Discontinuation of anti-TNF-α therapy in a Chinese cohort of patients with rheumatoid arthritis

The aim of this retrospective study was to examine the predictors of discontinuation of anti-tumor necrosis factor (TNF) therapy due to adverse events in Chinese patients with rheumatoid arthritis (RA). Anti-TNF-related adverse events were recorded and analyzed in 217 consecutive patients with RA followed in our institution from 2003 to 2010. Time to discontinuation of anti-TNF-α therapy was estimated using survival analysis techniques. The anti-TNF agents administered were etanercept in 181 patients and adalimumab in 36 patients. The mean age at diagnosis was 45.2?±?13.5?years, and mean age at initiation of anti-TNF therapy was 51.8?±?13.0?years. The mean duration of anti-TNF agent use was 36.0?±?26.5?months (range, 1.4–87.0; median, 26.4?months). Of the 217 patients, 39 (18.0?%) developed adverse events [etanercept in 34 (18.8?%] and adalimumab in 5 (13.9?%)] during the treatment period (tuberculosis in 5, bacterial infections in 19, virus infection in 7, neuropathy in 3, malignancy in 3, other drug-related events in 1, and appendicitis in 1). In patients with RA, older age (≥55?years) at initiation of anti-TNF therapy [odds ratio (OR), 3.20; 95?% confidence interval (CI), 1.67–6.20; p?<?0.001], Cr ≥1.5?mg/dL (OR, 5.72; 95?% CI, 1.17–27.90; p?=?0.031), and occurrence of adverse events (OR, 3.82; 95?% CI, 1.75–8.35; p?=?0.001) were associated with increased likelihood of discontinuation of anti-TNF treatment. In the present study, a significant proportion (7.8?%, 17/217) of patients with RA discontinued anti-TNF treatment because of adverse events. In the elderly and in patients with renal insufficiency, caution is needed when starting anti-TNF treatment.     

Serious infections under treatment with TNF-α antagonists compared to traditional DMARDs in patients with rheumatoid arthritis

Biological treatments aiming to neutralize TNF-α (tumour necrosis factor alpha) (infliximab, adalimumab and etanercept) are increasingly used to treat rheumatoid arthritis (RA). Although increased frequency has not been observed in randomized clinical trials with TNF-α antagonist agents, postmarketing surveillance suggests that infections might be serious consequences of these therapies. Our aim was to compare infections in patients with RA under treatment with disease-modifying antirheumatic drugs (DMARDs) and TNF-α antagonists in a university outpatient rheumatology clinic in Turkey. A total of 130 RA patients treated with DMARDs and 48 treated with TNF-α antagonists were analysed for the incidence of infections. Patients taking TNF-α antagonists were also reviewed for infections before these therapies. The incidence of serious infections was 7/100 patient-years before TNF-α antagonists and 8.6/100 patient-years in DMARDs group. The incidence rose to 17/100 patient-years during therapy with TNF-α antagonists. In patients with RA on routine follow-up, treatment with TNF-α antagonists seems to carry an increased risk of infections compared to traditional DMARDs.     

Preliminary evaluation in rheumatoid arthritis activity in patients treated with TNF-α blocker plus methotrexate versus methotrexate or leflunomide alone

Methotrexate (MTX) is a first-line disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA). Leflunomide (LEF) and the biologic agents entered the arsenal of DMARDs in 1998. Therapeutic properties of new drugs are still under survey. The purpose of this study was to evaluate and compare the efficacy of MTX, LEF and a biologic agent (TNF-α blocker) combined with MTX in reducing disease activity in RA. Seventy-eight patients with active RA underwent a 24-week treatment with MTX 15 mg/week (30 pts), LEF 20 mg/day (30 pts) or a TNF-α blocker (etanercept 25 mg 2× weekly or infliximab 3 mg/kg in the week 0, 2, 6 and every 8 weeks thereafter) plus MTX 15 mg/week (18 pts). Only patients with RA resistant to MTX were included in groups receiving LEF or a biologic agent. During follow-up, patients’ characteristics, disease characteristics, and clinical and laboratory data were registered. RA activity was evaluated using the ESR, tender and swollen joint counts, the duration of morning stiffness, disease activity score-28 (DAS 28), visual analogue scale (VAS) and health assessment questionnaire (HAQ). Treatment efficacy was demonstrated with ACR 20, 50 and 70 criteria. All groups revealed statistically significant improvement in all disease activity parameters measured. The percentage improvements were similar in groups treated with MTX and LEF and—except for VAS—significantly greater in the group treated with a biologic agent. Disease activity assessed by DAS 28 decreased significantly in all groups: the results were comparable in groups treated with MTX and LEF and significantly more prominent in the group treated with a TNF-α blocker. The ACR 20, 50 and 70 improvements amounted, respectively: 100, 50 and 7% in MTX group 87, 60 and 13% in LEF group and 100, 83 and 50% in a biologic agent group. The study revealed equal effectiveness of MTX and LEF in reducing disease activity in rheumatoid arthritis. The efficacy of a TNF-α blocker combined with MTX was higher than that of each conventional DMARDs, especially with regard to ACR 70 criteria (considerable improvement after treatment). LEF was equally effective as MTX in patients unable to continue MTX treatment due to the drug’s ineffectiveness.     

Detection of hearing loss in rheumatoid arthritis patients using extended high frequency audiometry: Is it related to disease activity and severity?

Aim of the workTo evaluate audiological characteristics in rheumatoid arthritis (RA) patients compared with controls using extended high frequency audiometry and analyze their correlations with RA activity and severity to identify patients at higher risk of hearing loss.Patients and methodsThe study was carried out on 95 RA patients and 100 controls. Every subject underwent pure tone audiometry (PTA) from 250 through 8000 Hz, speech audiometry and extended high frequency audiometry (EHFA) from 10,000 to 20000 Hz. Disease activity score (DAS28) and RA medical records-based index of severity (RARBIS) were assessed.ResultsPatients were 85 females and 10 males with age mean 46.5 ± 1.1 years and disease duration of 9.57 ± 0.61 years. The hearing thresholds (HT) of patients were significantly higher than those of controls at all PTA (p < 0.001) and EHFA frequencies (p < 0.001). Hearing loss (HL) was detected in 68.4% and 64.2% by using PTA, while EHFA revealed it in 100% and 97.9% of right and left ears of RA patients respectively. Hearing loss was bilateral, symmetrical and sensorineural in all cases. HT of EHFA significantly correlated with age (r = 0.63, p < 0.001), age at onset (r = 0.51, p < 0.001), disease duration (r = 0.3, p = 0.03), DAS28 (r = 0.31, p = 0.01) and RARBIS (r = 0.21, p = 0.03).ConclusionBilateral symmetrical sensorineural hearing loss (SNHL) is significantly more frequent in RA patients compared to control. EHFA is valuable test to detect HL in patients with RA. Older age, longer disease duration, higher disease activity and severity are important factors for the development of HL in RA.     

A systematic review of the effect of TNF-α antagonists on lipid profiles in patients with rheumatoid arthritis

Atherosclerosis plays a key role in cardiovascular disease in patients with rheumatoid arthritis (RA). Although therapy with TNF-α antagonists has resulted in dramatic improvement in the prognosis of RA, its effects on circulatory lipids are unclear. We conducted a systematic review of the literature to summarize the available evidence on lipid profile modification in patients with RA treated with TNF-α antagonists, with extensive searches in PubMed, the Cochrane Collaboration database (Central), and SCOPUS. Twenty-four observational studies met the inclusion criteria; 12 included only patients with RA treated with infliximab and three, patients with RA treated with adalimumab. The other nine included a mix of patients with various rheumatic diseases, or receiving one of several TNF-α antagonists. Eleven studies found a statistically significant increase in total cholesterol (TC) and high-density lipoprotein (HDL); six of 20 found significant increases in triglycerides (TG). Four of 13 studies found a statistical increase in low-density lipoprotein. No major changes were observed for ApoB/ApoA1 ratios. A small trend to increased TC was observed in patients receiving TNF-α antagonists, mostly due to an increase in HDL. There was a small trend to increased TG, and no changes in ApoB/ApoA1 ratio. The clinical impact of these findings is unclear, and further studies are needed to clarify the role of these lipid changes on cardiovascular morbidity in RA.     

Association of disease activity with acute exacerbation of interstitial lung disease during tocilizumab treatment in patients with rheumatoid arthritis: a retrospective,case–control study

The objective of the study was to identify risk factors for acute exacerbation of interstitial lung disease (ILD) during tocilizumab treatment in patients with rheumatoid arthritis (RA). This is a retrospective, case–control study. We reviewed 395 consecutive RA patients who received tocilizumab. First, we divided the patients according to the presence (RA-ILD) or absence of ILD (non-ILD) assessed by chest X-ray or high-resolution computed tomography, and compared them for characteristics relevant to RA-ILD. Subsequently, focusing on the patients with RA-ILD, we assessed their baseline characteristics and clinical courses comparing patients with acute exacerbation to those without. Comparing 78 with ILD and 317 without ILD, the following were identified as factors related to RA-ILD on multivariate analysis: age 60 years or older (OR 4.5, 95 % CI 2.2–9.4, P < 0.0001), smoking habit (OR 2.9, 95 % CI 1.5–5.5, P = 0.002), and high rheumatoid factor levels (OR 2.8, 95 % CI 1.4–5.5, P = 0.002). Of 78 RA-ILD patients, six developed acute exacerbation during tocilizumab treatment. The median duration between the initiation of tocilizumab treatment and the acute exacerbation occurrence was 48 weeks. While baseline characteristics did not differ between acute exacerbation and non-acute exacerbation groups, patients experiencing acute exacerbation had significantly higher Clinical Disease Activity Index (CDAI) at 24 weeks (20.8 vs. 6.2, P = 0.019). Univariate analysis showed that CDAI > 10 at 24 weeks was a risk factor for acute exacerbation (OR 4.7, 95 % CI 2.1–10.4, P = 0.02). Uncontrolled arthritis activity during tocilizumab treatment may be associated with acute exacerbation of RA-ILD, suggesting post-treatment monitoring of disease activity is important not only with respect to RA itself but also for RA-ILD.     

TNF-α inhibitors and tocilizumab do not influence hepatic steatosis in patients with rheumatoid arthritis

AIM: To investigate the influence, if any, of tumor necrosis factor(TNF)-α inihibitors and Tocilizumab, on hepatic steatosis(HS) in rheumatoid arthritis(RA) patients in the light of the known role of TNF-α and interleukin-6, which are key-cytokines in the pathogenesis of RA, in inducing HS in general population.METHODS: We retrospectively reviewed the clinical charts of 36 RA patients, out of whom 12 had been treated with Methotrexate(MTX), 12 with TNF inhibitors ± MTX and 12 with Tocilizumab ± MTX. The 3 subgroups of patients matched each other for sex, age, body mass index, metabolic syndrome(MS) and other risk factors for atherosclerosis. At baseline and after 12 mo each patient underwent an abdominal ultrasonog-raphy for the assessment of presence of HS and the evaluation of its grade.RESULTS: No difference was detected either in the prevalence of HS or in that of its distinct grades between the 3 groups of patients at baseline. After 12 mo, the HS grade unchanged in 20 patients(7 subjects treated with MTX, 7 with TNF-α inhibitors ± MTX and 6 Tocilizumab ± MTX); increased in 12 patients(4 subjects treated with MTX, 4 TNF-α blockers ± MTX and 4 Tocilizumab ± MTX); decreased in 4(1 treated with MTX, 1 with anti-TNF-α + MTX and 2 with TCZ ± MTX(P = 0.75). No correlation was found between getting remission or low disease activity and the course of either MS or HS.CONCLUSION: We failed to detect any influence of MTX ± TNF-α inhibitors or Tocilizumab in reducing MS and HS. A prospective study is needed to clarify the topic.     

Quantitative determination of steroid hormone receptor positive cells in the synovium of patients with rheumatoid arthritis and osteoarthritis: is there a link to inflammation?

BACKGROUND: Steroid hormone receptors such as glucocorticoid receptors, androgen receptors, and oestrogen receptors alpha (ERalpha) and beta (ERbeta) have been identified in synovial cells of patients with rheumatoid arthritis and osteoarthritis. OBJECTIVES: To find a quantitative relationship between the number of receptor positive cells and markers of inflammation, and to compare the two groups of patients with rheumatoid arthritis and osteoarthritis. METHODS: A total of 36 patients with rheumatoid arthritis (n = 17) and osteoarthritis (n = 19) were included, and receptor positive cells and cellular markers of synovial inflammation were quantified by immunohistochemistry and ELISA (interleukin 6 (IL6) and IL8). RESULTS: Patients with rheumatoid arthritis showed a higher degree of histologically determined inflammation compared with those with osteoarthritis. However, synovial density of gluco-corticoid receptor positive (GR+), androgen receptor positive (AR+), ERalpha+ and ERbeta+ cells were not different among patients with rheumatoid arthritis and osteoarthritis. In patients with osteoarthritis, the density of GR+ cells positively correlated with the density of AR+, ERalpha+ and ERbeta+ cells (p = 0.007), which was not observed in patients with rheumatoid arthritis. This indicates positively coupled steroid hormone receptor expression in patients with osteoarthritis but not in those with rheumatoid arthritis. In patients with rheumatoid arthritis, secretion of synovial IL6 and IL8 positively correlated with the density of ERalpha+ and ERbeta+ cells (not with gluco-corticoid receptor and androgen receptor), which was not found in the synovium of patients with osteoarthritis. This indicates that inflammatory factors might up regulate the expression of oestrogen receptors in patients with rheumatoid arthritis, or vice versa. CONCLUSIONS: In patients with osteoarthritis, expression of different steroid receptors is positively coupled, which was not observed in the synovium of patients with rheumatoid arthritis. This uncoupling phenomenon in rheumatoid arthritis might lead to an imbalance of the normal synovial homeostasis.     

TNF-α antagonist use and risk of hospitalization for infection in a national cohort of veterans with rheumatoid arthritis

Medications used to treat rheumatoid arthritis (RA) may confer an increased risk of infection. We conducted a retrospective cohort study of veterans with RA followed in the United States Department of Veterans Affairs health care system from October 1998 through September 2005. Risk of hospitalization for infection associated with tumor necrosis factor (TNF)-α antagonists therapy was measured using an extension of Cox proportional hazards regression, adjusting for demographic characteristics, comorbid illnesses, and other medications used to treat RA. A total of 20,814 patients met inclusion criteria, including 3796 patients who received infliximab, etanercept, or adalimumab. Among the study cohort, 1465 patients (7.0%) were hospitalized at least once for infection. There were 1889 hospitalizations for infection. The most common hospitalized infections were pneumonia, bronchitis, and cellulitis. Age and several comorbid medical conditions were associated with hospitalization for infection. Prednisone (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.88-2.43) and TNF-α antagonist use (HR, 1.24; 95% CI, 1.02-1.50) were associated with hospitalization for infection, while the use of disease-modifying antirheumatic drugs (DMARDs) other than TNF-α antagonists was not. Compared to etanercept, infliximab was associated with risk for hospitalization for infection (HR, 1.51; 95% CI, 1.14-2.00), while adalimumab use was not (HR, 0.95; 95% CI, 0.68-1.33). In all treatment groups, rate of hospitalization for infection was highest in the first 8 months of therapy. We conclude that patients with RA who are treated with TNF-α antagonists are at higher risk for hospitalization for infection than those treated with other DMARDs. Prednisone use is also a risk factor for hospitalization for infection.     

Reduction of plasma IL-6 but not TNF-α by methotrexate in patients with early rheumatoid arthritis: a potential biomarker for radiographic progression

Objective

To determine the effect of methotrexate (MTX) on plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and to investigate their associations with clinical and radiographic responses in patients with early rheumatoid arthritis (RA).

Methods

Sixty-two untreated RA patients with the disease duration of ≤36 months in whom MTX was initiated were consecutively identified in our prospective RA cohort and included in this study. Concomitant use of prednisolone and synthetic disease-modifying anti-rheumatic drugs with MTX was allowed, but patients who used biological agents were excluded. Plasma IL-6 and TNF-α levels were measured at the time of diagnosis (baseline) and 1 year later. The relationships of the clinical and radiographic data with plasma levels of IL-6 and TNF-α were analyzed.

Results

The median age of the patients was 57 years, 49 patients were female, and the median disease duration was 3 months. Forty-six (74.2 %) patients were anti-cyclic citrullinated protein antibody-positive. Serum C-reactive protein (CRP), plasma IL-6, and DAS28 decreased significantly (p <0.001) after MTX treatment, but plasma TNF-α did not. Radiographic progression was significantly correlated with disease activity score and plasma IL-6 levels but not with CRP or TNF-α after MTX treatment. Patients with plasma IL-6 level above 4.03 pg/ml showed clinically relevant radiographic progression with a sensitivity of 91.7 % and a specificity of 88.0 %.

Conclusion

In this early RA cohort, we demonstrated a significant (p <0.001) reduction of plasma IL-6, but not TNF-α, during MTX treatment. The post-treatment IL-6 level was a strong indicator of radiographic progression.     

Chloroquine-induced bull’s eye maculopathy in rheumatoid arthritis: related to disease duration?

Chloroquine diphosphate has been used in the treatment of various rheumatic diseases, including rheumatoid arthritis. The most important of its side effects is retinopathy. If not diagnosed early, this lesion can evolve into irreversible bull’s eye maculopathy and visual loss. The aim of this study was to define the outcome of chloroquine-induced maculopathy after cessation of chloroquine therapy and also to identify the risk factors involved in case of retinopathy evolution. The design of this cohort study was longitudinal and retrospective. Over the period spanning 2000 to 2005, out of 607 medical records of patients with rheumatoid arthritis followed in our Division of Rheumatology, 27 had been diagnosed with chloroquine-induced maculopathy through clinical funduscopy with pupil dilation. In all cases, there was immediate chloroquine intake cessation. After a mean time of 5 years, 16 of these patients were available for follow-up and underwent a new ophthalmologic evaluation by funduscopy, using biomicroscopy and angiofluorescein when necessary. Sequelae maculopathy were reconfirmed in all 16 cases, but progression to advanced stage (bull’s eye maculopathy) was found in half of the cohort, even though chloroquine had been suspended. All patients complained of visual alterations, but without progression. Comparison between patient groups with and without bull’s eye maculopathy revealed a statistically significant longer rheumatoid arthritis disease history in the former group. Also, the bull’s eye group had higher dose intakes of chloroquine and over a longer period compared to the other group, but not statistically significant. This study corroborates the progression of maculopathy even after cessation of chloroquine intake, pointing out the need for careful screening in the high-risk patients. Furthermore, it indicates that duration of rheumatoid arthritis disease could be a possible factor linked to worse prognosis of chloroquine-induced maculopathy.     

Drug-free holiday in patients with rheumatoid arthritis: a qualitative study to explore patients’ opinion

Clinical trials have shown that in patients with long-standing low disease activity, tapering and/or stopping antirheumatic medication is a realistic option. The objective of this study is to explore patients’ opinion about tapering and discontinuing antirheumatic drugs. This qualitative study is based on interviews with 20 patients with rheumatoid arthritis (RA) about RA treatment and treatment discontinuation through structured interviewing. Interviews were tape-recorded, transcribed verbatim, and screened by three assessors independently for meaning units. Not only positive emotions about drug discontinuation such as hope, happiness, and relief, but also fear and disappointment were mentioned. Some patients expect that drug discontinuation will be possible in other patients and/or themselves, while others do not expect this. The concept of increase in disease activity after discontinuing medication was mentioned, and while patients expect that disease activity will decrease again after restarting medication, they expect that this will take (too much) time. Positive emotions about the option to taper and discontinue antirheumatic medication, with negative expectations is a common combination in these RA patients. In particular, patients expect that disease activity will flare and that improvement upon restarting medication will take time. Patients’ expectations and feelings should be addressed before drug tapering is attempted in a clear strategy of continued monitoring of disease activity.     

Side effects of TNF-α blockers in patients with psoriatic arthritis: evidences from literature studies

Psoriatic arthritis is an inflammatory rheumatic disorder, which occurs in patients with skin and/or nail psoriasis. In psoriatic arthritis, the importance of biologic mediators modulating inflammatory reaction, such as tumor necrosis factor, and the knowledge on their role in the pathogenesis of psoriatic arthritis influence the therapeutic choices. In the last years, the introduction of biologic drugs has greatly changed the treatment of psoriasis and psoriatic arthritis. In fact, tumor necrosis factor-α blockers demonstrated an effective action in the treatment of both skin and joint manifestations of psoriatic arthritis, but they have some adverse effects. The aim of this review is to revisit the literature data on adverse effects of tumor necrosis factor-α blockers in patients with psoriatic arthritis.