomes in patients with systemic lupus erythematosus with and without a prolonged serologically active clinically quiescent period.

OBJECTIVE: Serologically active clinically quiescent (SACQ) systemic lupus erythematosus (SLE) patients' discordance presents a clinical dilemma. Does active serology alone warrant treatment? We explore outcomes in patients with and without a prolonged SACQ period, comparing the rate of damage accrual by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) and incidences of renal damage and coronary artery disease (CAD) over a decade. METHODS: SACQ was defined as a ≥2-year sustained period without clinical activity, with persistent serologic activity (increased anti-double-stranded DNA and/or hypocomplementemia). Antimalarials were permissible and corticosteroids/immunosuppressives were not. The SACQ patients were matched for relevant variables with SLE controls. Change in the SDI and incidences of CAD and renal damage were compared. Descriptive statistics were used; comparisons were made using t-tests and McNemar's tests. RESULTS: Fifty-five SACQ patients and 110 controls were identified. The mean ± SD SDI score at 3 years from the start of the SACQ period was 0.70 ± 1.27 in the SACQ patients versus 1.13 ± 1.54 in controls (P < 0.0001), and by 10 years was 1.26 ± 1.68 versus 2.26 ± 2.23 (P = 0.001); the intergroup difference in damage significantly increased over 10 years. Initially, 2 (3.6%) of the SACQ patients had CAD versus 7 (6.4%) of the controls (P = 0.32), with 1 (1.8%) new case in SACQ patients versus 8 (7.3%) new cases in controls over 10 years (P = 0.06). Baseline serum creatinine level did not differ between the groups. By definition, the SACQ patients had no baseline proteinuria versus 13 (12.3%) of the controls (P < 0.0001). By year 10, 2 (3.6%) SACQ patients versus 26 (23.6%) controls had renal damage (P < 0.0001). CONCLUSION: Patients with a prolonged SACQ period accrued less damage over a decade compared to matched controls, supporting management with active surveillance without treatment during an SACQ period.

Prolonged serologically active clinically quiescent systemic lupus erythematosus: frequency and outcome.

OBJECTIVE: Some patients with systemic lupus erythematosus (SLE) are clinically quiescent despite persistent serologic activity. We determined the frequency of serologically active clinically quiescent (SACQ) SLE and its outcomes in prospectively followed patients with SLE. METHODS: Patients with SLE followed between July 1970 and April 2008 with visits < or = 18 months apart were identified. SACQ was defined as a > or = 2-year sustained period without clinical activity with persistent serologic activity (increased anti-dsDNA and/or hypocomplementemia), during which antimalarials but neither steroids nor immunosuppressives were permissible. Characteristics of patients with an SACQ period and its features were analyzed. To determine flare predictors, anti-dsDNA and complement levels in SACQ patients who experienced flare were compared to levels in those who did not. Descriptive statistics were used; comparisons were made using t tests and chi-squared tests. RESULTS: Of the patients studied, 56/924 (6.1%) were SACQ. They differed significantly from the non-SACQ SLE population only in the presenting SLE Disease Activity Index 2000 (7.34 vs 10.1 in non-SACQ), and frequency of steroid use (33.9% vs 60.8% in non-SACQ) and immunosuppressive use (3.6% vs 19.4% in non-SACQ) at first visit. Median SACQ period was 158 weeks. Thirty-three (58.9%) patients who were SACQ experienced flare (at median 155 weeks), 6 (10.7%) became clinically and serologically quiescent (236 weeks), and 17 continued to be SACQ (159 weeks). Common flare manifestations were arthritis, mucous membrane involvement, and sterile pyuria. Fluctuations in anti-dsDNA or complement levels did not predict flare. CONCLUSION: Fifty-nine percent of SACQ patients experienced flare, but after a median of 3 years. Fluctuations in complement and anti-dsDNA levels did not predict flare, thus treatment decisions in these patients must rely upon close clinical observation. Alternative predictive biomarkers warrant study.