Medicine by Alexandros G. Sfakianakis: Clinical Rheumatology

Folate Supplementation for Methotrexate Therapy in Patients With Rheumatoid Arthritis: A Systematic Review

Objective To review the evidence for benefits and harms of folate (folic acid or folinic acid) supplementation on methotrexate (MTX) treatment for rheumatoid arthritis (RA), to assess whether or not folate supplementation would reduce MTX toxicity or reduce MTX benefits, and to decide whether a higher MTX dosage is essential. Methods We performed a sensitive search strategy and searched systematically the Medline, Embase, Web of Science and Cochrane Library databases from inception to 2 June 2016. Abstracts from major rheumatology meetings and major trial registers were also searched to retrieve all randomized controlled trials that interested us. Results Seven studies with 709 patients were included. No significant heterogeneity was found between these trials. For RA patients treated with MTX, those supplied with folate were less likely to have elevated transaminase (odds ratio [OR] 0.15; 95% confidence interval [95% CI] 0.10, 0.23 [p < 0.00001]) and gastrointestinal side-effects such as nausea and vomiting (OR 0.71; 95% CI 0.51, 0.99 [p = 0.04]). Folate appeared to promote compliance to MTX as it reduced patient withdrawal compared to placebo (OR 0.29; 95% CI 0.21, 0.42 [p < 0.00001]). There was no statistical difference for mouth sores between folate and placebo (OR 0.83; 95% CI 0.57, 1.22 [p = 0.35]). As the markers of disease activity in those trials were not consistent, it was impossible to decide whether folate supplementation reduced MTX efficacy. Besides, we compared high-dose folate (≥25 mg per week) and low-dose folate (≤10 mg per week) on MTX efficacy, finding no statistical difference (OR 2.07; 95% CI 0.81, 5.30 [p = 0.13]), nor on MTX toxicity (OR 1.56; 95% CI 0.80,3.04 [p = 0.19]). Conclusion Folate supplementation can reduce the incidence of hepatotoxicity and gastrointestinal side-effects of MTX in patients with RA. It can also reduce patient withdrawal from MTX treatment. Although it tended to reduce mouth sores, it had no statistical significance. No significant difference was found between high-dose folate and low-dose folate on MTX efficacy or toxicity.

Ultrasound as a Useful Tool in the Diagnosis of Rheumatoid Arthritis in Patients With Undifferentiated Arthritis

Background Nowadays, rheumatologists face challenges in finding an effective method to classify and treat patients with undifferentiated arthritis (UA). There is a need for new tools that could ensure accurate characterization of inflammatory processes in these patients. Objective The aim of this study was to investigate if a characterization of UA patients using ultrasound (US) may help to fulfill the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) rheumatoid arthritis (RA) classification criteria in a real-life cohort. Methods We conducted a cross-sectional study in 2 rheumatology care clinics. Patients not fulfilling the 2010 ACR/EULAR RA criteria were included. On the examination day, all patients underwent a physical examination, radiography, and US. The 7-joint US score was adopted to scan all patients. The US was performed according to EULAR criteria and interpreted by Outcome Measures in Rheumatology definitions. Gray-scale and power Doppler synovitis and tenosynovitis were scored. Bone erosions were also evaluated during the US examination. Results A total of 204 patients were included. The diagnosis was modified from UA to RA in 86 patients (42.1%). Also, the final score of the 2010 ACR/EULAR RA classification criteria changed from a mean of 4.6 to 6.5 after the US examination. In addition to synovitis, a wide range of tenosynovitis and bone erosions were detected by US. Synovitis was more frequently detected in second metacarpophalangeal joint followed by second metatarsophalangeal joint (MTPj) and fifth MTPj. The tendons of the wrist and second and third fingers were the most affected. In relation to bone erosions, second metacarpophalangeal joint and fifth MTPj were the joints with more proportion of anatomical damage. Conclusions The US demonstrated to be useful to help accurately classify as RA patients previously diagnosed with UA.

Physician's Experience and Disease Activity Affect the Impact of Ultrasound on the Treatment Decision in Rheumatoid Arthritis

Background/Objective The aim of this cross-sectional study was to explore which factors affect the impact of musculoskeletal ultrasound (MUS) on the treatment proposal among rheumatologists with different degree of experience. Methods Sixteen clinical vignettes summarized data from rheumatoid arthritis (RA) outpatients; vignettes included clinical evaluation and a blank section for a first treatment proposal; MUS information was then added, based on German Ultrasound score, followed by a blank section for treatment re-consideration, if applicable. During a 6 months period, each vignette was concomitantly presented to six trainees and six senior rheumatologists (SR); three SR had ≥15 years of experience. Participants were blinded to colleagues' responses. Appropriated statistics were used. Results Vignettes included data from female patients, who had a mean ± SD age of 43.3 ± 9 years, 7.6 ± 3.5 years of disease duration and comorbidities (68.8%). MUS induced treatment modification in 24% of evaluations, with similar percentage among SR and trainees. Within SR, more experienced rheumatologists (≥15 years) never translated MUS findings in a different treatment proposal, compared to 34% of those with lesser experience, p ≤ 0.0001. There were 60 clinical scenarios each, with remission and moderate disease activity, and 36 clinical scenarios each, with low and high disease activity. MUS-induced treatment modifications were more frequent in scenarios with low and moderate disease activity, compared to remission and high disease activity, p = 0.008. Conclusions Physician's experience and disease activity level affect the impact of MUS on the treatment decision in RA outpatients. RA patients with intermediate disease activity may benefit from MUS incorporation to standard assessments.

Evaluation of PR3-ANCA Status After Rituximab for ANCA-Associated Vasculitis

Introduction The value of antineutrophil cytoplasmic antibody (ANCA) measurements among patients with an established diagnosis of ANCA-associated vasculitis (AAV) to assess disease activity or predict relapse remains controversial, but recent evidence suggests a possible role for rituximab-treated patients. Patients and Methods All patients with active vasculitis and positive proteinase 3 (PR3)–ANCA who were starting a 2-year treatment course of rituximab for induction of remission at Addenbrooke's Hospital between January 2011 and January 2016 were included in this study. Common department practice consists of 6 g of rituximab given over 2 years, concomitant corticosteroids (0.5–1.0 mg/kg) with rapid taper over 3 months, and cessation of oral maintenance immunosuppressive agents at time of first rituximab dose. Clinical and laboratory data were collected retrospectively using electronic patient records. Results Fifty-seven patients with current PR3-ANCA positivity were included in the analysis. Median follow-up was 59 months. PR3-ANCA negativity was achieved in 25 patients (44%) with a median time of 14 months. Clinical remission was achieved in 53 patients (93%) with a median time of 3 months. Among the 53 patients who achieved remission during follow-up, 24 (45%) relapsed with a median time to relapse of 36 months from remission. Both PR3-ANCA–negative status and 50% reduction in PR3-ANCA from baseline (as time-varying covariates) were significantly associated with a longer time to relapse (PR3-ANCA–negative status: hazards ratio, 0.08 [95% confidence interval, 0.01–0.63, p = 0.016]; 50% reduction in PR3-ANCA: hazards ratio, 0.25 [95% confidence interval, 0.18–0.99, p = 0.046]). Conclusions Achieving and maintaining PR3-ANCA negativity after rituximab was associated with longer-lasting remission.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis–Like Lupus Erythematosus

Background/Objective Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)–like lupus erythematosus is a hyperacute and life-threatening form of cutaneous lupus erythematosus. Because of its rarity, little is known about this entity. We aimed to evaluate the clinical characteristics, laboratory findings, systemic manifestations, treatments, and outcome of SJS/ TEN-like lupus erythematosus. Methods We conducted a chart review study from July 2002 to September 2016 of all patients diagnosed with SJS/TEN-like lupus erythematosus who presented with gradual epidermal necrolysis without clear drug or infectious culprit. We evaluate for clinical features, extracutaneous involvement, Systemic Lupus Erythematosus Disease Activity Index, histologic findings, immunofluorescence pattern, serologic abnormalities, treatment, outcome, and recurrence of SJS/TEN-like lupus erythematosus. Results Of 9074 patients diagnosed with cutaneous lupus erythematosus and/or systemic lupus erythematosus, 6 patients justified the diagnosis of SJS/TEN-like lupus erythematosus (5 SJS/TEN-like acute cutaneous lupus erythematosus, 1 TEN-like subacute cutaneous lupus erythematosus), accounting for 0.07%. Fifty percent had epidermal necrolysis as the initial presentation of lupus with a median time from onset of 1.5 months (0–48 months). The median duration between initial rash and epidermal detachment was 4.5 days (3–14 days). All had internal organ involvement (hematologic and renal) and high Systemic Lupus Erythematosus Disease Activity Index score (median, 19.5 [16–24]). Most recovered with systemic corticosteroids, antimalarial drugs, and/or immunosuppressants. None had disease recurrence. Conclusions This is the largest single series of patients with SJS/TEN-like lupus erythematosus. Skin damage is an indicator of disease activity, and careful search for extracutaneous involvement to prevent further complications is mandatory.

Pain and Catastrophizing in Patients With Rheumatoid Arthritis: An Observational Cohort Study

Background The aims of this study were to define changes in catastrophizing that occur with initiation of a new disease-modifying antirheumatic drug (DMARD) and to examine the relationship between changes in Clinical Disease Activity Index (CDAI) and changes in catastrophizing. Methods Participants in an ongoing multisite, observational study completed the Pain Catastrophizing Scale (PCS) before and 12 weeks after DMARD initiation. We used multivariable linear regression models to examine the association between changes in CDAI as the exposure and change in pain catastrophizing as the outcome. We also assessed the relationship between changes in each component of CDAI and change in PCS, using multivariable linear regression models. Results Among the 165 rheumatoid arthritis patients with data on CDAI at both time points, CDAI decreased from 22 to 11.5 on a 76-point scale (p < 0.0001) after 12 weeks. Pain intensity decreased from a median of 5 to 3 on a 10-point numeric rating scale (p < 0.0001), and catastrophizing decreased, from 16.0 to 12.0 on the 52-point PCS (p = 0.0005). Among the 163 with complete data for the regression analysis, changes in CDAI were positively correlated with changes in catastrophizing (standardized β = 0.19, p = 0.01). Of the components of the CDAI, change in assessor global score was most strongly associated with changes in catastrophizing (standardized β = 0.24, p = 0.003). Conclusions Pain catastrophizing decreases, in conjunction with disease activity, after initiation of a new DMARD. These findings provide support for catastrophizing as a dynamic construct that can be altered with treatment directed at decreasing inflammatory disease activity and pain.

ARF, ARF!