Leroy R Lard

Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies

PURPOSE To compare the effect of delayed and early treatment strategies on disease outcome in patients with rheumatoid arthritis. SUBJECTS AND METHODS Between 1993 and 1995, 109 patients diagnosed with probable or definite rheumatoid arthritis of recent onset were initially treated with analgesics; if they had persistent active disease, they were treated subsequently with the disease-modifying drugs chloroquine or salazopyrine (delayed treatment). Between 1996 and 1998, similar patients (n = 97) were promptly treated with either chloroquine or salazopyrine (early treatment). RESULTS The median lag to the initiation of disease-modifying treatment was 15 days in the early treatment group and 123 days in the delayed treatment group. There was less radiologic joint damage after 2 years in the early treatment group (median Sharp score, 3.5; 95% confidence interval [CI]: 1 to 7) compared with the delayed treatment group (median Sharp score, 10; 95% CI: 5 to 15; P <0.05). The median area under the curve of the 2-year disease activity score was lower in the early treatment group (64 units; 95% CI: 59 to 69 units) compared with the delayed treatment group (73 units; 95% CI: 69 to 77 units; P = 0.002). CONCLUSION In this nonrandomized comparison, early introduction of disease-modifying antirheumatic drugs was associated with a better disease outcome after 2 years.

Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis

Background: Glucocorticoids induce hypercholesterolaemia, a cardiovascular risk factor, in patients with diseases other than rheumatoid arthritis (RA), but the data in RA are contradictory. Objective: To determine the effects of antirheumatic treatment, including prednisolone (combination) therapy on total and high density lipoprotein (HDL) cholesterol levels in RA, taking disease activity into account. Methods: HDL cholesterol and total cholesterol levels were determined in:(a) established RA (b) two cohorts with early active RA, (c) a previously conducted 56 week trial among patients with early RA comparing the value of intensive combination therapy (that included glucocorticoids) with sulfasalazine alone (COBRA trial). Results: In established RA total cholesterol levels were only slightly raised, irrespective of disease activity. However, HDL cholesterol was significantly higher in patients in remission than in patients with active disease. In contrast, in active early RA at baseline total cholesterol was low normal: between 4.6 and 5.1 mmol/l in the different populations. The level of HDL cholesterol was highly dependent on the duration of storage. In both COBRA groups total cholesterol increased by a mean of 0.6 mmol/l. HDL cholesterol increased by more than 50% after treatment, leading to an improvement of the total cholesterol/HDL ratio (atherogenic index). This increase (and index improvement) was much more rapid in the group receiving combination treatment. A similar pattern was seen in the 2001 cohort with early RA. In all the groups with active disease HDL and total cholesterol levels correlated inversely with disease activity. Conclusion: In established, but especially in early RA, disease activity is accompanied by atherogenic lipid levels. This dyslipidaemia can be rapidly reversed by aggressive antirheumatic treatment including glucocorticoids.

Radiological outcome after four years of early versus delayed treatment strategy in patients with recent onset rheumatoid arthritis

Objective: To determine the effect of different treatment strategies (early versus delayed) on the radiological progression of joint damage during 4 years. Additionally, to determine the effect of treatment strategy on the association of HLA class II alleles and joint damage. Methods: Progression of radiographic damage and association of radiographic damage and genetic predisposition were compared in two cohorts, one treated according to the delayed treatment strategy (initial treatment with analgesics), the other treated according to the early treatment strategy (treatment with disease modifying antirheumatic drugs (DMARDs) chloroquine or sulfasalazine). Radiographic damage was measured by the modified Sharp-van der Heijde method. Genetic predisposition was determined by high resolution HLA-DR and DQ typing. Results: A completers-only analysis of 153 patients (originally 206 patients) in a non-randomised design showed less radiographic progression from 0 to 4 years in the early treatment group (median Sharp progression rate 1.3 points/year, n = 75) than in the delayed treatment group (2.5 points/year, n = 78) (p = 0.03). The progression from 1 to 4 years did not differ significantly between the groups. At 4 years, joint destruction in both groups was positively correlated with the presence of the shared epitope. Conclusions: The beneficial effect of early DMARD treatment on the radiological progression of joint damage is still present at 4 years. However, the rate of joint destruction from 1 to 4 years did not differ between the delayed and early treatment group. Neither the radiographic nor the immunogenetic data suggest that longlasting disease modification has been induced by early treatment.

Matrix metalloproteinases-3, -8, -9 as markers of disease activity and joint damage progression in early rheumatoid arthritis

Objective: To analyse the relation between systemic levels of pro-MMP-3, -8, and -9 matrix metalloproteinase (MMP) activity in α2 macroglobulin (α2M)/MMP complexes and the progression of joint destruction in patients with recent onset rheumatoid arthritis (RA). Methods: 109 patients with RA of recent onset were entered into this longitudinal study. Patients were followed up for two years; clinical data, blood samples, and radiographs were obtained at baseline and at 1 and 2 years. Serum levels of MMPs were measured by sandwich ELISA and MMP activity assays. Results: During the two years joint damage progressed from 0 to 10 (median Sharp score, p<0.001). Stable levels of pro-MMP-3 and a significant decrease in the levels of pro-MMP-8 and -9 and α2M/MMP complexes were seen throughout the two years. Regression analysis showed that serum pro-MMP-3 levels at disease onset were independently associated with the progression of joint damage (B=0.7, 95% CI 0.3 to 1.1, p=0.001). Based on the rate of joint destruction, patients were divided into two subgroups: patients with mild and severe joint damage progression. The pro-MMP-3 levels were significantly higher in the group with severe compared with mild disease at all times. Levels of pro-MMP-8 and -9 were decreased in both groups, whereas α2M/MMP complex levels decreased in the group with mild disease only. Conclusion: Serum levels of the MMPs studied are associated with disease activity, but serum pro-MMP-3 levels at the onset of disease are also predictive of joint damage progression.

Health-related quality of life and functional ability in patients with early arthritis during remission steered treatment: results of the IMPROVED study.

IntroductionThe aim of this study was to investigate patient reported outcomes (PROs) of functional ability and health related quality of life (HRQoL) in patients with early (rheumatoid) arthritis during one year of remission steered treatment.MethodsIn this study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (Disease Activity Score (DAS) <1.6 after 4 months) tapered prednisone to zero and when in persistent remission, also tapered MTX. Patients not in early remission were randomized to either MTX + hydroxychloroquine + sulphasalazine + prednisone (arm 1) or to MTX + adalimumab (arm 2). Every 4 months, patients filled out the Health Assessment Questionnaire (HAQ) and the McMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR), the Short Form 36 (SF-36) and visual analogue scales (VAS). Change scores were compared between treatment groups. The association with achieving remission was analyzed using linear mixed models.ResultsDuring year 1, patients who achieved early remission had the most improvement in PROs with scores comparable to the general population. Patients in the randomization arms showed less improvement. Scores were comparable between the arms. There was a significant association between achieving remission and scores of HAQ, MACTAR and physical HRQoL.ConclusionsIn early arthritis, PROs of functional ability and HRQoL after one year of remission steered treatment reach normal values in patients who achieved early remission. In patients not in early remission, who were randomized to two strategy arms, PROs improved less, with similar scores in both treatment arms.Trial registrationsISRCTN11916566 and EudraCT2006-006186-16

Predictive factors of radiological progression after 2 years of remission-steered treatment in early arthritis patients: a post hoc analysis of the IMPROVED study

Objectives To identify predictive factors of radiological progression in early arthritis patients treated by remission-steered treatment. Methods In the IMPROVED study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and a tapered high dose of prednisone. Patients in early remission (disease activity score (DAS) <1.6 after 4 months) tapered prednisone to zero. Patients not in early remission were randomised to arm 1: MTX plus hydroxychloroquine, sulfasalazine and prednisone, or to arm 2: MTX plus adalimumab. Predictors of radiological progression (≥0.5 Sharp/van der Heijde score; SHS) after 2 years were assessed using logistic regression analysis. Results Median (IQR) SHS progression in 488 patients was 0 (0–0) point, without differences between RA or UA patients or between treatment arms. In only 50/488 patients, the SHS progression was ≥0.5: 33 (66%) were in the early DAS remission group, 9 (18%) in arm 1, 5 (10%) in arm 2, 3 (6%) in the outside of protocol group. Age (OR (95% CI): 1.03 (1.00 to 1.06)) and the combined presence of anticarbamylated protein antibodies (anti-CarP) and anticitrullinated protein antibodies (ACPA) (2.54 (1.16 to 5.58)) were independent predictors for SHS progression. Symptom duration <12 weeks showed a trend. Conclusions After 2 years of remission steered treatment in early arthritis patients, there was limited SHS progression in only a small group of patients. Numerically, patients who had achieved early DAS remission had more SHS progression than other patients. Positivity for both anti-CarP and ACPA and age were independently associated with SHS progression. Trial registration numbers ISRCTN Register number 11916566 and EudraCT number 2006 06186-16.

Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in patients with early arthritis: IMPROVED study

Objectives To determine the 5-year outcomes of early remission induction therapy followed by targeted treatment aimed at drug-free remission (DFR) in patients with early arthritis. Methods In 12 hospitals, 610 patients with early (<2 years) rheumatoid arthritis (RA) or undifferentiated arthritis (UA) started on methotrexate (MTX) 25 mg/week and prednisone (60 mg/day tapered to 7.5 mg/day). Patients not in early remission (Disease Activity Score <1.6 after 4 months) were randomised (single blind) to arm 1, adding hydroxychloroquine 400 mg/day and sulfasalazine 2000 mg/day, or arm 2, switching to MTX plus adalimumab 40 mg/2 weeks. Treatment adjustments over time aimed at DFR. Outcomes were remission percentages, functional ability, toxicity and radiological damage progression after 5 years. Results After 4 months, 387 patients were in early remission, 83 were randomised to arm 1 and 78 to arm 2. After 5 years, 295/610 (48%) patients were in remission, 26% in sustained DFR (SDFR) (≥1 year) (220/387 (57%) remission and 135/387 (35%) SDFR in the early remission group, 50% remission, 11% SDFR in the randomisation arms without differences between the arms). More patients with UA (37% vs 23% RA, p=0.001) and more anticitrullinated protein antibody (ACPA)-negative patients (37% vs 18% ACPA-positive, p<0.001) achieved SDFR. Overall, mean Health Assessment Questionnaire was 0.6 (0.5), and median (IQR) damage progression was 0.5 (0–2.7) Sharp/van der Heijde points, with only five patients showing progression >25 points in 5 years. Conclusions Five years of DFR-steered treatment in patients with early RA resulted in almost normal functional ability without clinically relevant joint damage across treatment groups. Patients who achieved early remission had the best clinical outcomes. There were no differences between the randomisation arms. SDFR is a realistic treatment goal.

Cellular-based immune modulation in arthritis

While the symptoms associated with rheumatoid arthritis (RA) are well described, the factors that are crucially involved in induction and/or progression of RA are poorly defined. Nonetheless, it is generally accepted that cells belonging to the adaptive immune system (i.e. B cells and T cells) are intimately engaged in the processes responsible for RA induction and/or progression. As these cells require triggering of their antigen receptors before they can exert their functions, it is likely that antigen recognition is important in the pathological processes driving RA. Unfortunately, no antigens casually related to the induction/perpetuation of RA are known. Nonetheless, studies addressing the question of how immunity against autoantigens is regulated, combined with studies aiming at defining the molecular identity of antigens involved in disease, will be important to gain a better understanding of the pathways involved in the induction/progression of RA. Recently, we have found that CD4+CD25+regulatory T cells play a pivotal role in the control of arthritis in mice. More importantly, treatment of established arthritis by adoptive transfer of these cells stopped further progression of disease. These data indicate the feasibility to inhibit ongoing disease by specific manipulation of the immune system. The data described also indicate that the class of immune response against autoantigens could profoundly influence the susceptibility for, and/or outcome of, autoimmune responses. However, until now, there has been only limited evidence for autoantigen-specific regulatory responses in humans. Here we analyzed the natural immune response against Human Cartilage gp39 (HC-Gp39), a candidate autoantigen in RA. Peripheral blood mononuclear cells from healthy individuals reacted against HC Gp39 with the production of IL-10, but not interferon gamma. Ex vivo assays indicated that the natural occurring HC Gp39-directed immune response in bulk is capable of suppressing cytotoxic T-cell and recall responses, indicating that, rather than being unresponsive, the HC Gp39-directed immune response in healthy individuals is biased towards a regulatory phenotype. Moreover, CD4+ T-cell lines directed against HC Gp39 expressed CD25, GITR, CTLA-4 and Foxp3 molecules and were capable of suppressing other immune responses. Cell–cell contact was required for this suppression. In contrast, the quality of the HC Gp39-directed immune response in patients with RA exhibits polarization toward a proinflammatory Th1 phenotype. Together these findings indicate that the presence of HC Gp39-specific immune responses in healthy individuals may have a profound inhibitory effect on inflammatory responses in areas were HC Gp39 is present, and imply that the balance of autoreactive proinflammatory and antiinflammatory HC Gp39-directed immune responsiveness is disrupted in RA patients.

OP0176 Five Year Outcomes of Remission Steered Treatment Including Drug Tapering Strategies in Early Arthritis Patients

Background The window of opportunity hypothesis suggests that early initiation of treatment targeted at remission in early arthritis patients may avoid chronicity of inflammation and may result in early drug-free remission (DFR). Objectives To assess clinical outcomes of induction therapy followed by 5 years DAS-remission targeted therapy including rapid drug tapering strategies in early arthritis patients. Methods The IMPROVED study included 610 early rheumatoid arthritis (RA, 2010 criteria) or undifferentiated arthritis (UA) patients starting with methotrexate (MTX) and tapered high dose of prednisone. Patients in early DAS-remission (ER) (disease activity score (DAS)<1.6 after 4 months) stopped prednisone and if remission persisted at t=8 months also MTX. Patients not in ER (DAS≥1.6) were randomized to MTX+sulfasalazine+hydroxychloroquine+low dose prednisone (arm 1) or MTX+adalimumab (arm 2), 50 patients were not randomized and were treated “outside of protocol” (OP). Four monthly treatment adjustments aimed at DAS<1.6; if DAS<1.6 taper/stop medication and if DAS≥1.6 restart/intensify medication. Percentages of patients in (drug free) DAS-remission after 5 years were compared between RA and UA patients and the different treatment strategies. Logistic regression analysis was used to identify predictive factors of DAS-remission and DFR after 5 years. Results After 5 years mean±SD DAS decreased and functional ability improved in all treatment groups without differences between arm 1 and 2. 295/610 (48%) patients were in DAS-remission: 220/387 (57%) in the ER group, 31/83 (37%) in arm 1, 29/78 (37%) in arm 2 (p=0.768 arm 1 vs arm 2) and 15/50 (30%) in OP. 134/610 (22%) patients were in DFR: 105/387 (27%) in the ER group, 9/83 (11%) in arm 1, 12/78 (15%) in arm 2 (p=0.374 arm 1 vs arm 2) and 8/50 (16%) in OP. DAS-remission was achieved in similar percentages in RA and UA patients and autoantibody positive (+) vs negative (−) patients. More UA than RA patients were in DFR at year 5 (33% vs 19%, p<0.001), and the same was true for anti-citrullinated protein antibodies (ACPA)− vs ACPA+ patients (31% vs 15%, p<0.001) and rheumatoid factor (RF)− vs RF+ positive patients (28% vs 17%, p<0.001). Between anti-carbamylated antibodies (anti-CarP)+ and − patients there was no difference in DFR rates. Predictors of DAS-remission were age (OR 0.97 (95% CI 0.96–0.99)), symptom duration (0.99 (0.98–0.99)), baseline tender joint count (0.95 (0.90–1.00)) and achieving ER (1.95 (1.23–3.10)) (figure). Predictors of DFR were symptom duration (0.99 (0.97–1.00) and ER (2.67 (1.48–4.84)). ACPA+ was mostly associated with less DFR. Conclusions After 5 years of DAS-remission steered treatment, 48% of early RA and UA patients were in DAS-remission and 22% in DFR. Remission results were better for patients who achieved ER and who had a shorter symptom duration. Remission results were similar for RA and UA patients, randomization arms and autoantibody status, but more UA than RA patients and more autoantibody? than + patients were in DFR. Disclosure of Interest G. Akdemir: None declared, L. Heimans: None declared, R. J. Goekoop: None declared, M. van Oosterhout: None declared, J. B. Harbers: None declared, C. Bijkerk: None declared, G. M. Steup-Beekman: None declared, L. Lard: None declared, P. B. J. de Sonnaville: None declared, B. A. M. Grillet: None declared, T. W. J. Huizinga: None declared, C. F. Allaart Grant/research support from: Year 1 of the IMPROVED study was sponsored by Abbott.

Just Another Case of Sjögren’s Syndrome?

To the Editor: A 60-year-old woman was seen at the outpatient clinic of the Department of Rheumatology because of increased complaints of xerophthalmia. In 1997, she had already been diagnosed with Sjogren’s syndrome (SS) based on xerophthalmia, xerostomia, bilateral salivary gland swelling, and positive sialography showing chronic inflammation without local obstruction. Antinuclear antibodies (ANA) and anti-SSA/SSB were negative. Because of persistent progressive salivary gland swelling at that time, a total bilateral submandibular gland excision was performed as development of non-Hodgkin lymphoma as a complication of SS was suspected. Histology showed sialoadenitis as seen in SS without signs of lymphoma. In 2002, a renal biopsy performed because of increased creatinine level without proteinuria revealed focal global glomerulosclerosis with interstitial nephritis due to SS or chronic ischemia. In an attempt to treat possible active interstitial nephritis due to SS, she was treated with 30 mg of prednisone and azathioprine. Prednisone was stopped after 6 months and azathioprine after one year, however, there was no …