Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer.

INTRODUCTION: Treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years with the introduction of cabazitaxel, abiraterone and enzalutamide. With new systemic therapies available, the optimal treatment sequence of these drugs in mCRPC becomes increasingly important. As shown recently, patients who had previously been treated with abiraterone showed impaired responses to docetaxel, suggesting clinical cross-resistance [1]. In the present study, we aimed to identify cross-resistance between taxanes (docetaxel and cabazitaxel) and the new hormonal agents abiraterone and enzalutamide. As a potential mechanism for cross-resistance, we investigated the effects on androgen receptor (AR) nuclear translocation of these compounds. METHODS: To identify cross-resistance, we determined the effects of docetaxel, cabazitaxel, abiraterone and enzalutamide on cell viability in prostate cancer cell lines with acquired resistance to abiraterone and enzalutamide. Time-lapse confocal microscopy was used to study the dynamics of AR nuclear translocation. RESULTS: We observed impaired efficacy of docetaxel, cabazitaxel and enzalutamide in the abiraterone-resistant cell line, compared to the non-resistant cell line, providing evidence for in vitro cross-resistance. Impaired efficacy of docetaxel, cabazitaxel and abiraterone was observed in the enzalutamide-resistant cell line. Furthermore, docetaxel and cabazitaxel inhibited AR nuclear translocation, which was also observed for abiraterone and enzalutamide. CONCLUSIONS: In conclusion we found substantial preclinical evidence for cross-resistance between the taxanes docetaxel and cabazitaxel, and AR targeting agents abiraterone and enzalutamide. Since these compounds all interfere with AR-signalling, this strongly suggests a common mechanism of action, and thus a potential mechanism for cross-resistance in mCRPC.

"The Leeds Idea": an historical account of the spondarthritis concept.

In the 1960s, Professor Verna Wright became increasingly interested in possible relationships between certain seronegative "variants of rheumatoid arthritis", as they were then generally known. At the Rheumatism Research Unit, a department within the division of medicine at Leeds University, he gathered around him a succession of research workers, whom he inspired to study aspects of these relationships. The focus was on family studies, as it was thought that genetic factors could be important. The striking association previously noted between sacroiliitis or full-blown ankylosing spondylitis and several of these disorders to be studied - e.g., psoriatic arthritis, ulcerative colitis, and the arthritis associated with Crohn's disease - was to be central for each of these studies. As a provisional collective name for these possibly related conditions, the term "Spondarthritides" was chosen. These were the days before HLA B27, and so the research tools were simply clinical, radiological (for sacroiliitis) and serological (for rheumatoid factor). The research programme confirmed not only links between the primary disorders with ankylosing spondylitis, but also links between the disorders themselves. Over subsequent years, the spondarthritis concept (dubbed by some "The Leeds Idea") has gained further strength from HLA studies internationally. And membership of the group of conditions fulfilling spondarthritis criteria has grown substantially. It is hoped that this now consolidated framework of spondylitis-related entities will pave the way for further research, with exciting prospects of gene-based prevention and/or cure through the increasing sophistication of molecular biology.

The place of psoriatic arthritis in the spondarthritides.

The place of psoriatic arthritis in the spondarthritides has been examined in terms of past, present and future aspects. It is concluded that: 1. PsA is a definite entity and separate from rheumatoid arthritis. 2. The spondarthritis concept is universally accepted, although still in an evolving stage. 3. A more definitive picture of the spondarthritides and of PsA itself could arise from a number of new approaches, some entirely novel, some extensions of work already in progress. Avenues of future research that are likely to be fruitful include those involving: more refined clinical studies; further applications of molecular mapping; and, common to both, conceptual advances using mathematical models to provide a more 'three-dimensional' picture.

Current thinking on spondarthritides.

In this article I have briefly considered current thinking in the field of spondarthritis. Etiopathogenetic aspects include the structure of the HLA-B27 molecule and the population distribution of B27, as well as the significance of bacterial infection in the disease process. Diagnostic aspects have focused on infrared thermography, radionuclide scintigraphy, and computerized tomography. The current therapeutic position involves the traditional combination of NSAID, exercises, and surgery, as well as a new interest in sulfasalazine.

Criteria for ankylosing spondylitis: facts and fallacies.

Weaknesses in existing clinical and radiological criteria for diagnosing ankylosing spondylitis are highlighted and suggestions for improvement made. It is suggested that a major stride forward would be to incorporate a system of probability weighting for individual criteria. This would not only allow diagnosis to be expressed in terms of statistical confidence but would also allow diagnosis to be codified. This latter could facilitate the interpretation of data.

Proper poster presentation: a visual and verbal ABC.

The 58 posters exhibited at the 1985 Annual General Meeting of the British Society for Rheumatology have been analysed for 13 variables considered important in the construction of a good poster. In particular the attributes of information, simplicity and visual attractiveness were studied. The time spent by viewers was also measured for one selected poster each in immunology, biochemistry, therapeutics and clinical medicine. On the basis of this survey, nine recommendations for proper presentation were made.

Seronegative arthropathies in the foot.

It has been seen that involvement of the foot in the seronegative arthropathies forms a regular and varied part of the clinical picture. This is often quite different from that seen in rheumatoid arthritis; its components, whether in joints, periarticular structures, or as surface manifestations, may be characteristic enough to raise the diagnosis of 'spondarthritis'. The features described, though characteristic of the spondarthritides, are, however, not pathognomonic. Thus, the osteolysis in psoriatic arthritis also occurs in neuropathic arthritis (e.g. syringomyelia, leprosy), psoriatic periosteal changes may mimic osteosarcomatous proliferations, and the calcaneal enthesitis so typical of spondylitis, Reiter's disease and psoriatic arthritis, may also be seen in metabolic arthropathies. It should also be mentioned here that the severe erosive osteolytic changes leading to psoriatic arthritis mutilans may also be seen, albeit rarely, in rheumatoid arthritis. Ankylosis, too, is not totally confined to the spondarthritides, having also been reported in occasional patients with rheumatoid arthritis. Calcaneal erosions, sometimes envisaged as a spondarthritic feature, also occur in rheumatoid patients. Within the spondarthritis matrix, a striking overlap is seen in the pattern of arthritis. Thus, involvement of the feet in psoriatic arthritis and in Reiter's disease shows many similarities, particularly the tendency to involve IP joints in asymmetrical oligoarticular fashion. In the hindfoot, too, parallels can be drawn between the tendency to Achilles and plantar insertion enthesitis in ankylosing spondylitis and Reiter's disease. On the other hand, the arthropathies of the chronic inflammatory bowel diseases, ulcerative colitis, Crohn's disease, and Whipple's disease, share with Behçet's syndrome an asymmetrical involvement of knees and ankles, but relative freedom from foot involvement. Regarding the surface features in the foot of spondarthritides, there is overlap here, too. For example, the nail dystrophy of psoriasis can be indistinguishable from that of Reiter's disease, and pustular psoriasis in its severe form cannot be differentiated from keratoderma blenorrhagica, even at the histological level. Other surface manifestations affecting the lower limb in general distribution may spread to the feet and thus fall within the ambit of this discussion. Such features include the lesions of erythema nodosum, patches of pyoderma gangrenosum, and the tender cords of thrombophlebitis, all of which have a higher prevalence in seronegative arthritis than in seropositive disease.(ABSTRACT TRUNCATED AT 400 WORDS)

New criteria for the diagnosis of ankylosing spondylitis.

Criteria for ankylosing spondylitis are useful for two main purposes. First, to provide unity of diagnosis in population surveys; secondly, in the field of therapeutic assessment. This paper is concerned with criteria used largely in the former role, i.e. as an epidemiological tool. Critical formulation and subsequent evaluation of criteria is important if a realistic measure of disease prevalence is to be obtained. The New York criteria have provided the general currency for diagnosis epidemiologically in recent years, but their value, in their originally published form, has been questioned for various reasons. Attempts have been made to improve these criteria or to suggest alternatives. Although increased sophistication of the original New York criteria has doubtless been achieved, the position regarding the diagnosis of ankylosing spondylitis continues to represent a challenge. The main concern is that the present "index of truth" for the disease, radiological sacroiliitis, is all too often a delayed feature, presenting only after pain has been present for some time. A second problem is the difficulty in diagnosing with confidence the early changes of sacroiliac sclerosis and erosion, and the degree of intra- and inter-observer error arising from these changes. Newer techniques such as radioisotope scintigraphy and computerised tomography (CT) are unlikely to replace the traditional pelvic radiograph. The way forward is more likely to be in the direction of how existing data are processed rather than what is used to obtain them. In this vein, suitable mathematical/biological models coupled with computer technology could provide realistic tools through a system of probability weighting of existing criteria.

Doctor-patient communication in rheumatology: studies of visual and verbal perception using educational booklets and other graphic material.

Patients (n = 404) with osteoarthrosis and control subjects (n = 233) were studied to examine the communicational value of five styles of illustration (cartoon (C), matchstick (M), representational (R), symbolic (S), photographic (P) and two levels of text ('easy', 'hard'), presented as educational booklets about osteoarthrosis. Booklet comprehension was tested with a multiple choice questionnaire (MCQ) scored by two raw score and two, more sensitive, weight-of-evidence methods. Further studies assessed perception of image detail, tone, and colour by ranking, rating, latency, and questionnaire methods. A subgroup was tested psychometrically. The main findings were: pictures in booklets enhance communication; perception of pictorial style depends on its vehicle of presentation, cartoons being most effective in booklets, photographs overall; simplifying text does not significantly enhance communication; certain picture-text 'interactions' appear to increase comprehension (e.g. 'hard' text with 'easy' pictures); several 'endogenous' factors are associated with increased comprehension: 'psychological' (e.g., intelligence, memory, reading skill); 'demographic' (e.g., the young, males, higher social grades, higher educational levels); 'disease' (e.g., longer disease duration, previous information about the disease).

Inflammatory bowel disease.

The place of inflammatory bowel disorders in the spondarthritis matrix has been discussed and aetiopathological and clinicoradiological features of their individual arthropathies described. Particular emphasis has been placed on the arthropathies of ulcerative colitis and Crohn's disease, but a comment is also included on the much rarer condition, Whipple's disease. The position of reactive arthritis resulting from enteric infection in relation to the spondarthritis concept is examined in the light of Reiter's-like clinical features and the association with HLA-B27. More 'peripheral' ideas of possible relevance to the spondarthritis idea (drug-induced colitis, intestinal-bypass syndrome) are included, together with a final section on experimental models of inflammatory bowel disease and of their arthropathies. It is concluded that certain inflammatory bowel disorders deserve a continuing place within the spondarthritis complex. Although their aetiopathogenesis is still imperfectly understood, it is likely that a blend of genes of small effect (polygenic inheritance) and environmental factors (e.g. microorganisms and/or their products) trigger disease processes which are enabled to manifest themselves by intermediary immunological processes. The precise way in which this is achieved is not yet known, but there is evidence that microorganisms (presumably in the gut of individuals genetically predisposed and suitably exposed environmentally) generate the formation of immune complexes. It is likely that these not only damage or further damage the mucosal lining of the bowel but also result in arthropathy and features of the disease 'distant' from bowel and joint (e.g. ocular inflammation, oral ulceration and skin manifestations). This concept is summarized in Figure 5.

Pathogenetic mechanisms in B27 associated diseases.

Various aspects of pathogenesis, or more broadly, aetiopathogenesis, in the field of B27 related disorders are considered. The main conclusions can be expressed as follows: Genetic factors are involved in the causation of the spondarthritides, although there is still controversy within individual disorders concerning the precise mode of inheritance. For instance, in some conditions evidence appears stronger for a Mendelian mechanism, in others for a multifactorial process. The mode of the HLA-B27-receptor interaction is not yet fully established, but there is strong support for the one gene cross-tolerance theory, in ankylosing spondylitis at least. It is likely that environmental factors 'collaborate' with genetic factors in causing spondarthritic disease. The factors in the environment have yet to be proved, but there is some evidence that micro-organisms such as Klebsiella and Yersinia are involved (e.g. ankylosing spondylitis, Reiter's disease, reactive arthritis). Of noninfective environmental factors, trauma could play a part, as suggested by the mode of onset and pattern of development of some examples of ankylosing spondylitis and psoriatic arthritis.

A comparison of three ways of measuring pain.

In a double-blind cross-over trial of azapropazone and indomethacin in 20 patients with osteoarthritis of the hip and knee with four weeks on each drug, three methods of assessing pain and pain relief were used. These methods were a simple five-point rating scale, an analogue scale and an eight-point scale using pictures. Acceptable correlation was shown between all three scales in measurement of changes in degree of pain. The picture scale could be useful in patients with language or mental capacity difficulties.

The clinical spectrum of psoriatic arthritis.

Epidemiologic, clinical, radiologic and serologic evidence suggests that psoriatic arthritis is a specific entity and not the coincidental occurrence of 2 common diseases, psoriasis and rheumatoid arthritis. Psoriatic arthritis may be defined as psoriasis associated with inflammatory arthritis (peripheral arthritis or spondylitis or both) and usually a negative serologic test for rheumatoid factor. Clinical characteristics of the disease include: almost equal distribution between males and females; peripheral arthritis involving only a few small joints in asymmetical fashion; involvement of distal interphalangeal joints; sausage digits; arthritis mutilans; ankylosing spondylitis; goutlike onset; and higher frequency of nail involvement than occurs in uncomplicated psoriasis. The rash may present with arthritis, or, equally, may precede or succeed joint involvement. With regard to pain and disability, the prognosis in psoriatic arthritis is better than in rheumatoid arthritis.

Diclofenac sodium (Voltarol) and indomethacin: a multicentre comparative study in rheumatoid arthritis and osteoarthritis.

A five-centre double-blind crossover trial of two two-week periods using diclofenac and indomethacin showed that both drug groups (51 patients) with rheumatoid arthritis responded similarly in relation to pain scores and morning stiffness. It was noted that the response was better in inpatients than in outpatients, despite differences in disease severity. In the osteoarthritis trial (58 patients) it was shown that neither drug significantly reduced resting pain, although both drugs were significantly better in reducing pain on movement; however, patient preference was for diclofenac. Three patients treated with indomethacin withdrew owing to side-effects, compared with one on diclofenac. A slight but significant decrease in haemoglobin levels was observed in both treatment groups with osteoarthritis, but this did not appear to be symptom-related.