Tumor Necrosis Factor Blocker Therapy Research Articles

Central nervous system involvement in rheumatoid arthritis: possible role of chronic inflammation and tnf blocker therapy.

Rheumatoid arthritis (RA) is a chronic disease, the etiology of which has yet to be clarified, which causes activation of proinflammatory pathways that bring about joint and systemic inflammation. Although peripheral nervous system anomalies are observed widely in RA, very few case reports on changes in the central nervous system (CNS) have been published. In recent years, the pathophysiology of CNS involvement that can occur in RA has attracted a great deal of attention. Emphasis has focused on the possibility that CNS involvement occurs due to blood-brain barrier (BBB) damage associated with chronic inflammation. The present study was performed to investigate the possible effects of BBB dysfunction and tumor necrosis factor (TNF) blocker therapy on BBB function, which may cause CNS damage in patients with RA. 58 RA patients [47 (81.0%) females, 11 (19.0%) males] and 34 healthy controls [24 (70.6%) females, 10 (29.4%) males] were included in the study. All RA patients were on synthetic DMARD therapy at the beginning. Thirty patients continued DMARD therapy, and 28 patients with high disease activity were started on TNF blocker therapy. All demographic characteristics of the patients were recorded. Disease activity was evaluated using the Disease Activity Score 28-joint count C reactive protein. The Mini-Mental State Examination was used to evaluate cognitive function, and the Fazekas scale was used to assess cranial lesions visualized by magnetic resonance imaging (MRI). Patients' peripheral blood S100β, glial fibrillary acidic protein (GFAP), claudin, interleukin (IL)-17, and IL-1β levels were measured at the beginning of the study and after 6months. Demographic characteristics (including sex, age, and body mass index) were similar in the RA and control groups. S100β and GFAP levels were significantly higher in the patient group than in the control group. In the group that was started on TNF blocker therapy, S100β and GFAP levels were significantly decreased 6months after commencement of treatment. No difference was observed between the RA and control groups in terms of hyperintense lesions seen on cranial MRI. The S100β levels increased with lesions in the deep white matter seen on cranial MRI in patients with RA. In conclusion, next to decreasing disease activity and joint erosions by suppressing inflammation, anti-TNF therapy in RA can also suppress potential CNS involvement linked to BBB (blood-brain barrier) dysfunction. Further studies with broader participation and longer patient follow-up are needed to reinforce this hypothesis.

Serological markers in diagnosis of pediatric inflammatory bowel disease and as predictors for early tumor necrosis factor blocker therapy

Objective: To describe the prevalence of serological markers in newly diagnosed treatment-naïve pediatric inflammatory bowel disease (IBD), their utility in differentiating Crohn’s disease (CD), ulcerative colitis (UC) and symptomatic non-IBD patients and whether serological markers are associated with early TNF blocker treatment.Material and methods: Ninety-six children and adolescents <18 years, 58 with IBD and 38 symptomatic non-IBD controls were included. At diagnosis and after 1–2 years, serological antibodies (anti-Saccharomyces cerevisiae antibodies (ASCA), perinuclear anti-neutrophil cytoplasmic antibody (pANCA), flagellin expressed by Clostridial phylum (anti-CBir1), outer membrane porin of Escherichia coli (anti-OmpC), Pseudomonas fluorescens-associated sequence (anti-I2), CRP, ESR and fecal calprotectin were analyzed. The choice of treatment was made at the discretion of the treating pediatrician.Results: Of the IBD patients, 20 (36%) and 26 (47%) were positive for ASCA and pANCA compared to 3(8%), p < .01 and 10 (27%), p = .04 of the controls. Thirteen (72%) of UC patients were pANCA positive, versus 13 (35%) of CD patients (p < .01). None of the UC patients was ASCA positive versus 20 (54%) of CD patients (p < .0001). Compared to conventionally treated patients, the 18 (49%) TNF blocker treated CD patients had higher presence of ASCA (p < .01), lower presence of pANCA (p = .02) and higher levels of fecal calprotectin, CRP and ESR at diagnosis. In multivariate analyses ASCA and pANCA status, but not CRP, ESR or calprotectin, were independently associated with early TNF blocker treatment.Conclusions: ASCA and pANCA status were associated with having IBD and with early TNF blocker treatment in CD.

Effective tumour necrosis factor-blocking therapy reduces reactive oxygen metabolite level in rheumatoid arthritis.

ObjectiveTo assess circulating levels of derived reactive oxygen metabolites (ROMs) in patients with active rheumatoid arthritis (RA), before and during antitumour necrosis factor (TNF)-α therapy.MethodsPatients with active RA and failed previous treatment with disease-modifying antirheumatic drugs received subcutaneous anti-TNF-α for 52 weeks. Circulating hydrogen peroxide was quantified as a marker of oxidative stress at baseline and at 24 and 52 weeks.ResultsThe study included 40 patients. Circulating dROM levels were significantly reduced compared with baseline after 24 and 52 weeks’ of anti-TNF-α treatment (33.2 ± 10.0 mgH2O2/dl, 29.5 ± 7.0 mgH2O2/dl and 29.3 ± 9.0 mgH2O2/dl, respectively). There was a significant direct correlation between disease activity score and ROM levels.ConclusionTNF-α inhibition can control disease activity and reduce circulating levels of reactive oxygen species in patients with RA.

Study on the protective effect of the KIR3DL1 gene in ankylosing spondylitis.

Ankylosing spondylitis (AS) is an autoimmune disease that mainly affects the sacroiliac joints and the spine of the lower back. The disease is strongly associated with HLA-B27. Additional genes, single-nucleotide polymorphisms, and molecular components have been identified to be associated with AS, but the exact mechanism that drives disease development remains poorly understood. The killer cell immunoglobulin-like receptors (KIRs) are regulators of cytotoxicity of natural killer cells and T cell subsets and may be relevant in binding to HLA-B27 and the development of AS. We undertook this study to identify possible associations of KIR genotype with susceptibility to AS and disease characteristics including the presence of the HLA-B27 allele, disease severity, and uveitis. We performed complete genotyping of the KIR locus in 303 Caucasian AS patients, 119 randomly selected healthy Caucasian controls, and 50 HLA-B27-positive healthy Caucasian controls by multiplex ligation-dependent probe amplification assay for detection of gene presence and copy number. We did not observe a significant association of any specific KIR gene or haplotype with susceptibility to AS or any other clinical manifestation. Disease severity, as measured by fulfilling the criteria for treatment with tumor necrosis factor blocking therapy, was linked to a lower number of genes for the functional variant of KIR3DL1 (P = 0.007). Our exploratory study indicates that KIR genes are not a major risk factor for susceptibility to AS. However, the data do suggest a role for KIRs in progression of the disease, whereby KIR3DL1 has a protective effect against the more severe manifestations of AS.

Tumor necrosis factor blocking therapy and congestive heart failure in patients with inflammatory rheumatic disorders: a systematic review.

Tumour necrosis factor (TNF) blocking therapy is an effective treatment for chronic inflammatory arthritis. As circulating TNF might induce or exacerbate the development of congestive heart failure (CHF), several trials have investigated the effect of TNF blocking therapy on CHF. However, due to inefficacy and even a risk of exacerbation of CHF, TNF blocking therapy has since then been contraindicated in patients with advanced CHF, New York Heart Association class III and IV. We review current knowledge on the pathophysiological mechanisms and safety of TNF blocking therapy in chronic inflammatory arthritis patients with regard to CHF. A systematic search of the literature published up till December 2013 was conducted in MEDLINE, EMBASE and the Cochrane Library to identify all studies investigating the effect of TNF blocking therapy on the occurrence and risk of CHF in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). All articles reporting data on the prevalence or incidence of CHF during treatment with TNF blocking therapy in patients with in RA, AS or PsA were included. Also imaging studies and studies with biomarkers, investigating the effect of TNF blocking therapy on cardiac function were included. In total, 54 studies were included. Results from large prospective registries suggest that first, a potentially harmful effect of TNF blocking therapy on the incidence of CHF in older RA patients cannot be excluded and that no harmful effect was observed of TNF blocking therapy in other patients. Second, we found that TNF blocking therapy potentially improves several echocardiographic parameters of cardiac function in RA, AS and PsA, but due to small sample sizes, these results require validation in larger studies. Third, we found improvement in NT-proBNP levels after use of TNF blocking therapy in both RA and AS. Based on current literature, in patients with chronic inflammatory arthritis and concomitant symptomatic mild-tomoderate CHF (NYHA class I or II), treatment with TNF blocking therapy is not contraindicated. In chronic inflammatory arthritis patients with concomitant symptomatic moderate-to-severe CHF, NYHA class III-IV, treatment with TNF blocking therapy should be avoided if possible. Whenever, treatment with TNF-blocking therapy is considered in these patients consultation with a cardiologist is recommended before treatment is initiated.

National and regional dose escalation and cost of tumor necrosis factor blocker therapy in biologic-naïve rheumatoid arthritis patients in US health plans

Objective:This study examined the proportion and magnitude of dose escalation nationally and regionally among rheumatoid arthritis (RA) patients treated with TNF-blockers and estimated the costs of TNF-blocker therapy.Methods:This retrospective cohort study used claims data from US commercially-insured adult RA patients who initiated adalimumab, etanercept, or infliximab therapy between 2005–2009. Biologic-naïve patients enrolled in the health plan for ≥6 months before and ≥12 months after therapy initiation were followed for 12 months. Dose escalation was assessed using three methods: (1) average weekly dose > recommended label dose, (2) average ending dispensed dose > maintenance dose, and (3) average dose after maintenance dose > maintenance dose. Annual cost of therapy included costs for mean dose and drug administration fees.Results:Overall, 1420 etanercept, 874 adalimumab, and 454 infliximab patients were included. A significantly lower proportion of etanercept-treated patients had dose escalation using the average weekly dose (3.9% vs 21.4% adalimumab and 69.6% infliximab; p < 0.0001), average ending dispensed dose (1.1% vs 10.6% adalimumab and 63.0% infliximab; p < 0.0001), and average dose after maintenance dose methods (2.8% vs 15.7% adalimumab and 69.6% infliximab; p < 0.0001). Regional dose escalation rates and magnitudes of escalation were directionally consistent with national rates. Etanercept had the lowest cost per treated RA patient ($19,690) compared to adalimumab ($23,020) and infliximab ($24,030).Limitations:Exclusion of patients not on continuous TNF-blocker therapy limits the generalizability; however, ∼50% of patients were persistent on therapy for 12 months. The study population comprised RA patients in commercial health plans, thus the results may not be generalizable to Medicare or uninsured populations.Conclusions:In this retrospective study, etanercept patients had the lowest proportions and magnitudes of dose escalation across all methods compared to adalimumab and infliximab patients nationally and regionally. Mean annual cost was lowest for etanercept-treated patients.

Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential.

Clinical and experimental evidence suggest that interleukin-17A (IL-17A; also known as IL-17) is an attractive therapeutic target in rheumatoid arthritis (RA). Rheumatoid synovial tissue produces IL-17A, which causes cartilage and bone degradation in synovial and bone explants. Overexpression of IL-17A induces synovial inflammation and joint destruction in animal RA models. These effects are attenuated in IL-17A-deficient animals and by agents that block IL-17A. Serum IL-17A levels and, to a greater extent, synovial fluid IL-17A levels are elevated in many patients with RA. In some RA cohorts, higher IL-17A levels have been associated with a more severe clinical course. Several IL-17A blockers, including the anti-IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials. Of these, secukinumab is the most advanced with respect to clinical evaluation in RA, with phase III trials ongoing in patients on background methotrexate who had inadequate responses to previous tumor necrosis factor blocker therapy.

Treatment Patterns in the First Year After Initiating Tumor Necrosis Factor Blockers in Real-World Settings

Tumor necrosis factor (TNF)-blockers are approved for use in several immune-related conditions, but treatment patterns, such as switching between TNF blockers or restarting treatment after a gap in therapy, are not clearly established. This analysis examined TNF blocker treatment patterns within the first year after initiating treatment with etanercept, adalimumab, or infliximab in patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis. Administrative claims data from the MarketScan® Commercial Claims and Encounters Database (Thomson Reuters, Ann Arbor, MI, USA) were analyzed for patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis who were continuously enrolled and newly initiated etanercept, adalimumab, or infliximab treatment between January 1, 2005 and July 1, 2009. Persistence (no treatment gap ≥45 days), restarting index therapy (after a ≥45-day treatment gap), switching to a different biologic of interest (certolizumab, golimumab, ustekinumab, alefacept, abatacept, rituximab, or tocilizumab), and stopping (≥45-day treatment gap with no restart or switch) were analyzed for the first year after the index date. A total of 8,454 patients had an index claim for etanercept (n = 4,224), adalimumab (n = 2,941), or infliximab (n = 1,289). Treatment patterns in the first year across all four conditions combined for etanercept, adalimumab, or infliximab, respectively, were: persistence, 42%, 47%, and 56%; restarting, 25%, 19%, and 12%; switching, 13%, 12%, and 13%; and stopping, 20%, 22%, and 19%. The combined rates of either persistence or restarting initial therapy after a treatment gap were 67%, 66%, and 68%, for etanercept, adalimumab, and infliximab, respectively. Most switches (66-92%) were between the three TNF blockers. In the first year after initiating TNF blocker therapy, patients often have a ≥45-day treatment gap; however, approximately two-thirds of patients are either persistent with or restart their index therapy in the year following TNF blocker initiation.

Tumor necrosis factor–blocker therapy persistence, gaps, and switching among patients with psoriatic arthritis

Tumor necrosis factor–blocker therapy persistence, gaps, and switching among patients with psoriatic arthritis

Tumor necrosis factor blocking therapy alters joint inflammation and hypoxia

To examine the effect of tumor necrosis factor (TNF) blocking therapy on hypoxia in vivo, macroscopic and microscopic inflammation, and magnetic resonance imaging (MRI) results in patients with inflammatory arthritis. Patients with inflammatory arthritis (n = 20) underwent full clinical assessment, arthroscopy, synovial biopsy, and MRI before and after initiation of biologic therapy. Macroscopic synovitis/vascularity was assessed with a visual analog scale, and tissue PO(2) (tPO(2) ) was measured at arthroscopy using a Licox probe. Cell-specific markers (CD4, CD8, CD68, CD20, and CD19) and blood vessel maturity were quantified by immunohistologic analysis and dual-immunofluorescence factor VIII/α-smooth muscle actin staining, respectively. Contiguous gadoteric acid-enhanced MRI of the target knee was used to assess synovial enhancement. Biologic therapy responders showed a significant increase of tPO(2) in vivo (P < 0.05). This response was associated with significant reductions in 28-joint Disease Activity Score using the C-reactive protein level (DAS28-CRP) (P = 0.012), macroscopic synovitis (P = 0.017), macroscopic vascularity (P = 0.05), CD4+ T cells (P < 0.041), and CD68+ macrophages (P < 0.011). Blood vessel numbers were also reduced in responders; however, this did not reach statistical significance. Strong inverse correlations were demonstrated between changes in tPo(2) levels and changes in DAS28-CRP (r = -0.53, P < 0.001), CD4 (r = -0.44, P < 0.026), CD68 (r = -0.46, P < 0.003), and macroscopic vascularity (r = -0.314, P = 0.049) after therapy. Furthermore, changes in inflammation as measured by MRI showed a strong inverse correlation with tPO(2) levels (r = -0.688, P < 0.002) and positive correlations with CRP levels (r = 0.707, P = 0.001), macroscopic synovitis (r = 0.457, P = 0.056), macroscopic vascularity (r = 0.528, P= 0.017), CD4 (r = 0.553, P < 0.032), and CD68 (r = 0.670, P < 0.002) after therapy. This is the first study to show that successful biologic therapy significantly improves in vivo synovial hypoxia. Changes are strongly associated with changes in macroscopic and microscopic measures of joint inflammation and MRI improvement. These data further strengthen the concept that hypoxia is an important event driving synovial inflammation.

Anti-TNF therapy in RA—towards personalized medicine?

A substantial proportion of patients with rheumatoid arthritis do not respond to tumor necrosis factor blocking therapy. Results of a large genome-wide association study demonstrate evidence of novel genetic factors that determine response to treatment, which could provide a basis for individualizing therapy.

Analysis of C-reactive protein levels and febrile tendency after joint surgery in rheumatoid arthritis patients treated with a perioperative 4-week interruption of tocilizumab

Tocilizumab is a humanized anti-human IL-6 receptor monoclonal antibody that has been demonstrated to improve rheumatoid arthritis (RA) symptoms [1–5]. However, it remains unclear whether the use of biological agents, including tocilizumab, constitutes an independent risk factor for postoperative surgical site infection (SSI). Some reports of joint surgeries in RA patients treated with tumor necrosis factor (TNF) alpha blockers have demonstrated no increase in the incidence of postoperative infection [6, 7]. In contrast, other reports have suggested higher complication rates with TNF blockers [8, 9]. We also reported that the use of TNF blockers was a likely cause of SSI [10], although we diagnosed SSI using the criteria for defining SSI in the Guideline for Prevention of Surgical Site Infection, 1999 [11]. These conflicting data make the effects of TNF blocker therapy on the risk of postoperative infection during orthopedic intervention unclear. Meanwhile, the perioperative mechanisms of tocilizumab are also currently under investigation. Unfortunately, only one study of the clinical features of tocilizumab-treated RA patients following joint surgery has been published [12]. Therefore, more data are required to fully evaluate the influence of tocilizumab on postoperative complications. We analyzed clinical features after 8 joint surgeries in 5 patients treated with tocilizumab (TCZ group) at our institute from October 2007 to September 2009. Moreover, as a retrospective 1:2 matched case–control study, 16 joint surgeries in anti-TNF-treated RA patients (TNF group) and 16 joint surgeries in patients treated with conventional disease-modifying antirheumatic drugs (DMARDs group), matched for type of surgery and gender, were compared to the TCZ group in order to evaluate laboratory data and body temperature changes during the 2 weeks following surgery (see Table 1 for the baseline characteristics of each study population). TCZ group surgeries included wrist arthroplasty (n = 2); unilateral, total hip arthroplasty (THA) (n = 3); unilateral, total knee arthroplasty (TKA) (n = 1); unilateral, total elbow arthroplasty (n = 1); and foot surgery (n = 1). The surgeries on patients treated with TNF blockers were performed in accordance with the British Society for Rheumatology and the Japan College of Rheumatology guidelines [13, 14]. Tocilizumab treatment was withheld for 4 weeks prior to surgery, and was restarted 4 weeks after surgery. Preoperative CRP levels in the TCZ group were within the normal range in all cases, except for one case with CRP 0.44 mg/dl. The average CRP levels in the TNF and DMARDs groups exceeded 8 mg/dl on postoperative day 2, while the average level in the TCZ group increased to only *2 mg/dl (TCZ vs. TNF blockers, P = 0.025 by Mann–Whitney U test) (Fig. 1). Additionally, patients in the TNF and DMARDs groups tended to become febrile; while the average body temperature also increased in the TCZ group, it never reached 37 C (Fig. 1). No differences in WBC count, hemoglobin level, or platelet count were R. Hiroshima K. Kawakami T. Iwamoto A. Tokita K. Yano Y. Sakuma K. Ikari S. Momohara (&) Department of Orthopaedic Surgery, Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada, Shinjuku, Tokyo 162-0054, Japan e-mail: smomohara@ior.twmu.ac.jp

Spielt TNF in der Pathogenese von soliden Tumoren eine Rolle?

Tumor necrosis factor (TNF)-alpha blocking agents play an important role in rheumatology. For this reason, questions about the pathogenic characteristics of TNF in carcinogenesis are of the utmost importance. The observation that TNF leads to necrosis in tumor tissue gave rise to the hope that an agent had been identified for the treatment of malignant tumors. However, this expectation remained unfulfilled, not the least due to the toxicity of systemically applied TNF. In addition, TNF is produced by many tumor cells. There is evidence that for some tumors TNF promotes tumor growth, invasiveness and metastasis. It is quite possible, therefore, that the inhibition of TNF-alpha has an inhibitive effect on carcinogenesis and/or tumor progression. In 2009 the US Food and Drug Administration (FDA) issued a cancer warning for the use of TNF inhibitors in children and adolescents. There is still some controversy as to whether TNF blocking therapy, co-medication or the rheumatic disease itself leads to an increased cancer risk in these young patients. In adults, safety information so far available suggests a favorable risk-benefit profile for the long-term use of TNF inhibitors. However, many questions remain unanswered as to the role TNF itself plays in the pathogenesis of solid tumors.

Recognition, Diagnosis, and Treatment of Histoplasmosis Complicating Tumor Necrosis Factor Blocker Therapy

Life-threatening histoplasmosis is one of the most common opportunistic infections in patients receiving tumor necrosis factor (TNF) blockers. Delays in considering the diagnosis may lead to increased morbidity and mortality. Most affected patients present with pneumonitis, usually accompanied by additional signs of progressive dissemination, or with signs of progressive dissemination alone. The diagnosis often can be promptly established using antigen detection or direct examination of bronchoalveolar lavage specimens. If histoplasmosis is diagnosed promptly, antifungal therapy is highly effective. After a favorable clinical response, the safety of both discontinuation of antifungal therapy and the resumption of TNF blocker remains undetermined. The management of the immune reconstitution inflammatory syndrome that may follow discontinuation of TNF blockers also requires investigation. Prescribers should become aware of the recognition, diagnosis, and treatment of histoplasmosis and educate recipients about decreasing their risk of exposure and both recognizing and reporting signs of early infection.

Association of prescription abandonment with cost share for high-cost specialty pharmacy medications.

In 2008, specialty medications accounted for 15.1% of total pharmacy benefit medication spending, and per member expenditures have increased by 11.1% annually from 2004 to 2008 within a commercially insured population of 8 million members. Insurers face increasing pressure to control specialty medication expenditures and to rely on increasing member cost share through creation of a fourth copayment tier within the incentive-based formulary pharmacy benefit system. Data are needed on the influence that member out-of-pocket (OOP) expense may have on prescription abandonment (defined as the patient never actually taking possession of the medication despite evidence of a written prescription generated by a prescriber). To explore the relationship between prescription abandonment and OOP expense among individuals newly initiating high-cost medication therapy with a tumor necrosis factor (TNF) blocker or multiple sclerosis (MS) biologic agent. This observational cross-sectional study queried a midwestern and southern U.S. database of 13,172,480 commercially insured individuals to find members with a pharmacy benefit-adjudicated claim for a TNF blocker or MS specialty medication during the period from July 2006 through June 2008. Prescription abandonment was assessed among continuously enrolled members newly initiating TNF blocker or MS therapy. Prescription abandonment was defined as reversal of the adjudicated claim with no evidence of a subsequent additional adjudicated paid claim in the ensuing 90 days. Separate analyses for MS and TNF blocker therapy were performed to assess the association between member OOP expense and abandonment rate using the Cochran-Armitage test for trend and multivariate logistic regression. Members were placed into 1 of the 7 following OOP expense groups per claim: $0-$100, $101-$150, $151-$200, $201-$250, $251-$350, $351-$500, or more than $500. The association of MS or TNF blocker abandonment rate with OOP expense was tested with logistic regression models using the $0-$100 OOP as the reference group and adjusting for age, gender, formulary status, ZIP code-level income and education, earliest specialty medication claim, and methotrexate use for the TNF blocker analysis. Of 2,791 members presenting a prescription to newly initiate high-cost MS therapy, 1,985 (71.1%) of the claims were for a 1-month supply with most of the remainder for a 3-month supply; 2,303 (82.5%) had an OOP expense of $0-$100, and 5.4% had an OOP expense greater than $500. The abandonment rate increased as OOP increased (test for trend, P < 0.001). Members with an OOP expense of $100 or less had an abandonment rate of 5.7%. Among members in all OOP expense groups greater than $200, the abandonment rate was significantly higher, with more than 1 in 4 members abandoning their MS claims (P < 0.001). In the multivariate logistic regression analysis, the abandonment rate became significantly higher at OOP expenses of $201 to $250 compared with an OOP expense of $100 or less (odds ratio [OR] = 7.3, 95% confidence interval [CI] = 3.3- 16.2). The odds ratios ranged between 6.1 and 7.3 for OOP expense groups greater than $200. Of 7,313 members presenting a prescription to newly initiate TNF blocker therapy, 5,809 (79.4%) of claims were for a 1-month supply with most of the remainder for a 3-month supply; 6,123 (83.7%) had an OOP expense of $0-$100 and 5.7% had an OOP expense greater than $500. The abandonment rate increased as OOP expense increased (test for trend, P < 0.001). In the multivariate logistic regression analysis, the TNF blocker medication abandonment rate was significantly higher for all OOP expense groups greater than $100, with abandonment odds ratios of 2.3 to 4.4 for OOP expense between $101 and $500 compared with OOP expense of $0-$100. The odds of abandonment at OOP expense of greater than $500 were 7-fold higher (OR = 7.0, 95% CI = 5.4-9.1). This is the first study to perform a focused assessment of an association between specialty medication OOP expense and new therapy prescription abandonment. The study found that per claim OOP expenses greater than $100 for TNF blocker medication and greater than $200 for MS medication were associated with increased prescription abandonment. These findings coupled with previous research identifying a negative relationship between OOP expense above $100 per month and adherence, and the commercial insurance market response to fourth-tier OOP expenses, suggests that insurers should consider the impact that specialty OOP expense may have on adherence and member satisfaction. Further prospective research should be performed to confirm these findings and assess the clinical outcomes associated with prescription abandonment.

Combination therapy for rheumatoid arthritis: methotrexate and sulfasalazine together or with other DMARDs

Early aggressive treatment of rheumatoid arthritis is associated with improved disease control, slower radiological progression and improved functional outcomes. Tumor necrosis factor blocking therapy is effective but there remain concerns about long-term risks. Combining disease-modifying antirheumatic drugs (DMARDs) is a widely used therapeutic alternative; however, there is uncertainty surrounding the most effective regimen. A popular combination is methotrexate plus sulfasalazine, but each of these DMARDs can also be used in combination with other DMARDs and in triple therapy regimens. However, wide variations in study size, design, steroid usage and approaches to combination therapy have made it difficult to form firm conclusions regarding their efficacy. Generally, combination therapy is well tolerated and associated with no significant increase in the rate of adverse events compared with monotherapy. Methotrexate-sulfasalazine, methotrexate-chloroquine, methotrexate-cyclosporin, methotrexate-leflunomide, methotrexate-intramuscular-gold and methotrexate-doxycycline are effective combination regimens. Triple DMARD therapy is better than various DMARD monotherapy and dual therapy regimens. Methotrexate and hydroxychloroquine may have synergistic anti-inflammatory properties. Clinical trial evidence to support the use of other methotrexate and sulfasalazine combinations is often weak or lacking. Further investigation is required to determine the most effective regimen and approach to combination therapy.

Management of extra-articular disease manifestations in rheumatoid arthritis.

To discuss the rationale for various treatment strategies in rheumatoid arthritis with extra-articular manifestations, and to review advances in understanding the impact of extra-articular rheumatoid arthritis and its management. Recent epidemiologic studies of extra-articular rheumatoid arthritis manifestations have emphasized their major role as predictors of premature mortality in patients with rheumatoid arthritis, and provide a rationale for aggressive ant-rheumatic treatment of extra-articular rheumatoid arthritis. Previous uncontrolled or nonrandomized studies favor the use of cyclophosphamide in patients with systemic rheumatoid vasculitis, and methotrexate in the case of other manifestations of extra-articular rheumatoid arthritis. Recent case reports indicate that patients with rheumatoid lung disease may respond to cyclosporine or tumor necrosis factor inhibitors, and that tumor necrosis factor blocking therapy also may be successful in cases of treatment-resistant vasculitis. By contrast, it has been suggested that tumor necrosis factor inhibitors may induce some manifestations of extra-articular rheumatoid arthritis. Data indicating a high risk of serious infections and cardiovascular disease in patients with extra-articular rheumatoid arthritis underline the importance of carefully monitoring such patients. Extra-articular rheumatoid arthritis is a serious condition, and rheumatoid arthritis patients with extra-articular manifestations should be aggressively treated and monitored. Advances in the understanding of the pathogenesis of rheumatoid arthritis and developments of new, more specific drugs may be of particular benefit to patients with extra-articular disease.