Sulphasalazine in ankylosing spondylitis: a double blind controlled study in 60 patients.

Sulphasalazine has been reported to be effective in ankylosing spondylitis with peripheral arthritis, but its efficacy in spondylitis is unknown. Thus 60 patients with active ankylosing spondylitis without peripheral arthritis or gastrointestinal symptoms were randomly allocated to one of two therapeutic groups. One group received 2 g sulphasalazine daily for six months and the other a placebo. Thirteen patients (six given placebo and seven given sulphasalazine) dropped out of the trial and were considered to be treatment failures. After six months'' follow up efficacy was rated as good or very good by 15 of the 30 patients given sulphasalazine and by only six of the 30 given placebo (p less than 0.02). Furthermore, in the patients given sulphasalazine the daily consumption of non-steroidal anti-inflammatory drugs, functional index, and plasma IgG concentrations had fallen significantly. These data suggest that sulphasalazine may be a safe and effective treatment for spondylitis in ankylosing spondylitis.     

PHENYLBUTAZONE (BUTAZOLIDIN) AND BUTAPYRIN?—A Study of Clinical Effects in Arthritis and Gout

A clinical evaluation of phenylbutazone and Butapyrin® (a mixture of phenylbutazone and aminopyrine) was made in 409 patients who had a variety of rheumatic diseases. Preliminary European claims were substantiated.In gout a specific favorable effect was brought about by phenylbutazone alone.Effects equivalent to the previously reported favorable response to Butapyrin (Irgapyrin) were observed when its constituent phenylbutazone was used alone. The drug had a suppressive effect in a high percentage of patients with rheumatoid arthritis, ankylosing spondylitis, arthritis with psoriasis and mixed arthritis (rheumatoid arthritis plus osteoarthritis). Favorable effect in peritendinitis of the shoulders, osteoporosis of the spine and acute lumbosacral strain also was noted.Toxicity resulted in discontinuance of medication in 10 per cent of patients with each drug. Manifestations of toxicity generally included fluid retention, nausea and rash, but there were several instances of transitory leukopenia and anemia. There was one instance of agranulocytosis with Butapyrin but none with phenylbutazone.^† Aggravation of peptic ulcer occurred in ten patients with hemorrhage in two. Generally the toxicity was of a low order as compared with that of other drugs having an antirheumatic effect.     

Diagnosis of “Rheumatoid Variants”: Ankylosing Spondylitis,the Arthritides of Gastrointestinal Diseases and Psoriasis,and Reiter's Syndrome

Four rheumatic diseases—ankylosing spondylitis, the arthritis accompanying ulcerative colitis or regional enteritis, psoriatic arthropathy, and Reiter''s syndrome—formerly considered to be forms of rheumatoid arthritis, are now distinguished from that disorder and should be recognized by the physician as entities. These arthritides may be distinguished from each other by a number of clinical and radiographic characteristics, principally (1) the roentgenographic appearance of the spine when spondylitis is present, (2) the location of periosteal new bone formation, (3) the location of arthritis in the joints of the limbs, and (4) the presence of characteristic skin lesions.     

Nervous System Involvement in Ankylosing Spondylitis

In a review of 45 patients with ankylosing spondylitis 10 had neurological symptoms and signs and three of them had two separate neuropathological disorders. The neurological profiles fell into five main categories—multiple sclerosis, the cauda equina syndrome, focal epilepsy, vertebrobasilar insufficiency, and peripheral nerve lesions. An association between ankylosing spondylitis and multiple sclerosis is suggested, possibly due to an immunological defect or to one being a complication of the other.     

Raised titres of anti-klebsiella IgA in ankylosing spondylitis,rheumatoid arthritis,and inflammatory bowel disease

Serum titres of IgA are raised in ankylosing spondylitis and increased titres of antibodies to klebsiella have also been reported. The humoral response was investigated in ankylosing spondylitis and other inflammatory disorders. IgA antibodies to klebsiella pneumoniae K43 were measured in patients with ankylosing spondylitis, Crohn''s disease, ulcerative colitis, and rheumatoid arthritis and in controls. Significantly raised median titres of anti-klebsiella IgA, measured as optical density at 405 nm with an enzyme linked immunosorbent assay (ELISA), were seen among the patients with ankylosing spondylitis (0·7), Crohn''s disease (0·8), rheumatoid arthritis (0·6), and ulcerative colitis (0·8) compared with controls (0·4). Activity of disease in ankylosing spondylitis and titres of anti-klebsiella IgA were not correlated. In contrast, titres of anti-klebsiella IgM were significantly lower in patients with ankylosing spondylitis and ulcerative colitis.The increase in the titres of anti-klebsiella IgA may be due to increased permeability of the gut to bacterial antigens, leading to an increased IgA response in the gut mucosa and permitting the release of IgA into the circulation. As the increased antibody titres were seen in Crohn''s disease and rheumatoid arthritis as well as in ankylosing spondylitis the response may be non-specific, occurring because of possible underlying inflammatory bowel disease in these conditions.     

Antibiotic therapy of abscess of the lung and bronchiectasis

A clinical evaluation of phenylbutazone and Butapyrin(R) (a mixture of phenylbutazone and aminopyrine) was made in 409 patients who had a variety of rheumatic diseases. Preliminary European claims were substantiated.In gout a specific favorable effect was brought about by phenylbutazone alone. Effects equivalent to the previously reported favorable response to Butapyrin (Irgapyrin) were observed when its constituent phenylbutazone was used alone. The drug had a suppressive effect in a high percentage of patients with rheumatoid arthritis, ankylosing spondylitis, arthritis with psoriasis and mixed arthritis (rheumatoid arthritis plus osteoarthritis). Favorable effect in peritendinitis of the shoulders, osteoporosis of the spine and acute lumbosacral strain also was noted. Toxicity resulted in discontinuance of medication in 10 per cent of patients with each drug. Manifestations of toxicity generally included fluid retention, nausea and rash, but there were several instances of transitory leukopenia and anemia. There was one instance of agranulocytosis with Butapyrin but none with phenylbutazone.dagger Aggravation of peptic ulcer occurred in ten patients with hemorrhage in two. Generally the toxicity was of a low order as compared with that of other drugs having an antirheumatic effect.     

Acetanilide Oxidation in Phenylbutazone-associated Hypoplastic Anaemia

Acetanilide like phenylbutazone is paraoxidized by the liver endoplasmic reticulum as a primary biotransformation step. Both compounds were given at different times to each of 10 healthy volunteer subjects and the plasma disappearances measured. Correlation was shown between plasma clearance values of the two compounds (r = + 0·7067; P < 0·05).Eight patients with hypoplastic anaemia after phenylbutazone therapy were investigated. Plasma clearance values and half lives of acetanilide were measured in this group of patients and compared with those of a group of 30 healthy volunteer controls. There was a significant decrease in clearance (P < 0·01) and lengthening of half lives (P < 0·001 in the patients with phenylbutazone-associated hypoplasia. Five patients with idiopathic aplastic anaemia—that is, without history of antecedent phenylbutazone ingestion—were similarly investigated with acetanilide and there was no significant difference between the results in these patients and those in the control group.It is suggested that relatively poor paraoxidation of phenylbutazone producing high blood concentrations on a given dose may be a factor responsible for the drug-associated hypoplasia even though it does not explain the similar pattern of adverse reactions reported in association with oral administration of the metabolite oxyphenbutazone.     

Evaluation of Indomethacin by a Controlled,Cross-over Technique in 30 Patients with Ankylosing Spondylitis

A clinical evaluation of indomethacin employing a controlled, cross-over technique with an inert placebo was undertaken in 30 patients with ankylosing spondylitis. Patients were studied for the frequency and dose relationship of side effects and for the subjective response of morning stiffness, chronic spinal pain, acute exacerbations of pain and peripheral arthralgia. Objective evaluation assessed measured change in movements of the cervical and lumbar spines, in chest expansion and in the range of movement of involved peripheral joints.Evaluation of the results indicated that a significant number of patients experienced side effects in the form of headache and dizziness while receiving indomethacin in doses above 150 mg. per day. Many other side effects reported by the patients were not found to occur at a statistically significant level. The significance of pulmonary infections encountered in three patients was reviewed. Relief of chronic spinal pain and peripheral arthralgia occurred in 14 and 16 patients, respectively (p < 0.05). Relief of morning stiffness and acute exacerbations of pain, and increase in the range of movement of any of the segments of the spine or the involved peripheral joints were not significant (p > 0.05). Based on the results of this study, it is suggested that the role of indomethacin in the management of ankylosing spondylitis be re-evaluated and that the daily therapeutic dose of this drug which has been heretofore recommended be decreased.     

The prevalence of clinically diagnosed ankylosing spondylitis and its clinical manifestations: a nationwide register study

IntroductionPrevalence estimates of ankylosing spondylitis vary considerably, and there are few nationwide estimates. The present study aimed to describe the national prevalence of clinically diagnosed ankylosing spondylitis in Sweden, stratified according to age, sex, geographical, and socio-economic factors, and according to subgroups with ankylosing spondylitis-related clinical manifestations and pharmacological treatment.MethodsAll individuals diagnosed with ankylosing spondylitis according to the World Health Organization International Classification of Disease codes, between 1967 and 2009, were identified from the National Patient Register. Data regarding disease manifestations, patient demographics, level of education, pharmacological treatment, and geographical region were retrieved from the National Patient Register and other national registers.ResultsA total of 11,030 cases with an ankylosing spondylitis diagnosis (alive, living in Sweden, and 16 to 64 years old in December 2009) were identified in the National Patient Register, giving a point prevalence of 0.18% in 2009. The prevalence was higher in northern Sweden, and lower in those with a higher level of education. Men had a higher prevalence of ankylosing spondylitis (0.23% versus 0.14%, P < 0.001), a higher frequency of anterior uveitis (25.5% versus 20.0%, P < 0.001) and were more likely to receive tumor necrosis factor inhibitors than women (15.6% versus 11.8% in 2009, P < 0.001). Women were more likely than men to have peripheral arthritis (21.7% versus 15.3%, P < 0.001), psoriasis (8.0% versus 6.9%, P = 0.03), and treatment with oral corticosteroids (14.0% versus 10.4% in 2009, P < 0.001).ConclusionThis nationwide, register-based study demonstrated a prevalence of clinically diagnosed ankylosing spondylitis of 0.18%. It revealed phenotypical and treatment differences between the sexes, as well as geographical and socio-economic differences in disease prevalence.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0627-0) contains supplementary material, which is available to authorized users.     

Non-secretion of ABO blood group antigens as a host susceptibility factor in the spondyloarthropathies.

Gram negative bacteria precipitate reactive arthritis and may be concerned in the pathogenesis of ankylosing spondylitis and other spondyloarthropathies. Susceptibility to many infectious agents is associated with ABO blood group or secretor state, or both. The distribution of the ABO blood group or secretor state, or both, was therefore determined in 87 patients with ankylosing spondylitis and 32 with other forms of spondyloarthropathy. The prevalence of non-secretors was significantly increased in the total patient group (54/114; 47%) and in the subgroup with ankylosing spondylitis (41/84; 49%) compared with local controls (89/334; 27%) (p less than 0.001). Other subgroups of patients showed a similarly increased prevalence of non-secretion (33-47%). The distribution of ABO blood groups did not differ between patients and controls. The association between non-secretor state and ankylosing spondylitis strengthens the hypothesis that ankylosing spondylitis is a form of reactive arthritis. It also suggests several pathogenic mechanisms which may be relevant to the initial hostparasite interaction in ankylosing spondylitis.     

The effects of a number of non-steroidal anti-inflammatory compounds on parturition in the rat

A method was developed for assessing non-steroidal anti-inflammatory compounds for their potency in blocking parturition, and prolonging gestation, in the rat. This consisted of injecting compounds into groups of 10 to 13 rat dams twice daily from Day 18 through Day 22 of pregnancy, and comparing the treated dams with appropriate controls on Day 23. The rate of blocked parturition appeared to be positively related to dose of non-steroidal anti-inflammatory agent and, therefore, this model and end-point appeared to be useful for assessing different non-steroidal anti-inflammatory compounds for potency. Among the twenty-seven non-steroidal anti-inflammatory agents evaluated by this method were: ibuprofen, phenylbutazone, tolmetin, flufenamic acid, 2(p-biphenyl) acetic acid, mefenamic acid, aspirin, fenoprofen calcium, flumazole, ketoprofen, naproxen, isoxicam, indomethacin, 2(p-biphenyl) propionic acid, 2(2′-fluoro-4-biphenyl) propionic acid, flurbiprofen, sudoxicam and piroxicam. Piroxicam, sudoxicam, flurbiprofen, 2(p-biphenyl) propionic acid and 2(2′-fluoro-4-biphenyl) propionic acid showed the greatest potency. The relationship between structure and activity and between the blocking of parturition and the inhibition of prostaglandin synthesis are discussed.     

Double-blind Evaluation of Verapamil,Propranolol, and Isosorbide Dinitrate against a Placebo in the Treatment of Angina Pectoris

In the treatment of angina pectoris a double-blind evaluation of verapamil (Cordilox) at two dose levels—namely, 80 mg thrice daily and 120 mg thrice daily—propranolol (Inderal) 100 mg thrice daily, and isosorbide dinitrate (Vascardin) 20 mg thrice daily has been made against a placebo. The assessment was based on relief from daily attacks of angina on effort and the response to a whole-body exercise test. We can find no statistically significant difference between the effects of verapamil (120 mg three times a day) and propranolol (100 mg three times a day) in the treatment of angina of effort. Both of these preparations are more effective than a placebo both in the reduction of daily attacks (P < 0·01) and in the prolongation of exercise test (P < 0·05). Isosorbide dinitrate (20 mg three times a day) appears to be no more effective than a placebo in the treatment of angina on effort, but 14 out of 32 patients experienced headache of such severity that even when the dose was reduced to 10 mg thrice daily this drug therapy had to be withdrawn. Both propranolol (100 mg three times a day) and verapamil (120 mg three times a day) had a significant lowering effect on the diastolic blood pressure as measured with the patient standing (P < 0·01).     

Fenoprofen in Treatment of Osteoarthrosis of Hip and Knee

Two studies on 41 patients with osteoarthrosis of the hip or knee have shown fenoprofen—a compound with analgesic and anti-inflammatory properties—to be an effective addition to the drug treatment of these conditions. It was found to be superior to paracetamol but no statistically significant difference was shown in a comparison with phenylbutazone.     

The antagonism by anti-inflammatory analgesics of prostaglandin F2α-induced contractions of human and rabbit myometrium

The anti-inflammatory analgesic drugs, aspirin, indomethacin, phenylbutazone, mefenamic acid, ibuprofen and flurbiprofen are shown to inhibit in a dose-dependent manner the force of contraction of isolated human pregnant myometrial strips which have been stimulated to contract by adding prostaglandin (PG) F_2α to the tissue bath. These drugs and also flufenamic acid and salicin show a similar antagonism of the action of PGF_2α with isolated rabbit non-pregnant myometrium. The ratio of the inhibitory concentration to the maximum plasma level after a normal dose suggests that phenylbutazone and possibly ibuprofen may be capable of inhibiting human uterine contractions . Patients who were treated with aspirin during induction of abortion using PGF_2α during the second trimester of pregnancy showed no significant change in the induction-abortion interval compared with patients not taking aspirin.     

The antagonism by anti-inflammatory analgesics of prostaglandin F2α-induced contractions of human and rabbit myometrium in vitro

The anti-inflammatory analgesic drugs, aspirin, indomethacin, phenylbutazone, mefenamic acid, ibuprofen and flurbiprofen are shown to inhibit in a dose-dependent manner the force of contraction of isolated human pregnant myometrial strips which have been stimulated to contract by adding prostaglandin (PG) F_2α to the tissue bath. These drugs and also flufenamic acid and salicin show a similar antagonism of the action of PGF_2α with isolated rabbit non-pregnant myometrium. The ratio of the inhibitory concentration in vitro to the maximum plasma level after a normal dose in vivo suggests that phenylbutazone and possibly ibuprofen may be capable of inhibiting human uterine contractions in vivo. Patients who were treated with aspirin during induction of abortion using PGF_2α during the second trimester of pregnancy showed no significant change in the induction-abortion interval compared with patients not taking aspirin.     

ABO blood group and secretor status in the spondyloarthropathies

Abstract The postulated role of infectious agents, genetic susceptibility of the host to infection and their interaction in the pathogenesis of ankylosing spondylitis, other spondyloarthropathies, and the associated primary (non-arthritic) diseases are reviewed.
Compared with a local control population there is a significantly increased prevalence of non-secretors amongst different groups of patients with spondyloarthropathy: ankylosing spondylitis, reactive arthritis and psoriatic arthropathy. No differences between secretor and non-secretor patients with respect to serum and salivary IgA levels, the occurrence of eye lesions or peripheral joint disease have been found. There is no evidence that ankylosing spondylitis or other spondyloarthropathies are associated with any particular ABO blood group.
The association between non-secretion and ankylosing spondylitis strengthens the hypothesis that ankylosing spondylitis has an infective aetiology. It also suggests several pathogenetic mechanisms which may be relevant to the initial host-parasite interactions in the spondyloarthropathies.     

ABO blood group and secretor status in the spondyloarthropathies

The postulated role of infectious agents, genetic susceptibility of the host to infection and their interaction in the pathogenesis of ankylosing spondylitis, other spondyloarthropathies, and the associated primary (non-arthritic) diseases are reviewed. Compared with a local control population there is a significantly increased prevalence of non-secretors amongst different groups of patients with spondyloarthropathy: ankylosing spondylitis, reactive arthritis and psoriatic arthropathy. No differences between secretor and non-secretor patients with respect to serum and salivary IgA levels, the occurrence of eye lesions or peripheral joint disease have been found. There is no evidence that ankylosing spondylitis or other spondyloarthropathies are associated with any particular ABO blood group. The association between non-secretion and ankylosing spondylitis strengthens the hypothesis that ankylosing spondylitis has an infective aetiology. It also suggests several pathogenetic mechanisms which may be relevant to the initial host-parasite interactions in the spondyloarthropathies.     

United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results

From 1979 to 1985, 2435 patients thought to have had a transient ischaemic attack or minor ischaemic stroke were allocated at random to receive long term blind treatment with either aspirin 600 mg twice daily (n=815), aspirin 300 mg once daily (806), or placebo (814). Treatment continued with about 85% compliance until September 1986 (mean four years). The odds of suffering one or more of four categories of event—namely, non-fatal myocardial infarction, non-fatal major stroke, vascular death, or non-vascular death—were 18% less in the two groups allocated to receive aspirin than in the group allocated to receive placebo (2p=0·01). The more relevant but less frequent composite event of disabling stroke or vascular death was reduced by only 7%; this reduction was not significantly different from zero, but nor was it significantly different from a 25% reduction. There was no definite difference between responses to the 300 mg and 1200 mg daily doses, except that the lower dose was significantly less gastrotoxic.     

Effectiveness of adalimumab in treating patients with ankylosing spondylitis associated with enthesitis and peripheral arthritis

Introduction

The purpose of this study was to investigate the effectiveness of adalimumab in enthesitis and peripheral arthritis in patients with ankylosing spondylitis (AS).

Methods

Adults with active AS (Bath ankylosing spondylitis disease activity index [BASDAI] ≥ 4) received adalimumab 40 mg every other week with standard antirheumatic therapies in a 12-week, open-label study. Effectiveness in enthesitis was assessed using the Maastricht ankylosing spondylitis enthesitis score (MASES, 0-13) and by examining the plantar fascia in patients with enthesitis (≥ 1 inflamed enthesis) at baseline; effectiveness in peripheral arthritis was evaluated using tender and swollen joint counts (TJC, 0-46; SJC, 0-44) in patients with peripheral arthritis (≥ 1 swollen joint) at baseline. Overall effectiveness measures included Assessment of SpondyloArthritis International Society 20% response (ASAS20).

Results

Of 1,250 patients enrolled, 686 had enthesitis and 281 had peripheral arthritis. In 667 patients with MASES ≥ 1 at baseline, the median MASES was reduced from 5 at baseline to 1 at week 12. At week 12, inflammation of the plantar fascia ceased in 122 of 173 patients with inflammation at baseline. The median TJC in 281 patients with SJC ≥ 1 at baseline was reduced from 5 at baseline to 1 at week 12; the median SJC improved from 2 to 0. ASAS20 responses were achieved by 70.5% of 457 patients with no enthesitis and no arthritis; 71.0% of 512 patients with only enthesitis; 68.0% of 107 patients with only arthritis; and 66.7% of 174 patients with both.

Conclusions

Treatment with adalimumab improved enthesitis and peripheral arthritis in patients with active AS.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00478660","term_id":"NCT00478660"}}NCT00478660.     

Lack of association of the G22A polymorphism of the ADA gene in patients with ankylosing spondylitis

Genes located outside the HLA region (6p21) have been considered as candidates for susceptibility to ankylosing spondylitis. We tested the hypothesis that the G22A polymorphism of the adenosine deaminase gene (ADA; 20q13.11) is associated with ankylosing spondylitis in 166 Brazilian subjects genotyped for the HLA*27 gene (47 patients and 119 controls matched for gender, age and geographic origin). The HLA-B*27 gene and the G22A ADA polymorphism were identified by PCR with sequence-specific oligonucleotide probes and PCR-RFLP, respectively. There were no significant differences in frequencies of ADA genotypes [odds ratio (OR) = 1.200, 95% confidence interval (CI) = 0.3102-4.643, P > 0.8] and ADA*01 and ADA*02 alleles (OR = 1.192, 95%CI = 0.3155-4.505, P > 0.8) in patients versus controls. We conclude that the G22A polymorphism is not associated with ankylosing spondylitis.