Response to lower dose TNF inhibitors in axial spondyloarthritis; a real-world multicentre observational study.

OBJECTIVE: Dose optimization of TNF inhibitors in axial spondyloarthritis (axSpA) is attractive, but it is unclear for which patients this approach might be appropriate. METHODS: Seventy-one patients with axSpA, from six UK centres, were identified who had reduced their dose of TNF inhibitor after being considered to be stable responders. All completed a questionnaire concerning their approach to and experience of dose reduction. Data on patient characteristics, metrology and CRP were retrieved retrospectively from patient records. RESULTS: Over 2 years of observation, 60 (84.5%) remained (REM) on reduced-dose medication and 11 (15.5%) reverted (REV) to the original dose. The overall mean dose reduction was 39% for REM patients and 44% for REV patients. Both groups initially responded in a similar manner to treatment, but the data showed a trend that younger women were more likely to revert. Neither BMI nor smoking was associated with continued low-dose responsiveness. Eight of the 11 REV patients reverted by 6 months. None reached criteria of secondary drug failure, and all regained control after increasing back to the original dose. Most patients in both groups reached the decision to reduce the dose jointly with clinicians. A preference for taking the reduced dose was not associated with low-dose drug survival. CONCLUSION: Many patients with axSpA remain well symptomatically after stepping down the dose of TNF inhibitor, but young women are less likely to do well on a reduced dose. Dose reduction should be one element of the management of patients with axSpA.

Influence of disease activity on RA treatment choices in countries with restricted access to expensive, innovative drugs: a discrete choice experiment among rheumatologists.

OBJECTIVE: To assess the influence of disease activity of patients with rheumatoid arthritis on treatment choices of rheumatologists in countries with restricted access to expensive, innovative drugs. METHODS: Rheumatologists from Hungary, Romania and UK were invited to complete two consecutive discrete choice experiments with hypothetical drug treatments for two different patient profiles: high and moderate disease activity. Rheumatologists were asked to choose repeatedly between two unlabelled treatment options that differed in five attributes: efficacy (expected improvement and achieved disease activity state), safety (probability of serious adverse events), patient's preference (level of agreement), total medication costs and cost-effectiveness. A heteroscedastic discrete choice model using interaction terms between attribute levels and patient profiles (binary variable) was used to assess the preferences of rheumatologists towards each attribute and the influence of the patient profile. RESULTS: Overall, 148 rheumatologists completed the survey (46% females, mean age 49 years, 49% academic). For both patient profiles, efficacy dominated the treatment choice over patient's preference, safety and economic aspects. However, for patients with high compared with moderate disease activity, the importance of drug efficacy significantly increased (from 48% for moderate to 57% for high disease activity), whereas the importance of patient's preference significantly decreased (from 15% to 11%). No significant differences were observed for economic and safety considerations. CONCLUSION: Rheumatologists were willing to give up some efficacy to account for patient's preference when choosing treatments for patients with moderate compared to high disease activity. Disease activity however did not influence importance of economic aspects in treatment choices.

Should axial spondyloarthritis without radiographic changes be treated with anti-TNF agents?

A spectrum of disease extends beyond the rigid confines of ankylosing spondylitis (AS). Axial spondyloarthritis (axSpA) encompasses non-radiographic axSpA (nr-axSpA) in individuals without established radiographic changes but with other clinical/imaging axSpA features and AS in those with definite sacroiliac joint changes on pelvic X-rays. A broad consensus about the management of nr-axSpA is emerging among clinicians, but the evidence base remains open to question. To explore whether nr-axSpA and AS should be treated similarly, we examined the literature on their prevalence, natural history, disease burden, and treatment. There is strong evidence that nr-axSpA and AS are expressions of the same disease. Approximately 10% of patients with nr-axSpA will develop radiographic disease over 2 years; after >20 years, the figure may exceed 80%. Nr-axSpA patients have lower CRP and less spinal inflammation on MRI than AS patients but similar disease activity, pain, and quality-of-life impairment. Most patients with nr-axSpA manage well with conservative treatment, but a minority has severe disabling symptoms. Anti-TNF therapy has demonstrated similar efficacy and safety in nr-axSpA and AS. Current evidence does not clearly indicate that anti-TNF treatment can inhibit or limit bony progression of AS, the basis of conservative and anti-TNF treatment is control of symptoms and function. For some patients with nr-axSpA, the need for powerful treatments is as great as in some with AS; thus, treatment of axSpA should be consistent across the axSpA spectrum with anti-TNF agents being available, irrespective of radiographic change, according to the same criteria as those applied to AS.

The British Society for Rheumatology Biologics Registers in Ankylosing Spondylitis (BSRBR-AS) study: Protocol for a prospective cohort study of the long-term safety and quality of life outcomes of biologic treatment.

BACKGROUND: Axial spondyloarthropathy typically has its onset in early adulthood and can impact significantly on quality of life. In the UK, biologic anti-tumour necrosis factor therapy is recommended for patients who are unresponsive to non-steroidal anti-inflammatory drugs. There remain several unresolved issues about the long-term safety and quality of life outcomes of biologic treatment in axial spondyloarthropathy. Long-term "real-world" surveillance data are required to complement data from randomised controlled trials. METHODS/DESIGN: We are conducting a UK-wide prospective cohort study of patients with axial spondyloarthropathy who are naïve to biologic therapy at the time of recruitment. Those about to commence anti-tumour necrosis factor biologic therapy will enter a "biologic" sub-cohort with other patients assigned to a "non-biologic" sub-cohort. The primary objective is to determine whether the use of biologic therapy is associated with an increased risk of serious infection, while secondary objectives are to assess differences in malignancy, serious comorbidity, all-cause mortality but also assess impact on specific clinical domains (physical health, mental health and quality of life) including work outcomes between biologic and non-biologic patient cohorts. Patients will be followed-up for up to 5 years. Data are obtained at baseline and at standard clinical follow-up visits - at 3, 6 and 12 months and then annually for the biologic cohort and annually for the non-biologic cohort. This study will also collect biological samples for genetic analysis. DISCUSSION: Although biologic therapy is widely used for ankylosing spondylitis patients who are unresponsive to non-steroidal anti-inflammatory drugs, the majority of the available safety information comes from rheumatoid arthritis, where increased infection risk has consistently been shown. However, given the typical demographic differences between rheumatoid arthritis and axial spondyloarthropathy patients, it is important to develop an epidemiologically rigorous cohort of patients receiving biologic therapy to effectively evaluate outcomes with regard not only to safety but also to quantify benefits across clinical, psychosocial and work outcomes. CLINICAL TRIAL REGISTRATION: This is an observational cohort study and clinical trial registration was not required or obtained.

Observations on Chlamydia trachomatis and other microbes in reactive arthritis.

There are problems in attributing causality in inflammatory arthritis. So far as C. trachomatis and sexually acquired reactive arthritis are concerned, there is much in favour of a causal relationship, although there are important caveats which need to be explored before it is possible to say unreservedly that C. trachomatis plays a causative role in reactive arthritis. For example, micro-organisms have never been cultured from synovial effusions in early disease, and only once has substantial benefit of antimicrobial treatment been reported. The claim that ocular strains of C. trachomatis are of over-riding importance in pathogenesis needs confirmation before it can be accepted. No conclusion can be made about the possibility of other small intracellular bacteria in joints having a role in causing disease. However, if it can be shown that eradication of the micro-organism, which may be difficult to prove, coincides with clinical recovery, it would go some way to recognising causality. In spite of the recognised difficulties, antibiotic studies have an important role in identifying aetiology. They need to focus on very early disease and on eradication of intra-articular bacteria. Treatment of established disease is likely to be less informative. Although a combination of antibiotics might have a future in treating established disease, diagnosing and treating non-gonococcal urethritis as soon as possible should be the aim in order to prevent the development of reactive arthritis.

Saddle-nose deformities in the rheumatology clinic.

Saddle-nose deformity can occur as a result of trauma to the nose, but it has also been well described in the setting of infections such as leprosy and syphilis and idiopathic inflammatory conditions such as granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) and relapsing polychondritis. Since these deformities may also arise without an evident precipitating cause, they can pose a diagnostic conundrum. We review 2 cases of saddle-nose deformity that were treated at Northwick Park Hospital in Middlesex, England. The first patient was a 53-year-old woman who presented with epistaxis and deviation of the nasal septum. She subsequently developed a saddle-nose deformity and a septal ulcer. An autoimmune screen was negative, and histologic findings were nonspecific. She underwent successful reconstruction with a polyethylene implant. The second patient was a 21-year-old woman who presented with nasal obstruction and a nasal septal deviation. Two years later, she was diagnosed with Crohn disease and treatment with azathioprine was commenced. Eventually, the cartilaginous dorsum of her nose collapsed. A biopsy of the area revealed nonspecific, active, chronic inflammation. A polyethylene implant was placed to correct the deformity, but part of the implant became dislodged, and revision surgery was not successful. A subsequent revision was performed, and the early results were encouraging. Saddle-nose deformity may be a manifestation of underlying connective tissue disease, so it is important to detect and treat any such condition before embarking on surgical repair of the deformity. Our 2 cases indicate that this very deforming condition is poorly understood and treatment can be unsatisfactory.

Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis.

OBJECTIVES: To evaluate the efficacy and safety of an oral phosphodiesterase 4 inhibitor, apremilast, in treatment of ankylosing spondylitis (AS) by monitoring symptoms and signs in a pilot study including exploratory investigation of effects of PDE4 inhibition on blood biomarkers of bone biology. METHODS: In this double-blind, placebo-controlled, single-centre, Phase II study, patients with symptomatic AS with active disease on MRI were randomised to apremilast 30 mg BID or placebo over 12 weeks. Bath Indices were monitored serially. Patients were followed for 4 weeks after stopping medication. Bone biomarkers were assessed at baseline and day 85. RESULTS: 38 subjects were randomised and 36 subjects completed the study. Although the primary end-point (change in BASDAI at week 12) was not met, apremilast was associated with numerically greater improvement from baseline for all clinical assessments compared with placebo with mean change in BASDAI (-1.59±1.48 vs -0.77±1.47), BASFI (-1.74±1.91 vs -0.28±1.61) and BASMI (-0.51±1.02 vs -0.21±0.67); however, differences did not achieve statistical significance. The clinical indices returned to baseline values by 4 weeks after cessation of apremilast. Six apremilast patients (35.3%) vs 3 placebo (15.8%) achieved ASAS20 responses (p=0.25). There were statistically significant decreases in serum RANKL and RANKL:osteoprotegrin ratio and plasma sclerostin but no significant changes in serum DKK-1, bone alkaline phosphatase, TRAP5b, MMP3, osteoprotegrin, or osteocalcin. CONCLUSIONS: Although a small pilot study, these results suggest that apremilast may be effective and well tolerated in AS and modulates biomarkers of bone biology. These data support further research of apremilast in axial inflammation.

Comparison of two referral strategies for diagnosis of axial spondyloarthritis: the Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) study.

OBJECTIVE: To determine which of two referral strategies, when used by referring physicians for patients with chronic back pain (CBP), is superior for diagnosing axial spondyloarthritis (SpA) by rheumatologists across several countries. METHODS: Primary care referral sites in 16 countries were randomised (1 : 1) to refer patients with CBP lasting >3 months and onset before age 45 years to a rheumatologist using either strategy 1 (any of inflammatory back pain (IBP), HLA-B27 or sacroiliitis on imaging) or strategy 2 (two of the following: IBP, HLA-B27, sacroiliitis, family history of axial SpA, good response to non-steroidal anti-inflammatory drugs, extra-articular manifestations). The rheumatologist established the diagnosis. The primary analysis compared the proportion of patients diagnosed with definite axial SpA by referral strategy. RESULTS: Patients (N=1072) were referred by 278 sites to 64 rheumatologists: 504 patients by strategy 1 and 568 patients by strategy 2. Axial SpA was diagnosed in 35.6% and 39.8% of patients referred by these respective strategies (between-group difference 4.40%; 95% CI -7.09% to 15.89%; p=0.447). IBP was the most frequently used referral criterion (94.7% of cases), showing high concordance (85.4%) with rheumatologists' assessments, and having sensitivity and a negative predictive value of >85% but a positive predictive value and specificity of <50%. Combining IBP with other criteria (eg, sacroiliitis, HLA-B27) increased the likelihood for diagnosing axial SpA. CONCLUSIONS: A referral strategy based on three criteria leads to a diagnosis of axial SpA in approximately 35% of patients with CBP and is applicable across countries and geographical locales with presumably different levels of expertise in axial SpA.

Management of persistent inflammatory large joint monoarthritis.

Persistent inflammatory monoarthritis is inflammation of one joint, with symptoms lasting beyond 3 months. Approximately 50 % of cases are self-limiting; others will transform into oligo- or polyarticular disease, but a significant minority remain as a persistent inflammatory monoarthritis, which are often resistant to standard therapies used for oligo- or polyarticular disease and constitute a difficult therapeutic problem. However, there are no clear guidelines for treatment of this category of patients or an evidence-based consensus view on best treatment. A literature search was done through PubMed using 'monoarthritis', 'chronic synovitis' and 'persistent inflammatory monoarthritis' as search terms. Reports were located using references to related articles; reports in humans and animals, published in English, were included. Persistent inflammatory monoarthritis has a variable disease course, generally with a better prognosis than polyarthritis. There is no clear evidence for the use of traditional DMARDS in monoarthritis, and treatment algorithms are extrapolated from oligo- or polyarticular disease. Intra-articular anti-tumour necrosis factor (TNF) has been used with similar efficacy to intra-articular corticosteroids, and as yet, there are no reported cases of systemic anti-TNF use in monoarthritis. Synovectomy may be of use, with lower risk of recurrent disease, in open synovectomy. There is paucity of evidence for best practice in the management of chronic monoarthritis. Questions remain concerning the indications for invasive procedures and the balance between toxicity of systemic therapies versus the intended benefits to prevent disability. There is a pressing need for further studies and randomised controlled trials to be performed in this subset of patients.

Spondyloarthritides: evolving therapies.

TNF blockade therapy has substantially advanced the treatment of peripheral spondyloarthritides but revolutionised the treatment of severe ankylosing spondylitis. The capacity of biologic treatment to improve dramatically symptoms and quality of life in patients with spinal disease is undoubted, although important questions remain. Notable amongst these are concerns about skeletal disease modification and the true balance between costs and effectiveness. Guidelines for the biologic treatment of ankylosing spondylitis and psoriatic arthritis have been introduced in North America and Europe with considerable consensus. However, the absence of clear criteria for the diagnosis of early disease leaves the issue of biologic treatment of ankylosing spondylitis at the pre-radiographic stage unresolved. Newer biologic agents are entering the field, although superiority over TNF blockers will be difficult to demonstrate.

Lupus and leg ulcers--a diagnostic quandary.

Leg ulcerations can occur in systemic lupus erythematosus (SLE) patients with antiphospholipid (aPL) antibodies and/or vasculitis, and it has been suggested that aPL antibodies may play a pathogenetic role in skin manifestations of SLE. To our knowledge, there is only one report of an aPL antibody-negative patient who developed pyoderma gangrenosum (PG) several years before the diagnosis of SLE. We describe a case of a young male affected by SLE who developed leg ulcers diagnosed as PG in the absence of aPL antibodies, where the onset of PG was associated with reactivation of SLE. Effective treatment led to significant improvement in skin lesions and SLE activity.

A still image of a transient rash captured by a mobile phone.

The diagnosis of adult onset Still's disease (AOSD) can be difficult as the differential diagnosis is broad, it is based on clinical criteria and the signs, for example rash, can be transient. Clinical photography has an obvious role, and with modern technology, is now in the hands of physicians. We report a case of AOSD where an image of a transient rash taken with a camera phone allowed the diagnosis to be established. Further, we discuss the controversies around hospital bans on mobile phones (due to potential incompatibility with medical devices) and the reality of their widespread use. We conclude that, providing safeguards of consent and data storage are in place, the camera phone is a useful tool in rheumatology practice.

A case of polymyalgia rheumatica, microscopic polyangiitis, and B-cell lymphoma.

BACKGROUND: A 73-year-old, previously well woman was admitted to an emergency department because of a 3-month history of severe proximal girdle pain and stiffness with loss of appetite and weight. She was referred to a rheumatologist 10 days after her initial presentation. Within 4 weeks she presented to an outpatient clinic with nausea, vomiting, shortness of breath, painful mouth ulcers, rash on her legs and a further decline in appetite; she was readmitted to hospital. Within 4 months of initial presentation she became jaundiced. INVESTIGATIONS: At initial presentation, physical examination, biochemical, hematological and autoimmune screening, radiography of the pelvis, an abdominal ultrasound, and electromyography were conducted. At referral to a rheumatologist similar tests were repeated. At presentation to the outpatient clinic, hematological and biochemical screening, and a urine dipstick test were conducted. At readmittance to hospital, infectious and autoimmune screening, radiography of the chest, electrocardiogram, ultrasound of the abdomen, and renal biopsy were conducted. At the time of development of jaundice, biochemical and hematological screening, CT of the abdomen and ultrasound-guided biopsy of a pancreatic mass were conducted. DIAGNOSIS: Polymyalgia rheumatica, antineutrophil-cytoplasmic-antibody-positive microscopic polyangiitis with renal involvement and B-cell lymphoma of the head of the pancreas. MANAGEMENT: The patient received oral prednisolone 15 mg daily for polymyalgia rheumatica along with alendronate 70 mg weekly. The patient received intravenous cyclophosphamide 500 mg and methylprednisolone 500 mg every 2 weeks for her microscopic polyangiitis with renal involvement. For B-cell lymphoma of the head of the pancreas, the patient received cyclophosphamide, doxorubicin, vincristine and prednisolone once monthly.