Traditional Disease-modifying Antirheumatic Drugs Research Articles

Tofacitinib in Adult Patients with Active Rheumatoid Arthritis: Budget Impact Analysis

Tofacitinib is a new drug in Russian pharmaceutical market indicated for adult patients with active rheumatoid arthritis (RA) and an inadequate response or intolerance to previous treatment with one or more traditional disease-modifying antirheumatic drugs (DMARDs). To assess the budget impact of tofacitinib for RA treatment from Russian healthcare perspective. The Excel-based budget impact model (BIM) compared two scenarios of RA treatment: current practice without tofacitinib (1) and new practice when tofacitinib is one of the treatment options (2). Current practice included RA treatment with traditional basic DMARDs, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticosteroids (GCS) and biologic drugs which are recommended by guidelines and commonly prescribed in Russia (adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, abatacept, tocilizumab and rituximab). BIM considered 3-year time horizon and included direct medical costs for drugs and their administration. Costs calculations were based on the registered marginal sales prices of drugs except tofacitinib, when the proposed manufacturer’s price was used; and tariffs for medical services in Russian healthcare in 2016. The market share of tofacitinib was modeled due to manufacture’s forecast. Scenario with tofacitinib is a cost saving option for Russian healthcare due to its lower price if compared with biologic drugs and possible use in outpatient setting. 8,223, 8,285 and 8,348 patients are treated in the 1-st, 2-nd and 3-rd year respectively, with the gradual increase of tofacitinib market share from 0% to 8.3%. The total costs for three years will be 22.5 billion rubles (€350.05 million) and 21.8 billion rubles (€339.34 million), for the 1st and 2nd scenarios respectively. Thus, the budget expenditures due to introduction of tofacitinib are reduced for 688.35 million rubles (€10.71 million) within 3 years. Introduction of tofacitinib into medical practice of active RA treatment will significantly reduce the Russian healthcare system expenses.

RABBIT risk score and ICU admission due to infection in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) patients are at increased risk of infection. Aim of the present study was to investigate whether RA patients admitted to an intensive care unit (ICU) due to infection have higher Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) risk scores compared to control RA patients. Seventy-four RA patients (32.4% male) admitted to an ICU due to infection (from January 2002 to December 2013) and 74 frequency-matched control RA patients (16.2% male) were included in this cross-sectional study. There was strong evidence for a higher RABBIT risk score in ICU patients (median 2.0; IQR 1.3-3.2) as compared to controls (1.3; IQR 0.8-2.0; p<0.0001). Traditional disease-modifying anti-rheumatic drugs (DMARDs) (82.4 vs 64.9%; p=0.015) and biological DMARDs (28.4 vs 14.9%; p=0.012) were more frequently given to RA patients without ICU admission. Glucocorticoid users were more frequently found in the ICU group (51.4 vs 31.1%; p=0.012). In a multivariable analysis tDMARD use was associated with lower (OR 0.38; 95% CI 0.15-0.93; p=0.034) and glucocorticoid use with borderline higher odds of ICU admission (OR 2.05; 95% CI 0.92-4.58; p=0.078). Chronic obstructive pulmonary disease (OR 2.89; 95% CI 1.10-7.54; p=0.03), chronic kidney disease (OR 16.08; 95% CI 2.00-129.48; p=0.009), and age category (OR 2.67; 95% CI 1.46-4.87; p=0.001) were strongly associated with ICU admission. There was a strong trend towards higher odds of ICU admission with increasing RABBIT risk score. Use of tDMARDs was associated with lower odds of ICU admission. In an adjusted analysis, bDMARDs were not associated with ICU admission. COPD, CKD, and age were strong risk factors for ICU admission.

Spa therapy adjunct to pharmacotherapy is beneficial in rheumatoid arthritis: a crossover randomized controlled trial.

This study aims to investigate whether 2-week spa therapy, as an adjunct to usual pharmacological therapy, has any beneficial effect in patients with rheumatoid arthritis (RA). In this single-blind crossover study, 50 patients were randomly assigned in a 1:1 manner to receive usual pharmacological therapy plus 2-week spa therapy or usual pharmacological therapy alone (period 1.6months); after a 9-month washout, patients were crossed over to the opposite assignment (period 2.6months). Spa therapy program included a daily saline balneotherapy session at 36-37°C for 20min except Sundays. The clinical outcomes were evaluated at baseline, after spa therapy (2weeks) and 3 and 6months after the spa therapy in both period and were pain (Visual Analogue Scale (VAS)), patient and physician global assessments (VAS), Health Assessment Questionnaire (HAQ), and Disease Activity Score (DAS28). Spa therapy was superior to control therapy in improving all the assessed clinical outcomes at the end of the spa therapy. This superiority persisted significantly in physician global assessment (p=0.010) and with a trend in favor of spa group in patient global assessment (p=0.058), function (p=0.092), and disease activity (p=0.098) at 3months. Statistically significant improvements were found in spa therapy compared to control in disease activity (p=0.006) and patient (p=0.020) and physician global (p=0.011) assessments, and a trend toward improvements in pain (p=0.069) and swollen joints (p=0.070) at 6months. A 2-week spa therapy adjunct to usual pharmacological therapy provided beneficial clinical effects compared to usual pharmacological therapy alone, in RA patients treated with traditional disease-modifying antirheumatic drugs. These beneficial effects may last for 6months.

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty.

This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data.

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty.

This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data.

Comparative study of elderly-onset versus young-onset rheumatoid arthritis: clinical features and treatment

Objective To compare the clinical features and treatment between elderly onset rheumatoid arthritis(EORA)and young onset rheumatoid arthritis(YORA). Methods The EORA patients(n=60)and the YORA patients(n=90)were compared regarding sex ratio, activity of pathogenetic condition, disease severity, extra-articular manifestations, complications, laboratory indexes, and therapeutic schedules. Results The female/male ratio was 36/24(1.50∶1.0)in group EORA, and 69/21(3.3∶1.0)in group YORA, with higher female/male ratio in in group YORA.The frequency of morning stiffness, proximal interphalangeal joint involvement and metacarpophalangeal joint involvement were lower in group EORA(53.3%, 46.676% and 61.67%)than in group YORA(72.2%, 77.8%, 81.11%)(χ2=5.521, 15.385, 6.960, P=0.018, 0.000, 0.008 respectively). Large joints involvement at onset of rheumatoid arthritis was higher in group EORA(38.33%)than in group YORA(18.89%)(χ2=6.960, P=0.008). The joint swollen and tender counts were comparatively less(16.51±7.34)and(15.92±8.44)in group EORA than in group YORA(22.46±7.58)and(23.8±8.93)(t=5.080、5.740, all P=0.000)respectively.The accumulated disease activity score(DAS28)was higher in group EORA(5.86±1.57)than in YORA(4.92±1.64)(t=3.360, P=0.001). HAQ score was lower in group EORA(0.83±0.85)than in group YORA(1.16±0.91)(t=2.43, P=0.02). Comorbid conditions such as osteoarthritis, osteoporosis, cardiovascular disease and chronic renal insufficiency were more frequent in group EORA(51.7%, 31.7%, 18.3% and 15.00%)than in group YORA(27.8%, 15.6%, 5.6% and 4.4%)(χ2=11.722, 5.445, 6.168, 5.067, P=0.001, 0.020, 0.013, 0.024). The positive rate of RF were more higher in YORA(70.00%)than in group EORA(48.33%)(χ2=7.126 P=0.008). The synthetic or biologic traditional DMARDs(disease modifying anti-rheumatic drugs)were widely used in group YORA(78.9% and 31.1%)than in group EORA(40.0% and 10.0%)(χ2=14.940, 9.153, P=0.000, 0.002). The more frequently used program with glucocorticoids hormonal therapy was received in group EORA(38.3%)than in group YORA(20.00%)(χ2=6.092 P=0.014). Conclusions EORA patients differs from YORA patients in many of ways, including a more balanced gender distribution, atypical presentation at onset of disease, more frequent involvement of large joints, seronegativity in a higher percentage, and less frequent positivity of anti CCP-antibody, which makes diagnosis more difficult in the earlier period.Therapy of EORA with DMARDs should be instituted based on disease activity, if there is no contraindication. Key words: Elderly onset rheumatoid arthritis; Disease activity

Malignancy Incidence, Management, and Prevention in Patients with Rheumatoid Arthritis.

Traditional and biologic disease-modifying antirheumatic drugs (DMARDs) are effective medications for the management of rheumatoid arthritis (RA). However, the effects of these medications on immune function raises concern that they may increase long-term cancer risk. The baseline risk for some cancers appears to differ in patients with RA compared to the general population, with the former having an increased risk of lymphoma, lung cancer and renal cancer, but a decreased risk of colorectal and breast cancer. Some DMARDs appear to increase the rate of specific cancer types (such as bladder cancer with cyclophosphamide), but few appear to increase the overall cancer risk. Studying the link between lymphoma and disease severity in RA is complicated because patients with persistently active disease are at increased risk for lymphoma, and disease severity correlates with more intense use of immunosuppressive medications. Overall, cancer risk in patients with RA is slightly above that of the general population, with the increased risk likely secondary to an increased risk of lymphomas in those with high disease activity. Risk mitigation includes management of RA disease activity as well as age- and sex-appropriate cancer screening.

Cardiovascular disease in rheumatoid arthritis: medications and risk factors in China.

This study aims to assess the risk factors of cardiovascular disease (CVD) and to determine the association of traditional and biologic disease-modifying anti-rheumatic drugs (DMARDs) with risk for CVD in Chinese rheumatoid arthritis (RA) patients. A cross-sectional cohort of 2013 RA patients from 21 hospitals around China was established. Medical history of CVD was documented. The patients' social background, clinical manifestations, comorbidities, and medications were also collected. Of the 2013 patients, 256 had CVD with an incidence of 12.7%. Compared with non-CVD controls, RA patients with CVD had a significantly advanced age, long-standing median disease duration, more often male and more deformity joints. Patients with CVD also had higher rates of smoking, rheumatoid nodules, interstitial lung disease, and anemia. The prevalence of comorbidities, including hypothyroidism, diabetes mellitus (DM), hypertension, and hyperlipidemia, was also significant higher in the CVD group. In contrast, patients treated with methotrexate, hydroxychloroquine (HCQ), and TNF blockers had lower incidence of CVD. The multivariate analysis showed that the use of HCQ was a protective factor of CVD, while hypertension, hyperlipidemia, and interstitial lung disease were independent risk factors of CVD. Our study shows that the independent risk factors of CVD include hypertension, hyperlipidemia, and interstitial lung disease. HCQ reduces the risk of CVD in patients with RA.

Treatment with belimumab in systemic lupus erythematosus does not impair antibody response to 13-valent pneumococcal conjugate vaccine.

Background/purpose The objective of this study was to explore the impact of systemic lupus erythematosus and belimumab given in addition to standard of care therapy on 13-valent conjugated pneumococcal vaccine (PCV13) response. Methods Forty-seven systemic lupus erythematosus patients and 21 healthy controls were immunized with a single dose of 13-valent conjugated pneumococcal vaccine. Forty systemic lupus erythematosus patients were treated with traditional disease-modifying anti rheumatic drugs, 11 of those received belimumab in addition, and 32 patients were treated with concomitant prednisolone. Quantification of serotype specific IgG levels to 12 pneumococcal capsular polysaccharides was performed in serum taken before and four to six weeks after vaccination using multiplex fluorescent microsphere immunoassay. IgG levels against serotypes 23F and 6B were also analyzed using standard enzyme-linked immunosorbent assays. Opsonophagocytic assay was performed on serotype 23F to evaluate the functionality of the antibodies. Pre- and post-vaccination log transformed antibody levels were compared to determine the impact of systemic lupus erythematosus diagnosis and different treatments on antibody response. Results Systemic lupus erythematosus patients as a group showed lower post-vaccination antibody levels and lower fold increase of antibody levels after vaccination compared to controls ( p = 0.02 and p = 0.009, respectively). Systemic lupus erythematosus patients treated with belimumab in addition to standard of care therapy or with only hydroxychloroquine did not differ compared to controls, whereas the other treatment groups had significantly lower fold increase of post-vaccination antibody levels. Higher age was associated with lower post-vaccination antibody levels among systemic lupus erythematosus patients. Conclusion Belimumab given in addition to traditional disease-modifying anti rheumatic drugs or prednisolone did not further impair antibody response to 13-valent conjugated pneumococcal vaccine.

Psoriatic arthritis: state of the art review

Psoriatic arthritis (PsA) accounts for around 20% of referrals to the early arthritis clinic and presents a significant diagnostic and management challenge. Early diagnosis is important to prevent long term functional disability and to ensure optimal management of arthritis and key comorbidities. From the rheumatologist's perspective, the differential diagnosis includes rheumatoid arthritis, gout and other inflammatory arthritides. Once diagnosed, it is essential to assess the disease fully, including arthritis, enthesitis, dactylitis, skin/nail disease and axial involvement. Using this information, appropriate treatment can be planned using therapies that are effective at treating the relevant domains of disease. Despite poor data, traditional disease-modifying anti-rheumatic drugs are commonly used and have been effective in observational studies. Following tumour necrosis factor inhibitors, which have proven excellent efficacy in multiple domains of PsA, new biologics are available or in development and will improve treatment options for people with refractory PsA.

An overview of the biological disease modifying drugs available for arthritic conditions in South Africa

The past decade has seen a major change in the treatment options and strategies for rheumatoid arthritis (RA) and the other immune-mediated arthritic diseases. The disease modifying antirheumatic drugs (DMARDs) are now used in early stages of the disease in order to preserve joint architecture. There are two groups of DMARDs, the small molecules, like methotrexate, and the biological DMARDs, which are frequently referred to as “magic bullets” since they target specific cytokines and immune cells associated with arthritic conditions. They are monoclonal antibodies or fusion proteins designed to bind and inactivate immune targets.Tumour necrosis factor-alpha (TNF-α) plays an important role in the pathogenesis of rheumatoid disorders and is the target of four biological DMARDs, etanercept, infliximab, golimumab and adalimumab. The other biological DMARDs include abatacept, rituximab and tocilizumab and these prevent T-cell costimulation, cause the depletion of mature CD20 positive B cells or prevent the activation of the interleukin-6 receptor molecule, respectively. Ustekinumab, a monoclonal antibody against IL12/IL23 is effective in psoriatic arthritis.Biological agents are indicated when patients do not respond adequately to the traditional DMARDs. Numerous clinical trials have shown that the biological agents reduce joint inflammation and erosive damage, especially when used in combination with methotrexate.Apart from their prohibitive cost, the biological agents are not without potentially serious adverse effects with infections being the main concern. The TNF-α inhibitors increase the risk for tuberculosis and other opportunistic infections, whereas the non-TNF-α immune inhibitors increase the risk for opportunistic viral, fungal and bacterial infections. This review provides an overview of the biological agents currently available in South Africa.

Use of Tumor Necrosis Factor-Alpha Inhibitors in Children and Young Adults With Juvenile Idiopathic Arthritis or Rheumatoid Arthritis.

To characterize the use of tumor necrosis factor-α inhibitors (TNFIs) in children with juvenile idiopathic arthritis (JIA) and young adults with rheumatoid arthritis (RA). Patients with incident JIA or RA were identified by using the Truven Health MarketScan Commercial Claims and Encounters database from 2009 to 2013. The incident diagnosis was defined as no prior claims with a JIA/RA code and no JIA/RA medications recorded during the previous 6 months. TNFI use patterns were examined, including switching among TNFIs, adherence, persistence, and time from diagnosis to TNFI use. Earlier TNFI treatment without prior use of traditional disease-modifying antirheumatic drugs (DMARDs) and use of specific TNFIs were analyzed by age group. Of 6929 children and young adults with new diagnoses of JIA/RA, 18.6% were treated with TNFIs. In these TNFI users, 39.1% received earlier TNFI therapy without prior use of DMARDs. The use of TNFIs was higher in patients diagnosed between 2012 and 2013 than that in patients diagnosed between 2009 and 2011 (hazard ratio 1.13, 95% confidence interval 1.00-1.28). Etanercept was the most commonly used, especially by children aged < 12 (75.5%) and adolescents aged 12 to 17 (62.5%) years. Adherence measured as mean proportion of days covered ranged from 70.4% to 93.2% for individual TNFI agents. Only about 60% of patients continuously took TNFIs for 12 months. When switching occurred, switching from etanercept to adalimumab was the most common pattern. Earlier TNFI therapy was observed in 39.1% of children and young adults taking TNFIs. In addition, the time to the first TNFI prescription became shorter over the study period. Future research should evaluate the long-term effectiveness and safety of this more aggressive TNFI therapy.

Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane Systematic Review and network meta-analysis (NMA).

Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane Systematic Review and network meta-analysis (NMA).

Cardiovascular risk in patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis: a prospective study of data from the Secure Anonymised Information Linkage databank

BackgroundThe increased risk of cardiovascular disease in individuals with rheumatoid arthritis, psoriatic arthritis, and psoriasis is well known. However, the precise cardiovascular risk in psoriasis and psoriatic arthritis is less understood, particularly the relative contribution of traditional cardiovascular risk factors, such as obesity, smoking, and systemic inflammation as measured by C-reactive protein and erythrocyte sedimentation rate. The objective of this study was to compare the incidence of major adverse cardiac events (MACE) among patients with rheumatoid arthritis, psoriatic arthritis, and psoriasis with population controls adjusting for traditional cardiovascular risk factors, systemic inflammation, and disease-modifying anti-rheumatic drug (DMARD) treatment to better define cardiovascular risk in patients with these conditions. MethodsThe study used linked, routinely collected Welsh health data from 1999 to 2013 available from the Secure Anonymised Information Linkage (SAIL) databank, which includes datasets from general practice (GP), hospitals, and rheumatology clinics. Incidence and first occurrence of a MACE was investigated in individuals who were present in the GP system and positive for Read codes for rheumatoid arthritis (n=8650), psoriatic arthritis (2128), psoriasis (24 630), and controls without codes for the conditions investigated (1 187 706). We controlled for traditional cardiovascular risk factors, such as age, sex, smoking, body-mass index, comorbidities (hyperlipidaemia, diabetes, and hypertension), and medication (non-steroidal anti-inflammatory drugs, DMARDs, and steroids). We used a Cox proportional hazard model with the st command in Stata (version 13). FindingsWhen controlling for traditional risk factors, cardiovascular risk was significantly increased for individuals with rheumatoid arthritis (number of MACE events 548, hazard ratio 1·2, 95% CI 1·0–1·3; p=0·038) and psoriasis (879, 1·1, 1·0–1·3; p=0·025), but not for those with psoriatic arthritis (43, 1·0, 0·7–1·5; p=0·887). No interaction between DMARDs and MACE occurrence was observed. InterpretationThere is an increased incidence of cardiovascular disease for patients with rheumatoid arthritis and psoriasis, but not for those with psoriatic arthritis. This finding demonstrates the varying mediators of cardiovascular risk across these conditions and highlights the importance of cardiovascular risk reduction strategies, especially for patients with rheumatoid arthritis and psoriasis, who may benefit from closer monitoring to help reduce the incidence of MACE. FundingSupported by a Pfizer Inflammation Competitive Research Programme grant. The funder had no involvement in the study.

Incidence of Malignancies in a Cohort of Psoriatic Arthritis Patients Taking Traditional Disease Modifying Antirheumatic Drug and Tumor Necrosis Factor Inhibitor Therapy: An Observational Study.

Psoriatic arthritis (PsA) is an inflammatory arthropathy, associated with skin and/or nail psoriasis. As suggested in 2012 by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), studies devoted to assess cancer in the PsA population are still limited and need to be increased. Therefore, the aim of this study was to determine the incidence of malignancies in patients with PsA who are taking conventional and biologic therapies. A cohort of patients with PsA was followed prospectively. At first visit, as well as at each 3-4 month followup visit, according to standardized clinical practice, medical history, and physical and laboratory findings were recorded. Information on the presence of comorbidities, as well as malignancies, was collected. At each visit, data were recorded on radiography and pathology, confirming malignancy diagnosis, when present. A total of 618 patients with PsA were included in the study. In particular, 296 were taking anti-tumor necrosis factor-α (anti-TNF) agents and 322 were taking disease-modifying antirheumatic drugs (DMARD). During the observation period, in the total group, 44 patients (7.1%) had a diagnosis of malignancy. Of them, 14 (4.7%; 95% CI 2.8-7.8; 0.52/100 patient-yrs) received anti-TNF therapy and 30 (9.3%; 95% CI 6.6-13.0; 1.03/100 patient-yrs) received traditional DMARD (p = 0.019). However, after adjusting for major demographic and clinical characteristics, the difference between the 2 treatments was no longer significant (p = 0.480), and the only predictor of malignancy occurrence was age (HR 1.04, 95% CI 1.009-1.073, p = 0.012). Data from this study confirm that biological therapies do not lead to any increased risk for cancer development, when adequately administered and with proper followup.

Infections With Biologics in Rheumatoid Arthritis and Related Conditions: a Scoping Review of Serious or Hospitalized Infections in Observational Studies.

Biologic use is a major advance in the treatment of several autoimmune conditions, including rheumatoid arthritis. In this review, we summarize key studies of serious/hospitalized infections in rheumatoid arthritis (RA). RA is a risk factor for infections. High RA disease activity is associated with higher risk of serious infection. The risk of serious infections with tumor necrosis factor inhibitor (TNFi) biologics is increased in the first 6months of initiating therapy, and this risk was higher compared to the use of traditional disease-modifying anti-rheumatic drugs (DMARDs). Emerging data also suggest that biologics may differ from each other regarding the risk of serious or hospitalized infections. Past history of serious infections, glucocorticoid dose, and older age were other important predictors of risk of serious infections in patients treated with biologics.

Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: A network meta-analysis.

Methotrexate is considered the preferred disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis, but controversy exists on the additional benefits and harms of combining methotrexate with other DMARDs. To compare methotrexate and methotrexate-based DMARD combinations for rheumatoid arthritis in patients naïve to or with an inadequate response (IR) to methotrexate. We systematically identified all randomised controlled trials with methotrexate monotherapy or in combination with any currently used conventional synthetic DMARD , biologic DMARDs, or tofacitinib. Three major outcomes (ACR50 response, radiographic progression and withdrawals due to adverse events) and multiple minor outcomes were evaluated. Treatment effects were summarized using Bayesian random-effects network meta-analyses, separately for methotrexate-naïve and methotrexate-IR trials. Heterogeneity was explored through meta-regression and subgroup analyses. The risk of bias of each trial was assessed using the Cochrane risk of bias tool, and trials at high risk of bias were excluded from the main analysis. The quality of evidence was evaluated using the GRADE approach. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior. 158 trials with over 37,000 patients were included. Methotrexate-naïve: Several treatment combinations with methotrexate were statistically superior to oral methotrexate for ACR50 response: methotrexate + sulfasalazine + hydroxychloroquine ("triple therapy"), methotrexate + several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%, moderate to high quality evidence), compared with 41% for methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression (moderate to high quality evidence) but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of five units on the Sharp-van der Heijde scale. Methotrexate + azathioprine had statistically more withdrawals due to adverse events than oral methotrexate, and triple therapy had statistically fewer withdrawals due to adverse events than methotrexate + infliximab (rate ratio 0.26, 95% credible interval: 0.06 to 0.91). Methotrexate-inadequate response: In patients with an inadequate response to methotrexate, several treatments were statistically significantly superior to oral methotrexate for ACR50 response: triple therapy (moderate quality evidence), methotrexate + hydroxychloroquine (low quality evidence), methotrexate + leflunomide (moderate quality evidence), methotrexate + intramuscular gold (very low quality evidence), methotrexate + most biologics (moderate to high quality evidence), and methotrexate + tofacitinib (high quality evidence). There was a 61% probability of an ACR50 response with triple therapy, compared to a range of 27% to 64% for the combinations of methotrexate + biologic DMARDs that were statistically significantly superior to oral methotrexate. No treatment was statistically significantly superior to oral methotrexate for inhibiting radiographic progression. Methotrexate + cyclosporine and methotrexate + tocilizumab (8 mg/kg) had a statistically higher rate of withdrawals due to adverse events than oral methotrexate and methotrexate + abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments. We found moderate to high quality evidence that combination therapy with methotrexate + sulfasalazine+ hydroxychloroquine (triple therapy) or methotrexate + most biologic DMARDs or tofacitinib were similarly effective in controlling disease activity and generally well tolerated in methotrexate-naïve patients or after an inadequate response to methotrexate. Methotrexate + some biologic DMARDs were superior to methotrexate in preventing joint damage in methotrexate-naïve patients, but the magnitude of these effects was small over one year.

Sjögren Syndrome: Why Do Clinical Trials Fail?

Sjögren syndrome (SS) comprises glandular and extraglandular manifestations. Double-blind prospective trials of traditional disease-modifying antirheumatic drugs and biologics have failed because they have not improved benign symptoms, the major cause of lowered quality of life. Rituximab has proven effective in SS patients with associated mixed cryoglobulinemia, parotid gland swelling, lymphocytic interstitial pneumonitis, thrombocytopenia, and other manifestations. There were few of these SS patients in the trials required for FDA approval. Most patients had benign symptoms and did not show benefit, leading to failure of the study. This article examines the reasons for these failures and proposes future directions.

Differential response of serum amyloid A to different therapies in early rheumatoid arthritis and its potential value as a disease activity biomarker.

BackgroundThe aim was to compare the effect of etanercept (ETN) and conventional synthetic disease-modifying anti-rheumatic drug (DMARD) therapy on serum amyloid A (SAA) levels and to determine whether SAA reflects rheumatoid arthritis (RA) disease activity better than C-reactive protein (CRP).MethodsWe measured SAA and CRP at baseline, 24, 48, and 102 week follow-up visits in 594 patients participating in the Treatment of early RA (TEAR) study. We used Spearman correlation coefficients (rho) to evaluate the relationship between SAA and CRP and mixed effects models to determine whether ETN and methotrexate (MTX) treatment compared to triple DMARD therapy differentially lowered SAA. Akaike information criteria (AIC) were used to determine model fits.ResultsSAA levels were only moderately correlated with CRP levels (rho = 0.58, p < 0.0001). There were significant differences in SAA by both visit (p = 0.0197) and treatment arm (p = 0.0130). RA patients treated with ETN plus MTX had a larger reduction in SAA than patients treated with traditional DMARD therapy. Similar results were found for serum CRP by visit (p = 0.0254) and by treatment (p < 0.0001), with a more pronounced difference than for SAA. Across all patients and time points, models of the disease activity score of 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) using SAA levels were better than models using CRP; the ΔAIC between the SAA and CRP models was 305.ConclusionsSAA may be a better biomarker of RA disease activity than CRP, especially during treatment with tumor necrosis factor (TNF) antagonists. This warrants additional studies in other cohorts of patients on treatment for RA.Trial registration(ClinicalTrials.gov identifier: NCT00259610, Date of registration: 28 November 2005)

Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis.

Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis.