Peter Maddison

Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus

OBJECTIVE The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. METHODS The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. RESULTS Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). CONCLUSION The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-double-stranded DNA antibodies.

Serological markers in progressive systemic sclerosis: clinical correlations.

The relation between clinical and serological findings was studied in 75 patients with definite progressive systemic sclerosis (PSS). Antinuclear antibodies were detected by indirect immunofluorescence in 95% of the patients by means of HEp-2 cells. The centromere pattern was observed in 50% of the patients with calcinosis, Raynauds phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia (CREST) and only 7% of the group with diffuse disease. Precipitating antibodies to nuclear and cytoplasmic antigens were detected by immunodiffusion in 53% of the patients and identified as anti Scl-70 in 16 (21%). We confirmed that autoantibodies are very frequent in PSS but varied in specificity. A combination of immunodiffusion and indirect immunofluorescence was useful in detecting antibodies characteristic of PSS (i.e., anti-Scl-70 and anticentromere) in 51% of these patients. Anticentromere antibody has a high specificity for CREST and identifies patients with less severe disease (i.e., more prolonged course and less involvement of internal organs). Anti-Scl-70 was associated with a high frequency of lung involvement.

A randomized placebo-controlled trial of MTX in PsA

Objective. MTX is widely used to treat synovitis in PsA without supporting trial evidence. The aim of our study was to test the value of MTX in the first large randomized placebo-controlled trial (RCT) in PsA. Methods. A 6-month double-blind RCT compared MTX (15 mg/week) with placebo in active PsA. The primary outcome was PsA response criteria (PsARC). Other outcomes included ACR20, DAS-28 and their individual components. Missing data were imputed using multiple imputation methods. Treatments were compared using logistic regression analysis (adjusted for age, sex, disease duration and, where appropriate, individual baseline scores). Results. Four hundred and sixty-two patients were screened and 221 recruited. One hundred and nine patients received MTX and 112 received placebo. Forty-four patients were lost to follow-up (21 MTX, 23 placebo). Twenty-six patients discontinued treatment (14 MTX, 12 placebo). Comparing MTX with placebo in all randomized patients at 6 months showed no significant effect on PsARC [odds ratio (OR) 1.77, 95% CI 0.97, 3.23], ACR20 (OR 2.00, 95% CI 0.65, 6.22) or DAS-28 (OR 1.70, 95% CI 0.90, 3.17). There were also no significant treatment effects on tender and swollen joint counts, ESR, CRP, HAQ and pain. The only benefits of MTX were reductions in patient and assessor global scores and skin scores at 6 months (P = 0.03, P < 0.001 and P = 0.02, respectively). There were no unexpected adverse events. Conclusions. This trial of active PsA found no evidence for MTX improving synovitis and consequently raises questions about its classification as a disease-modifying drug in PsA. Trial registration. Current Controlled Trials, www.controlled-trials.com, ISRCTN:54376151.

Effects of high-intensity resistance training in patients with rheumatoid arthritis: A randomized controlled trial

OBJECTIVE To confirm, in a randomized controlled trial (RCT), the efficacy of high-intensity progressive resistance training (PRT) in restoring muscle mass and function in patients with rheumatoid arthritis (RA). Additionally, to investigate the role of the insulin-like growth factor (IGF) system in exercise-induced muscle hypertrophy in the context of RA. METHODS Twenty-eight patients with established, controlled RA were randomized to either 24 weeks of twice-weekly PRT (n = 13) or a range of movement home exercise control group (n = 15). Dual x-ray absorptiometry-assessed body composition (including lean body mass [LBM], appendicular lean mass [ALM], and fat mass); objective physical function; disease activity; and muscle IGFs were assessed at weeks 0 and 24. RESULTS Analyses of variance revealed that PRT increased LBM and ALM (P < 0.01); reduced trunk fat mass by 2.5 kg (not significant); and improved training-specific strength by 119%, chair stands by 30%, knee extensor strength by 25%, arm curls by 23%, and walk time by 17% (for objective function tests, P values ranged from 0.027 to 0.001 versus controls). In contrast, body composition and physical function remained unchanged in control patients. Changes in LBM and regional lean mass were associated with changes in objective function (P values ranged from 0.126 to <0.0001). Coinciding with muscle hypertrophy, previously diminished muscle levels of IGF-1 and IGF binding protein 3 both increased following PRT (P < 0.05). CONCLUSION In an RCT, 24 weeks of PRT proved safe and effective in restoring lean mass and function in patients with RA. Muscle hypertrophy coincided with significant elevations of attenuated muscle IGF levels, revealing a possible contributory mechanism for rheumatoid cachexia. PRT should feature in disease management.

Atherosclerotic vascular events in a multinational inception cohort of systemic lupus erythematosus

To describe vascular events during an 8‐year followup in a multicenter systemic lupus erythematosus (SLE) inception cohort and their attribution to atherosclerosis.

A randomized and controlled trial of hydrotherapy in rheumatoid arthritis.

OBJECTIVE The aim of this study was to evaluate the therapeutic effects of hydrotherapy which combines elements of warm water immersion and exercise. It was predicted that hydrotherapy would result in a greater therapeutic benefit than either of these components separately. METHODS One hundred thirty-nine patients with chronic rheumatoid arthritis were randomly assigned to hydrotherapy, seated immersion, land exercise, or progressive relaxation. Patients attended 30-minute sessions twice weekly for 4 weeks. Physical and psychological measures were completed before and after intervention, and at a 3-month followup. RESULTS All patients improved physically and emotionally, as assessed by the Arthritis Impact Measurement Scales 2 questionnaire. Belief that pain was controlled by chance happenings decreased, signifying improvement. In addition, hydrotherapy patients showed significantly greater improvement in joint tenderness and in knee range of movement (women only). At followup, hydrotherapy patients maintained the improvement in emotional and psychological state. CONCLUSIONS Although all patients experienced some benefit, hydrotherapy produced the greatest improvements. This study, therefore, provides some justification for the continued use of hydrotherapy.

The efficient production of stable, human monoclonal antibody-secreting hybridomas from EBV-transformed lymphocytes using the mouse myeloma X63-Ag8.653 as a fusion partner.

The mouse myeloma X63-Ag8.653 was fused to peripheral blood lymphocytes (PBL) from apparently healthy individuals, autoimmune patients and volunteers immunised with Rhesus (D) positive erythrocytes. Fusions were performed with or without prior transformation of PBL with Epstein-Barr virus (EBV). Using untransformed PBL, under the best conditions a mean fusion frequency of 8.4 X 10(-6) was obtained, with 22% of the resulting hybridomas secreting human immunoglobulin. Fusions with EBV-transformed cells gave fusion frequencies of 1.0 X 10(-4), with 85-90% of hybridomas secreting human immunoglobulin. The heterohybridomas formed in both cases cloned efficiently and had doubling times of 24-30 h. The heterohybridomas secreted human IgM, IgG and IgA of both kappa and lambda isotypes and culture supernatants contained up to 50 micrograms ml-1 of human immunoglobulin. Mouse immunoglobulin was not detected in the culture supernatants. 28 hybrids were selected for vigorous growth and antibody production by repeated cloning. Immunoglobulin synthesis was stabilised in 26 of these hybridomas after two or three cloning steps. The heterohybridomas have been successfully grown in large volumes for periods up to 15 months. It is concluded that the mouse myeloma X63-Ag8.653 is a suitable fusion partner with EBV-transformed B cells in the efficient production of human monoclonal antibodies.

Osteoarthritis and articular chondrocalcinosis in the elderly.

One hundred consecutive admissions to an acute geriatric unit were examined for clinical and radiographic evidence of osteoarthritis (OA) and articular chondrocalcinosis (ACC). Thirty-four patients had ACC. This was age related, the prevalence rising from 15% in patients aged 65-74 years to 44% in patients over 84 years. The commonly involved joints were the knee (25%), public symphysis (15%), and wrist (9%). No other aetiological factors predisposing to ACC were found. Of the 25 patients with ACC in the knee 7 had no symptoms or signs and no radiographic evidence of OA at that site. However, the combination of ACC and radiographic OA was characterised by an increase in clinical joint disease. Features of inflammation (joint swelling and joint line tenderness) involving the knee, wrist, and elbow were particularly common in ACC. It is concluded that ACC is common in the elderly and is associated with an increased incidence of joint disease.

The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations.

Thirty-two patients with the Felty syndrome, defined by the presence of rheumatoid arthritis, splenomegaly, and neutropenia, have been studied in comparison with 32 patients with rheumatoid arthritis matched for age, sex, and disease duration, and 9 patients with rheumatoid arthritis and idiopathic neutropenia. Patients with the Felty syndrome had severe destructive arthritis, which progressed during follow-up despite little evidence of objective synovitis, and a higher frequency of extra-articular manifestations, including vasculitis. Bacterial infection tended to occur in patients with the lowest neutrophil count but continued to occur in some despite normalization of the WBC. Prognosis was poor and 8 deaths occurred, predominantly from sepsis. Serologic features were prominent. High titers of IgG rheumatoid factor and circulating immune complexes characterized patients with persistent neutropenia. A family history of rheumatoid arthritis was more common in patients with the Felty syndrome. The association with HLA DR4 was very strong; in addition there was an increased frequency of the DQw3 variant, 3b, suggesting that HLA Class II genes in linkage with DR4 may contribute to disease expression.

Benefits of exercise in Rheumatoid Arthritis.

This paper aims to highlight the importance of exercise in patients with rheumatoid arthritis (RA) and to demonstrate the multitude of beneficial effects that properly designed exercise training has in this population. RA is a chronic, systemic, autoimmune disease characterised by decrements to joint health including joint pain and inflammation, fatigue, increased incidence and progression of cardiovascular disease, and accelerated loss of muscle mass, that is, “rheumatoid cachexia”. These factors contribute to functional limitation, disability, comorbidities, and reduced quality of life. Exercise training for RA patients has been shown to be efficacious in reversing cachexia and substantially improving function without exacerbating disease activity and is likely to reduce cardiovascular risk. Thus, all RA patients should be encouraged to include aerobic and resistance exercise training as part of routine care. Understanding the perceptions of RA patients and health professionals to exercise is key to patients initiating and adhering to effective exercise training.