Medical management of polymyalgia rheumatica

Importance of the field: Polymyalgia rheumatica (PMR) is a relatively frequent condition in individuals older than 50 who originate from Western countries. Corticosteroids constitute the cornerstone therapy in the management of patients with PMR.

Areas covered in this review: This review summarizes the current literature on clinical clues for the diagnosis of PMR, conditions mimicking PMR, relapses in the setting of PMR and the main therapeutic strategies.

What the reader will gain: With this information, the reader receives an overview on the current available data on clinical diagnosis and treatment options in PMR.

Take-home messages: An initial dose of prednisone of 10 – 20 mg/day yields clinical improvement in the majority of patients with PMR. This is generally achieved within 7 days of the onset of this therapy. Conditions different from isolated PMR should be considered in atypical cases or when a good response to 20 mg/day of prednisone is not achieved. Relapses of PMR are not uncommon when the dose of prednisone is equal to or below than 5 mg/day. Methotrexate is the most commonly used corticosteroid sparing agent. Osteoporosis prophylaxis is also recommended.     

TNF blockade in the treatment of rheumatoid arthritis: infliximab versus etanercept

There is accumulating evidence that tumour necrosis factor (TNF) plays a major role in the pathogenesis of rheumatoid arthritis (RA). Recent biotechnological advances have allowed for the development of agents that directly target TNF, a pro-inflammatory cytokine. In the last 2 years, the US FDA and the EU’s Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of IgG1 and the extracellular domain of the TNF receptor (p75). Infliximab is a chimeric monoclonal antibody (mAb) composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well-tolerated in RA patients. This review evaluates the available TNF inhibitors, summarises pertinent clinical trials and underscores differences between the two agents in terms of molecular structure, efficacy, safety data, antigenicity and pharmacokinetics.     

TNF-alpha antagonist induced lupus on three different agents

Tumor necrosis factor alpha (TNF alpha) antagonists are biologic agents used in the management of inflammatory conditions such as rheumatoid arthritis, seronegative spondyloarthropathies and inflammatory bowel disease. These agents have been recently shown to cause a syndrome called anti-TNF induced lupus (ATIL), a rare condition which has similar clinical manifestations to idiopathic systemic lupus erythematosus (SLE). Given that extra-intestinal manifestations of inflammatory bowel disease include arthritis, it can be difficult to separate arthritis due to underlying disease from drug-induced arthritis. We present a case of a 28-year-old female with Crohn’s disease, who developed disabling arthritis as a clinical manifestation of ATIL following treatment with three anti-TNF agents, namely infliximab, adalimumab and certolizumab.     

Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study

BACKGROUND & AIMS: Infliximab therapy is an effective approach to treating Crohn's disease. Development of antinuclear antibodies has been described in patients treated, but the size of the problem and the relationship with autoimmunity have not been investigated. We investigated the occurrence of antinuclear antibodies in 125 consecutive Crohn's disease patients and studied the relationship with symptoms of autoimmunity. METHODS: Autoantibodies and clinical data were investigated before and 1, 2, and 3 months after infliximab infusion. If antinuclear antibodies were > or =1:80, further study of double-stranded DNA, single-stranded DNA, histones, and ENA was performed. RESULTS: Cumulative antinuclear antibody incidence at 24 months was 71 of 125 (56.8%). Almost half of these patients developed antinuclear antibodies after the first infusion, and >75% became antinuclear antibody positive after fewer than 3 infusions. So far, only 15 of 71 patients have become seronegative, after a median of 12 months. Of 43 antinuclear antibody-positive patients who were further subtyped, 14 of 43 (32.6%) had double-stranded DNA, 17 (39.5%) had single-stranded DNA, 9 (20.9%) had antihistone, and 0% were ENA positive. Two patients (both antihistone and double-stranded DNA positive) developed drug-induced lupus without major organ damage, and 1 developed autoimmune hemolytic anemia. Antinuclear antibodies were associated with the female sex (odds ratio, 3.166; 95% confidence interval, 1.167-8.585; P = 0.024) and with papulosquamous or butterfly rash (odds ratio, 10.016; 95% confidence interval, 1.708-58.725; P = 0.011). CONCLUSIONS: The cumulative incidence of antinuclear antibodies was 56.8% after 24 months in this cohort of infliximab-treated Crohn's disease patients. Antinuclear antibodies persisted up to 1 year after the last infusion, and only a few patients became seronegative. Two patients developed drug-induced lupus erythematosus. Antinuclear antibodies were associated with the female sex and skin manifestations.     

An update on the use of tumor necrosis factor alpha inhibitors in the treatment of ankylosing spondylitis

Introduction: Ankylosing spondylitis is a chronic immune-mediated disease affecting the sacroiliac joints and the spine manifesting with new bone formation and osteopenia. Over the past decade, tumour necrosis factor alpha (TNF-α) inhibitors (TNFi) have become the cornerstone for therapy in improving functional outcomes, and decreasing disease activity in patients with a marginal benefit from non-steroidal anti-inflammatory (NSAID) therapy. At this time, it remains to be determined whether these agents decrease new bone formation, although some studies have recently suggested that.

Areas covered: In this review we discuss the factors that favour a good response to these agents both initially and during maintenance, and some of the more recent studies outlining strategies for dose reduction.

Expert commentary: Finally, we discuss the importance of using more objective tools for disease activity, such as magnetic resonance imaging, as a complementary tool for clinical assessments in both predicting responses to treatment but also in selecting patients most suited for targeted therapy.     

Limited granulomatosis with polyangiitis in an adolescent with Crohn's disease on infliximab therapy: cause or coincidence?

Pulmonary involvement in Crohn's disease (CD) may precede the development of intestinal inflammation, but in most cases occurs during the course of treatment, either as an extra‐intestinal manifestation, because of secondary infections, or as a side effect of the therapy itself. This case highlights the differential diagnosis and work up for multiple pulmonary nodules that developed in a patient with CD who had been in remission on infliximab therapy. Even though infectious causes, such as Mycobacteria and Fungi, account for majority of these cases, the possibility of non‐infectious conditions such as autoimmune disorders should also be considered.     

Infliximab (Remicade®): from bench to clinical practice. A paradigm shift in rheumatology practice

Infliximab (Remicade®) is a chimeric monoclonal antibody that binds tumour necrosis factor–alpha (TNF‐α) and inhibits its biologic activity. Infliximab has been approved by the FDA for the treatment of a variety of immune‐mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), Crohn's disease (CD), ankylosing spondylitis (AS), ulcerative colitis (UC), and psoriatic arthritis (PsA). This is a brief review of the development of infliximab primarily in RA and CD; the pathogenesis of RA and CD as applicable to TNF‐α activity; conventional therapies available for RA and CD; early clinical trials and those leading to approval for RA, CD and other indications; coadministration with methotrexate (MTX), and the safety of infliximab as a therapeutic agent for IMIDs.     

Higher anti-TNF serum levels are associated with perianal fistula closure in Crohn’s disease patients

Objectives: Anti-TNF agents are effective to treat perianal Crohn’s disease (CD). Evidence suggests that Crohn’s disease patients with perianal fistulas need higher infliximab (IFX) serum concentrations compared to patients without perianal CD to achieve complete disease control. Our aim was to compare anti-TNF serum concentrations between patients with actively draining and closed perianal fistulas.

Methods: A retrospective survey was performed in CD patients with perianal disease treated with IFX or adalimumab (ADL). Fistula closure was defined as absence of active drainage at gentle finger compression and/or fistula healing on magnetic resonance imaging.

Results: We identified 66?CD patients with a history of perianal fistulas treated with IFX (n?=?47) and ADL (n?=?19). Median IFX serum trough concentrations ([interquartile range]) were higher in patients with closed fistulas (n?=?32) compared to patients with actively draining fistulas (n?=?15): 6.0?µg/ml [5.4–6.9] versus 2.3?µg/ml [1.1–4.0], respectively (p?<?.001)). A similar difference was seen in patients treated with ADL: median serum concentrations were 7.4?µg/ml [6.5–10.8] in 13 patients with closed fistulas versus 4.8?µg/ml [1.7–6.2] in 6 patients with producing fistulas (p?=?.003). Serum concentrations of ≥5.0?µg/ml for IFX (area under the curve of 0.92; 95% CI: 0.82–1.00)) and 5.9?µg/ml for ADL (area under the curve of 0.89; 95% CI 0.71–1.00) were associated with fistula closure.

Conclusion: Cut-off serum concentrations ≥5.0?µg/ml for IFX and ≥5.9?µg/ml for ADL were associated with perianal fistula closure. Hence, patients with producing perianal fistulas may benefit from anti-TNF dose intensification to achieve fistula closure.     

Early serum infliximab trough level and mucosal healing could be predictors for one-year outcome after initiating therapy in Crohn’s disease

Abstract

Background and aims

Serum infliximab trough level(S-IFX) and antibody were documented to correlate with clinical response. The aim of this study was to identify the relationship between early S-IFX, early mucosal healing (MH) and one-year outcome in a cohort on maintenance IFX therapy in Crohn’s disease (CD).