Andrew Keat

Detection of Chlamydia trachomatis DNA in joints of reactive arthritis patients by polymerase chain reaction

In 1986, Chlamydia trachomatis elementary bodies were found by direct immunofluorescence (DIF) in synovial-fluid cell deposits and synovial-membrane biopsy samples from five of eight patients with sexually acquired reactive arthritis (SARA) but in none of eight controls with other types of arthritis. Cells from the original slides (stored at 4 degrees C) have now been examined by a polymerase chain reaction (PCR) that amplifies DNA for the major outer membrane protein of C trachomatis. Chlamydial DNA was found in samples from four DIF-positive patients, one DIF-negative patient, and one DIF-negative control. Overall, there was 80% concordance for DIF and PCR results. This study supports our previous finding of chlamydiae in joints in reactive arthritis.

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.

Work disability among people with ankylosing spondylitis

OBJECTIVE To investigate work disability among people with ankylosing spondylitis (AS) in terms of correlates and coping mechanisms. METHODS The sample group (n = 133) was recruited through 2 sources: 1) consecutive patients attending outpatient clinics over a 6-month period, and 2) a random sample of members of the National Ankylosing Spondylitis Society. We used a cross-sectional survey with data collected by self-administered questionnaires and telephone interviews with a randomly selected subsample (n = 6). RESULTS The majority of participants were men. The mean age was 49 years; the mean disease duration was 28 years. Thirty-one percent were unable to work because of AS, with an additional 15% reporting changes to their working lives attributable to AS (e.g., reduction in hours worked, change of job). Compared with being in full-time work, work disability was associated with being older, longer disease duration, lower educational standard, comorbidity, greater physical impairment, pain, fatigue, stiffness, anxious and depressed mood, and lower self-esteem. Descriptive data added further insight into the experience of work disability and coping with AS in a work environment. CONCLUSION Work disability is worthy of further investigation to determine exact prevalence rates and psychosocial implications. Work disability could be addressed with simple interventions or adaptations in the workplace.

Assessment of the impact of flares in ankylosing spondylitis disease activity using the Flare Illustration

OBJECTIVES Many AS patients report periods of perceived higher disease activity (flares). This pilot study aims to document disease activity patterns reported by AS patients and examine associations with disease-specific health status measures. METHODS Consecutive AS patients (n = 114) were asked whether they experience flares, and if they experience symptoms of AS between flares. They were shown the Flare Illustration of disease patterns over time and asked to select the pattern that best described their disease (i) since symptom onset and (ii) in the past year. Associations between reported disease pattern and disease activity (Bath AS Disease Activity Index, BASDAI); functional impairment (Bath AS Functional Index, BASFI); AS Quality of Life (ASQoL); Back Pain (Nocturnal and Overall) and demographic features were assessed in a subsample (n = 83) (statistical significance defined at P <or= 0.05). RESULTS Since disease onset 108/113 patients (96%) reported flares, and 82/99 (83%) reported symptoms of AS between flares. Flares typically lasted days or weeks. When patients were asked to characterize their disease pattern using the Flare Illustration, patterns with constant symptoms predominated (>70% of patients) and patterns with constant symptoms since onset (vs intermittent symptoms) were associated with worse health status (ASQoL: P = 0.007; BASDAI: P = 0.029; BASFI: P = 0.013, overall back pain: P = 0.025). CONCLUSIONS Almost all AS patients report flares in disease activity: 70-80% report constant symptoms with single/repeated flares, while 20-30% report flares with no intermittent symptoms. The former is associated with a significantly poorer health status. These findings will be validated in a prospective study.

Evidence that Chlamydia trachomatis causes seronegative arthritis in women.

Chlamydia trachomatis elementary bodies (EBs) were found in synovial membranes or synovial fluid cell deposits from five of 15 women with seronegative mono- or oligoarthritis by means of a fluorescein conjugated anti-chlamydial monoclonal antibody (Micro Trak; Syva). Genital tract specimens were taken from only five of the patients, one of whom had intra-articular EBs, but none was chlamydia positive. Six of 10 patients tested were HLA-B27 positive, and chlamydial IgG antibody, measured by microimmunofluorescence, was present at a titre of 1/greater than or equal to 64 in the sera of five of the 15 patients, three of the five having EBs in their joints. In contrast, chlamydial EBs were not detected in the joints of a control group of 10 other women, most of whom had rheumatoid arthritis. None of them was HLA-B27 positive, and only one had a chlamydial antibody titre of 1/greater than or equal to 64. Neither Mycoplasma hominis nor ureaplasmas were isolated from the synovial fluids of seven patients and five controls who were tested. Antibody to M genitalium, however, was detected in five of the 10 patients but in none of the controls. This evidence apart, there was no other suggest that mycoplasmas or ureaplasmas might be responsible for arthritis which could not be attributed to chlamydiae.

Chlamydia trachomatis in reactive arthritis

SummaryEvidence of deposition of chlamydial antigen in the joint was sought in 10 patients (9 of them male) with classic sexually acquired reactive arthritis, 15 women with unclassified seronegative oligoarthritis involving the knee and 15 individuals with established rheumatic disorders not associated with genital-tract or other infections. Using a fluorosceinated monoclonal antibody to the major outer membrane protein of Chlamydia trachomatis (Micro Trak, Syva) in a direct immunofluorescence test, particulate antigen with physical characteristics of chlamydial elementary bodies was seen in synovial fluid cell smears or synovial biopsies, or both, from 6, 5, and 0 patients, respectively. No typical chlamydial intracellular inclusions were seen. Corroborative evidence of recent chlamydial infection was provided by the finding of high titres of serum chlamydial antibody in all antigen-positive patients with sexually acquired reactive arthritis, including 3 from whom a genital-tract isolate was obtained, and 3 of the 5 women with unclassified arthritis. It is postulated that Chlamydia trachomatis organisms reach the joint during acute genital-tract infection, and the processing and presentation by class I major histocompatibility determinants of chlamydial antigens is a critical step in the initiation of reactive arthritis in some patients.

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.

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.

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.

Calcinosis of joints and periarticular tissues associated with vitamin D intoxication.

We describe a patient with rheumatoid arthritis and widespread joint and periarticular calcinosis related to self-medication with vitamin D, which was aggravated by oral phosphate therapy prescribed for her hypercalcaemia. Hydroxyapatite was shown in the synovial fluid from affected joints. The role played by tissue injury in the pathogenesis of soft tissue calcification is discussed.