Dr. C. Balakrishnan, Consultant Rheumatologist, Hinduja Hospital, Mumbai

Differences in the symptomatic phase preceding ACPA-positive and ACPA-negative RA: A longitudinal study in arthralgia during progression to clinical arthritis. Ann Rheum Dis. 2017 Oct;76(10):1751-1754.

Objective

Although anticitrullinated protein antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis (RA) has different etiopathologies, the clinical presentation at the time of diagnosis is similar. This study evaluated whether there are phenotypic differences in the symptomatic pre-RA phase.

Methods

Patients with arthra lgia included in the Leiden clinically suspect arthralgia cohort who developed arthritis during follow-up were studied (n=67). Symptoms at symptom onset, symptoms and signs at presentation with arthralgia, and time to arthritis development were compared between ACPA-positive and ACPA-negative patients.

Results

In ACPA-negative patients (n=37), the location of initial symptoms less often included the lower extremities (22% vs 50%, p=0.014). At presentation with arthralgia, ACPA-positive patients had a longer symptom duration (median, 22 vs 14 weeks, p=0.005), less tender joints (mean, 5 vs 9, p=0.007), and less difficulty making a fist (11% vs 43%, p=0.004). However, after presentation with arthralgia, ACPA-positive patients developed arthritis more quickly (median, 6 vs 18 weeks, p=0.015). A partial least squares regression analysis showed clustering of ACPA-positive and ACPA-negative patients based on the abovementioned clinical variables.

Conclusion

This study is the first showing that ACPA-positive and ACPA-negative patients have clinical differences in the symptomatic phase preceding clinical arthritis. This contributes to the notion that ACPA-positive and ACPA-negative RA develop differently.

Criticism: it is a poorly designed study with a small sample size.

Extended report: Long-term outcomes after disease activity-guided dose reduction of TNF inhibition in rheumatoid arthritis: 3-year data of the DRESS study – a randomized controlled pragmatic non-inferiority strategy trial Annals of the Rheumatic Diseases 2017;76:1716-1722.

Objective

Tumor necrosis factor inhibitors (TNFi) are effective in rheumatoid arthritis (RA), but disadvantages include adverse events (AEs) and high costs. This can be improved by disease activity-guided dose reduction (DR). We aimed to assess long-term outcomes of TNFi DR in RA by using 3-year data from the Dose REduction Strategy of Subcutaneous TNF inhibitors (DRESS) study.

Methods

In the intervention phase (month 0–18) of the DRESS study (Dutch trial register, NTR 3216), patients were randomized to DR or usual care (UC). In the extension phase (month, 18–36), treatment strategies in both groups converged to continuation of protocolized tight control and allowed dose optimization. Intention-to-treat analyses were done on flare, disease activity (28 joint count-based disease activity score with C reactive protein [DAS28-CRP]), functioning (health assessment questionnaire-disability index [HAQ-DI]), quality of life (Euroqol 5 dimensions 5 levels questionnaire [EQ5D–5L]), medication use, radiographic progression (Sharp van der Heijde score [SvdH]), and AE.

Results

A total of 172/180 patients in the DRESS study were included in the extension phase. Cumulative incidences of major flare were 10% and 12% (−2%, 95% CI: −8 to 15) in the DR and UC groups in the extension phase and 17% and 14% (3%, 95% CI: −9 to 13) from 0 to 36 months, respectively. Cumulative incidences of short-lived flares were 43% (33 to 52%) and 35% (23 to 49%) in the DR and UC groups in the extension phase and 83% (75 to 90%) and 44% (31 to 58%) from 0 to 36 months, respectively. Mean DAS28-CRP, HAQ-DI, EQ5D-5L, and SvdH remained stable and not significantly different between groups. TNFi use remained low in the DR group and decreased in the UC group. Cumulative incidences of AE were not significantly different between groups.

Conclusion

Safety and efficacy of disease activity-guided TNFi DR in RA are maintained up to 3 years, with a large reduction in TNFi use, but with no other benefits. Implementation of DR would vastly improve the cost-effectiveness of TNFi.

Extended report: The yield of a positive MRI of the spine as imaging criterion in the ASAS classification criteria for axial spondyloarthritis: Results from the SPACE and DESIR cohorts Annals of the Rheumatic Diseases 2017;76:1731-1736.

Objective

To assess the prevalence of spinal inflammation on MRI in patients with chronic back pain (CBP) of maximally 3 years duration and to evaluate the yield of adding a positive MRI-spine as imaging criterion to the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA).

Methods

Baseline imaging of the sacroiliac joints (X-SI), MRI of the sacroiliac joints (MRI-SI), and MRI-spine were scored by >2two or more experienced central readers per modality in the SPondyloArthritis Caught Early (SPACE) and DEvenir des Spondylarthropathies Indifférenciées Récentes (DESIR) cohorts. Inflammation suggestive of axSpA was assessed in the entire spine. A positive MRI-spine was defined by the presence of >5 inflammatory lesions. Alternative less strict definitions were also tested.

Results

In this study, 541 and 650 patients with CBP from the SPACE and DESIR cohorts, respectively, were included. Sacroiliitis on X-SI and MRI-SI was found in 40/541 (7%) and 76/541 (14%) patients in the SPACE cohort, and in 134/650 (21%) and 231/650 (36%) patients in the DESIR cohort, respectively. In the SPACE and DESIR cohorts, a positive MRI-spine was seen in 4/541 (1%) and 48/650 (7%) patients. Of the patients without sacroiliitis on imaging, 3/447 (1%) (SPACE) and 8/382 (2%) (DESIR) patients had a positive MRI-spine. Adding positive MRI-spine as imaging criterion led to new classification in only one patient in each cohort, as the other patients already fulfilled the clinical arm. Other definitions of a positive MRI-spine yielded similar results.

Conclusion

In two cohorts of patients with CBP with a maximum symptom duration of 3 years, a positive MRI-spine was rare in patients without sacroiliitis on MRI-SI and X-SI. Addition of MRI-spine as an imaging criterion to the ASAS axSpA criteria had a low yield of newly classified patients and is therefore not recommended.

Tofacitinib or Adalimumab versus placebo for Psoriatic Arthritis N Engl J Med 2017; 377:1537-1550 October 19, 2017

Background

Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who previously had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs).

Methods

In this 12-month, double-blind, active-controlled, and placebo-controlled, phase 3 trial, we randomly assigned patients in a 2:2:2:1:1 ratio to receive one of the following regimens: tofacitinib at a 5-mg dose taken orally twice daily (107 patients), tofacitinib at a 10-mg dose taken orally twice daily (104), adalimumab at a 40-mg dose administered subcutaneously once every 2 weeks (106), placebo with a blinded switch to the 5-mg tofacitinib dose at 3 months (52), or placebo with a blinded switch to the 10-mg tofacitinib dose at 3 months (53). Placebo groups were pooled for analyses up to month 3. Primary endpoints were the proportion of patients who had an American College of Rheumatology 20 (ACR20) response (≥20% improvement from baseline in the number of tender and swollen joints and at least three of five other important domains) at month 3 and the change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI) score (scores range from 0 to 3, with higher scores indicating greater disability) at month 3.

Results

ACR20 response rates at month 3 were 50% in the 5-mg tofacitinib group and 61% in the 10-mg tofacitinib group, as compared with 33% in the placebo group (p=0.01 for the comparison of the 5-mg dose with placebo; p<0.001 for the comparison of the 10-mg dose with placebo); the ACR20 response rate was 52% in the adalimumab group. The mean change in the HAQ-DI score was −0.35 in the 5-mg tofacitinib group and −0.40 in the 10-mg tofacitinib group, as compared with −0.18 in the placebo group (p=0.006 for the comparison of the 5-mg dose with placebo; p<0.001 for the comparison of the 10-mg dose with placebo); the HAQ-DI score change was −0.38 in the adalimumab group. The rate of adverse events through month 12 was 66% in the 5-mg tofacitinib group, 71% in the 10-mg tofacitinib group, 72% in the adalimumab group, 69% in the placebo group that switched to the 5-mg tofacitinib dose, and 64% in the placebo group that switched to the 10-mg tofacitinib dose. There were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib during the trial.

Conclusion

The efficacy of tofacitinib was superior to that of placebo at month 3 in patients with psoriatic arthritis who previously had an inadequate response to conventional synthetic DMARDs. Adverse events were more frequent with tofacitinib than with placebo.

Defining Low Disease Activity in Systemic Lupus Erythematosus Arthritis Care & Research Vol. 69, No. 7, July 2017, pp 997–1003

Objective

To define and identify a group of systemic lupus erythematosus patients with low disease activity (LDA) and to examine whether LDA is similar to patients in remission and different from a high disease activity group (HDA) in short-term outcomes.

Methods

The LDA group was defined as Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) 6. The time frame for inclusion in each group was at least 1 year.

Results

Of the 620 patients with active disease who were seen between 1970 and 2015, 80 patients (12.9%) fulfilled the criteria for LDA, 191 (30.8%) for remission, and 349 (56.3%) for HDA. The LDA patients with and without positive serology results were similar at baseline and with prior disease characteristics. After 2 years of follow-up, the LDA and remission groups were similar in their adjusted mean SLEDAI-2K score, organ involvement, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score, mortality, and therapies. After 2 and 4 years of follow-up, the HDA group had a higher adjusted mean SLEDAI-2K score, more major organ involvement, a higher SDI score, higher mortality, and more therapy compared with the combined LDA/remission groups.

Conclusion

LDA and remission groups had similar short-term outcomes, and both had better outcomes and prognosis than the HDA group. LDA may be used as an outcome measure in therapeutic trials or in treat-to-target regimens.

Comments

LDA and remission groups had similar short-term outcomes, and both had better outcomes and prognosis than the HDA group. LDA may be used as an outcome measure in therapeutic trials or in treat-to-target regimens. Domains with scores of 1 and 2 such as dermatological, serological, mucosal, hematological domains are included in SLEDAI 2K scoring. Isolated involvement of them is considered as an LDA.

Extended report: Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis Annals of the Rheumatic Diseases 2017;76:1662-1668.

Objective

A prospective randomized trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV).

Methods

Patients with AAV were recruited 18–24 months after diagnosis if they were in stable remission after cyclophosphamide/prednisolone-based induction followed by azathioprine/prednisolone maintenance therapy. They were randomized (1:1) to continually receive azathioprine/prednisolone up to 48 months from diagnosis (continuation group) or to withdraw azathioprine/prednisolone by 24 months (withdrawal group). The primary endpoint was the relapse risk, from randomization to 48 months from diagnosis.

Results

A total of 117 patients were randomized and 110 remained until the trial end. At entry, median serum creatinine was 116 μmol/L (range 58–372), and 53% were ANCA positive. The percentage of patients presenting with relapse was higher in the withdrawal than in the continuation treatment group (63% vs 22%, p<0.0001, OR: 5.96, 95% CI: 2.58–13.77). ANCA positivity at randomization was associated with relapse risk (51% vs 29%, p=0.017, OR: 2.57, 95% CI: 1.16–5.68). Renal function, ANCA specificity, vasculitis type and age were not predictive of relapse. Severe adverse events were more frequent in the continuation than withdrawal groups (9 vs 3 events), but the continuation group had better renal outcome (0 vs 4 cases of end-stage renal disease), with no difference in patient survival.

Conclusion

Prolonged remission maintenance therapy with azathioprine/prednisolone, beyond 24 months after diagnosis reduces relapse risk out to 48 months and improves renal survival in AAV.

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