Polymyalgia rheumatica can be distinguished from late onset rheumatoid arthritis at baseline: results of a 5-yr prospective study.

OBJECTIVE: To describe the pattern of arthropathy and HLA-DRB1 alleles associated with PMR in order to develop a diagnostic algorithm that could help distinguish PMR and RF-negative (RF -ve) late-onset RA (LO-RA) at presentation. METHODS: This was a prospective study of all patients presenting with PMR or LO-RA over a 10-yr period to one physician. Demographic, clinical and laboratory data were collected at presentation and during a minimum of 5 yrs of follow-up. The accuracy of the initial diagnosis was systematically reviewed. RESULTS: One hundred and forty-two patients with LO-RA, 147 with PMR and 42 with PMR + TA were studied. Peripheral synovitis was observed in 23% of the PMR patients. In comparison with RF -ve LO-RA, PMR patients were younger (P < 0.001), myalgia more frequent [100 vs 16% (P < 0.001)] and arthritis of PIP, MCP and wrist were less frequent (P < 0.001). The combination of wrist + MCP/PIP or wrist + PIP + MCP were highly suggestive of RF -ve LO-RA (P < 0.001). HLA-DRB1*0101/0102 and *0401 were significantly increased in PMR patients compared with healthy controls. Plasma viscosity and arthritis in the wrist, in combination with at least one MCP or PIP joint at disease onset, were predictive of whether a non-erosive RF -ve patient would ultimately be diagnosed as having RF -ve LO-RA or PMR (+/-/arthritis). CONCLUSION: Our longitudinal follow-up data were consistent with RF -ve LO-RA being a separate disease entity to PMR despite some phenotypic and immunogenetic similarities at disease onset. A diagnostic algorithm was derived using baseline clinical features to predict the final diagnosis of RF -ve, non-erosive patients.

Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study.

OBJECTIVE: Primary Sjögren syndrome (pSS) causes significant systemic symptoms including fatigue as well as glandular dysfunction. There are currently no effective systemic therapies; however, open label series have suggested that rituximab may be beneficial for systemic and glandular manifestations. Therefore, we performed a double blind, placebo-controlled, randomised pilot study of the efficacy of rituximab in reducing fatigue in pSS. METHODS: A total of 17 patients with pSS and a score on fatigue visual analogue scale (VAS) >50 were randomised to receive either 2 infusions of rituximab 1 g or placebo; patients also received oral and intravenous steroids. Outcome measures included: the proportion of patients with >20% reduction in fatigue VAS, changes in pSS related symptoms, health related quality of life and immunological parameters of pSS. These were measured 6 months after therapy. RESULTS: There was significant improvement from baseline in fatigue VAS in the rituximab group (p<0.001) in contrast to the placebo group (p = 0.147). There was a significant difference between the groups at 6 months in the social functioning score of SF-36 (p = 0.01) and a trend to significant difference in the mental health domain score of SF-36 (p = 0.06). There was one episode of serum sickness in the rituximab treated group. CONCLUSIONS: This is the first double blind study of rituximab in pSS to show benefit; further studies are justified.

Analysis of the insertion/deletion related polymorphism within T cell antigen receptor beta variable genes in primary Sjögren's syndrome.

OBJECTIVE: To analyse T cell receptor beta variable (TCRBV) gene polymorphisms (insertion/deletion related polymorphism (IDRP) and BV6S7) in primary Sjögren's syndrome (PSS). METHODS: Genomic DNA was extracted from blood samples from patients fulfilling the modified European criteria for PSS (n = 61). Healthy control blood samples were obtained from the Blood Transfusion Service (n = 121). As a disease control group, samples from patients with systemic lupus erythematosus (n = 42) were analysed. BV6S7 was genotyped using an established PCR/RFLP method. The IDRP was determined by comparison of the intensity of PCR product bands from within BV9S2 and an internal control region (BV9S1), to ascertain whether 0, 1, or 2 copies of the insertion were present. RESULTS: There was a decrease (p = 0.018) in the proportion of PSS patients with the deleted/deleted genotype. There was no association with specific BV6S7 alleles or genotypes with either the PSS group or the hypergammaglobulinaemic subgroup. There were no significant differences in haplotype frequencies after Bonferroni correction. CONCLUSIONS: A reduced proportion of patients with PSS have the deleted/deleted genotype. Eighty nine per cent of PSS patients have at least one extra germline copy of BV13S2*1. This may relate to previous observations of increased BV13 specific T cells and mRNA in the salivary glands.

FcgammaRIIIA-158V and rheumatoid arthritis: a confirmation study.

OBJECTIVES: To develop a robust assay for genotyping the FcgammaRIIIA-158V/F polymorphism and to confirm the putative association between the FcgammaRIIIA-158V allele and rheumatoid arthritis (RA). METHODS: This allelic association study examined the FcgammaRIIIA-158V/F polymorphism for association with RA. A novel single-stranded conformational polymorphism assay was used to genotype 828 RA patients and 581 controls from the UK. RESULTS: The FcgammaRIIIA-158V allele was associated with both RA (P=0.02) and nodules (P=0.04). Individuals homozygous for this higher affinity allele had a significantly increased risk of RA (OR 1.53, 95% CI 1.08-2.18) and the development of nodules (OR 2.20, 95% CI 1.20-4.01). There was no evidence of an interaction with the shared epitope. CONCLUSIONS: We have developed a novel assay to genotype the FcgammaRIIIA-158F/V polymorphism and confirmed that homozygosity for the FcgammaRIIIA-158V allele is associated with UK Caucasian RA, particularly in those individuals with nodules, suggesting FcgammaRIIIA may play a role in determining disease severity or in the development of nodules per se.

Does the age of onset of rheumatoid arthritis influence phenotype?: a prospective study of outcome and prognostic factors.

OBJECTIVE: To identify factors affecting prognosis in patients with late-onset rheumatoid arthritis (RA). METHODS: A total of 400 patients with RA fulfilling the American College of Rheumatology criteria for diagnosis were prospectively recruited from two hospital rheumatology centres. Of these patients, 214 had disease onset above age 65 yr (LORA) and 186 below age 65 yr (YORA). Follow-up clinical, functional, laboratory and radiological assessments were compared. The Ritchie articular index (RAI) and joint erosions were used as markers of disease activity and damage, respectively. Disability was assessed using the Stanford Health Assessment Questionnaire (HAQ). RESULTS: At median follow-up of 3.6 yr, the frequency of joint erosions was similar (YORA, 51.6%; LORA, 54.2%). The remission rate was greater in the LORA group (YORA, 20.4%; LORA, 45.8%, P < 0.01). Factors associated with the development of erosions were: IgM rheumatoid factor (RF) seropositivity [odds ratio (OR) = 4.24, 95% confidence interval (CI) 2.56, 6.94], HLA DR4 (OR = 2.07, 95% CI 1.28, 3.35) and elevated inflammatory markers (OR = 1.81, 95% CI 1.04, 3.14). Continuous steroid use >3 months for the LORA group was associated with increased erosions (OR = 4.09, 95% CI 1.81, 9.27). LORA patients (OR = 2.99, 95% CI 1.77, 5.02) were more likely to go into remission and IgM RF-seropositive patients less likely to go into clinical remission (OR = 0.47, 95% CI 0.28, 0.77). Female patients with a high HAQ score at presentation experienced a poor functional outcome (female OR = 3.01, 95% CI 1.59, 5.68; high HAQ OR = 3.02, 95% CI 1.98, 4.62). CONCLUSION: LORA can be as damaging as classical RA and joint erosions are often observed at presentation. Being RF seropositive, DR4 positive, and having elevated inflammatory markers at onset, were associated with poor radiological outcome irrespective of age of onset. Being female and having marked disability at presentation were associated with poor functional outcome in both groups. These findings suggest that treatment approaches used in classical YORA should be instituted with equal vigour in patients with LORA.

Late-onset rheumatoid arthritis: is pitting oedema of the hands at onset a good prognostic indicator?

This prospective study compares the clinical and radiological outcome of patients with late-onset (age 65 yr and over) rheumatoid arthritis (RA) presenting with and without pitting oedema of the hands (POH). Twenty-two patients with POH (Group 1) were compared with 81 (Group 2) without POH (median age of onset of RA-Group 1: 74.3; Group 2: 73.1; female to male. ratio-Group 1: 1.2:1; Group 2: 2.5:1). The median time between the onset of arthritis and baseline assessment was 3 months. Minimum follow-up was 1 yr (median 2.4). Outcome was defined by (1) the development of erosions of the hands, wrists or feet and (2) the number of patients in remission (clinically inactive disease on two clinic visits 3 months apart with no intervening history of inflammatory joint disease). IgM rheumatoid factor (IgM RF) was less frequent in patients with POH (Group 1:8.2%; Group 2: 43.2%, P < or = 0.05). Logistic regression analysis showed that POH at onset was independent of IgM RF in determining outcome. Patients with POH were less likely to develop erosions [odds ratio (OR) = 0.16, 95% confidence interval (CI) 0.03, 0.89]. Although initial cross-tabulation suggested an increased frequency of remission in Group 1 (Group 1: 90.9%; Group 2: 55.5%, P = 0.02), POH was not found to be a significant predictor using the logistic regression model (OR = 7.42, 95% CI 0.84, 65.7). Patients with IgM RF were more likely to develop erosions (OR = 5.1, 95% CI 1.46, 17.67) and less likely to go into remission (OR = 0.19, 95% CI 0.06, 0.68).

Insufficiency fractures of the distal tibia.

Eight patients are described who had sustained insufficiency fractures of the distal tibia, in one case, bilaterally. Seven of the eight patients had RA. Features common to most patients were delay in diagnosis, low body weight, pain and swelling around the ankle joint, steroid therapy, generalized osteopenia and relatively young age. Patients with RA all had ankle joint involvement and impaired mobility.

Serological and immunogenetic markers of extraglandular primary Sjögren's syndrome.

The clinical course of 48 patients with primary Sjögren's syndrome (primary SS) was reviewed. Forty-three north European patients were typed for HLA class I and class II alloantigens. In this population with primary SS HLA B8, DR3 and DRw52 all occurred more frequently than in the control population (P < 0.009, P < 0.0035, P < 0.02 respectively). The subgroup of primary SS patients with antibodies to Ro and/or La antigen had the greatest prevalence of DR3 (relative risk 33.4). The primary SS patients fall into two distinct groups: those with extraglandular disease in whom lymphopaenia, hypergammaglobulinaemia, antibodies to Ro and/or La and HLA DR3 were all more frequent and those patients with either glandular disease alone or only one extraglandular feature. There was no difference in disease duration between the two groups, although on average the latter group were 10 years older.

The arthropathy of Sjögren's syndrome.

The clinical course of 48 patients with primary SS has been reviewed with particular reference to the articular manifestations. The incidence of arthritis and/or arthralgia was 54%. In a third of these patients it was a presenting feature and preceded sicca symptoms. The arthropathy tended to be polyarticular, the most frequent joint involved being the knee. It was symmetrical in 55% of cases. Joint symptoms or signs were intermittent, lasting less than a month in 55% of cases. The acute onset of purpuric vasculitis was associated with an acute arthritis in four out of the nine patients with such a vasculitis. Joint deformity was unusual, ulnar deviation occurring in only six patients. Hand X-rays obtained from primary SS patients revealed evidence of joint erosions in 33% of PIP joints, 27% of MCP joints and 12% of wrist joints.

Clinical, serological, and HLA phenotype subsets in Sjögren's syndrome.

The clinical and laboratory features of 89 patients with Sjögren's syndrome (SS) have been reviewed. Forty-eight of the patients had primary SS, of whom 27 had antibodies to Ro and/or La. The anti-Ro/La antibody positive patients showed a higher frequency of systemic clinical features, as well as high IgG levels and rheumatoid factors compared to those without the antibodies. Patients with SS-SLE developed symptoms of SS at the same age as those with primary SS but facial rashes, photosensitivity, and serositis were more common. Otherwise the clinical and laboratory features were indistinguishable from primary SS with anti-Ro/La. The frequency of HLA DR3 and HLA DRW 52 in European Caucasians with primary SS was 67% and 82% (92% in those with anti-Ro/La) respectively. DRW 53 occurred in 94% of all patients with SS-RA.

Anti-La (SS-B): a diagnostic criterion for Sjögren's syndrome?

We examined the diagnostic sensitivity and specificity of antibodies to Ro (SS-A) and La (SS-B) in Sjögren's syndrome (SS) by counterimmunoelectrophoresis and immunodiffusion. Anti-Ro was found in 56% and anti-La in 42% of patients with SS and in 38% and 6% respectively in SLE. Anti-La was rare (less than 1%) in other connective tissue diseases. As a more stringent test of diagnostic specificity, 88 patients whose sera contained anti-La and/or anti-Ro were carefully examined for evidence of Sjögren's syndrome. Of 35 patients whose sera contained anti-La, 29 (83%) fulfilled criteria for SS, and four out of 6 of the remainder showed some evidence of early disease. Of 53 patients with anti-Ro (without anti-La), only 42% had Sjögren's syndrome, 45% had SLE and 13% other connective tissue diseases. These data confirm that anti-La, but not anti-Ro, has a high diagnostic specificity for Sjögren's syndrome and merits inclusion as separate diagnostic criterion for the disease.

Polymorphonuclear leucocyte motility in men with ankylosing spondylitis.

The polymorphonuclear leucocyte (PMN) response to a chemotactic or chemokinetic stimulus is enhanced in men with ankylosing spondylitis (AS). This effect does not parallel the severity of disease activity or the size of the acute phase response, and it is independent of non-steroidal anti-inflammatory drug treatment. Polymorph function is normal in HLA-B27 positive brothers of probands with AS and in other HLA-B27 positive individuals in the absence of disease. Polymorph motility is also normal in patients with psoriasis vulgaris or Crohn's disease, indicating that enhanced PMN motility is not a non-specific consequence of all inflammatory disorders.

Ankylosing spondylitis without B27: no evidence for gene conversion.

Isoelectric focusing gel electrophoresis was used to look for variant HLA molecules in five patients with HLA-B27 negative ankylosing spondylitis (AS). The isoelectric points of the HLA-A and B antigens from these patients and HLA paired controls were identical. This implies that the HLA-A and B antigens from the patients with AS and the controls are similar. Gene conversion of a nucleotide sequence from a B27 positive gene is thus unlikely to be the explanation for the existence of AS in patients who are HLA-B27 negative by alloantisera typing.

Polymorphonuclear leukocyte function in psoriasis vulgaris.

Polymorphonuclear leukocyte (PMN) migration was assessed in vitro using the agarose plate method in patients with psoriasis vulgaris, and compared with an age- and sex-matched control group. No significant difference was found between the two groups in the PMN response to the chemotactic substances F-Met-Leu-Phe (FMLP) or zymosan activated serum (ZAS). Equally, the chemokinetic or chemotactic potential of psoriatic serum did not differ from control serum. Our results do not support a primary abnormality of PMN function in psoriasis.

The myocardium in ankylosing spondylitis. A clinical, echocardiographic, and histopathological study.

Cardiac function was investigated in men with ankylosing spondylitis (AS) age 21-65 years who had no cardiorespiratory symptoms or known abnormalities of heart or lungs. Chest radiographs and standard electrocardiograms were normal in 73 of 74 subjects. In echocardiographs of 30 men, left atrial size and left ventricular cavity size and wall thickness were normal. Minor abnormalities in the valve roots were present in 3 older men. Early diastolic abnormalities of the left ventricle were demonstrated in 16 of 30 subjects. This finding was confirmed by repetition of the echocardiography a year later in 15 subjects and by comparison of 11 probands with their healthy brothers. Myocardial tissue obtained at necropsy from 28 AS patients without ischaemic or valvular heart disease or hypertension was studied. A mild, diffuse increase of interstitial connective tissue was seen but there was no inflammatory change or amyloid. Computerised image analysis showed 30.7% interstitial reticulin compared with 17.7% in age/sex matched controls (p less than 0.0001).

IgA antibodies to gram-negative bacteria in the serum and saliva of patients with ankylosing spondylitis.

The concentration of IgA and titre of IgA antibodies to several Gram-negative bacteria were measured in the serum and parotid saliva of patients with AS and normal tissue-typed individuals. Salivary IgA and antibody levels in the patients were identical with the control population. The serum antibody level against Yersinia enterocolica 0:3 was slightly raised in patients but there was no difference in the reactions to Klebsiella oxytoca strain MX100 or Escherichia coli 0111.B4. The serum IgA level was elevated in patients with AS, irrespective of HLA B27. We conclude that this approach is unlikely to provide convincing evidence of a link between Gram-negative bacteria and ankylosing spondylitis.

Double-blind trial of flurbiprofen and phenylbutazone in acute gouty arthritis.

Flurbiprofen has been compared with phenylbutazone in a double-blind study involving 33 patients with acute gout. Patients received either flurbiprofen 400 mg daily for 48 h followed by 200 mg daily, or phenylbutazone 800 mg daily for 48 h followed by 400 mg daily. The drugs were of comparable efficacy, while side-effects were uncommon and relatively mild. Flurbiprofen appears to be a satisfactory alternative to phenylbutazone in the management of acute gouty arthritis.