Rheumatoid arthritis: TNF-α antagonists [link]
Rheumatoid arthritis: comparison of TNF-α antagonists [link]
Rheumatoid arthritis: infliximab [link]
Rheumatoid arthritis: early treatment [link]
Rheumatoid arthritis: B cell targeted therapy [link]
Arthritis: cardiovascular outcomes with drug therapies [link]
Ankylosing spondylitis: TNF-α antagonists [link]
Gout: NSAIDs and COX-2 inhibitors [link]
Scleroderma lung disease: cyclophosphamide [link]
Painful shoulder: corticosteroid injection vs physiotherapy [link]
In the fourth century B.C., the Greek physician, Hippocrates, developed a medical theory called humoralism, which held that four humors (liquids) coursing through the human body determined a person’s temperament and state of health. He used the term rheuma, which literally means ‘flowing’, to describe an excess of the watery humor thought to flow down from the brain. The words rheuma and catarrhos (‘flowing down’) were used interchangeably by ancient Greeks to describe a variety of illnesses including joint problems. The French physician, Ballonius, in 1642 coined the term ‘rheumatism’ and distinguished noxious humors that affected joints from those that caused catarrh (hay fever, head colds, and sinusitis).
Thomas Sydenham (1624–89), a London physician who himself suffered from gout, distinguished the acute arthritis that attacked young people (probably rheumatic fever) from a chronic, crippling arthritis (probably rheumatoid arthritis) that came to be called rheumatic gout. Another British physician, AB Garrod, whose practice was devoted to studying ‘articular affections’, introduced the term ‘rheumatoid arthritis’ (from the Greek arthron, ‘joint’) in 1858 because, he insisted, the majority of patients said to have ‘rheumatic gout’ had an affliction that was related ‘neither to true gout nor to true rheumatism.’ Osteoarthritis (from the Greek osteon, ‘bone’) was commonly used as a synonym for rheumatoid arthritis. A clear distinction between the two ailments emerged at the beginning of the 20th century. In 1904, a Boston physician, Joel E Goldthwait, described the differences he saw using X-rays. In 1909, physicians, Edward H Nichols and Frank L Richardson of New York, reported on the pathological differences between osteoarthritis and rheumatoid arthritis. Today, there are clear criteria established for the clinical manifestations of rheumatic diseases, but there is still a long way to go in terms of establishing a clear understanding of their pathogenesis.
Rheumatoid arthritis: TNF-α antagonists
A multicentre randomised, double-blind, clinical trial of combination therapy with adalimumab plus methotrexate vs methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.
In patients with early (<3y), aggressive rheumatoid arthritis (RA), combination therapy with adalimumab and methotrexate is significantly superior to either methotrexate alone or adalimumab alone in improving signs, and symptoms, inhibiting radiographic progression, and effecting clinical remission.
Tumour necrosis factor-α (TNF-α) antagonists are now routinely used in the treatment of RA in patients who have active disease. The best efficacy is achieved when they are used in combination with methotrexate.
Both TNF-α antagonist, adalimumab, and methotrexate had previously been shown to be effective in the treatment of RA. However, no trial had assessed their use in combination. This trial explored the effectiveness of combination therapy in the treatment of early, aggressive RA.
• Diagnosis of RA (according to the 1987 American College of Rheumatology (ACR) criteria);
• Disease duration <3y;
• Age ≥18y;
• Active disease with ≥8 swollen joints and ≥10 tender joints, plus 1 of: early morning stiffness for >45min; ESR >28mm/h; CRP >15mg/L;
• Rheumatoid factor +ve or erosion of at least 1 joint.
• Previous immunosuppressant/disease-modifying anti-rheumatic drug (DMARD) therapy.
• Active infections, including tuberculosis.
All patients received concomitant folic acid 5-10mg/wk;
• Adalimumab 40mg SC fortnightly + methotrexate 20mg/wk (n=268);
• Adalimumab 40mg SC fortnightly + placebo (n=274);
• Placebo SC fortnightly + methotrexate 20mg/wk (n=257).
50% improvement (ACR50) at 1y and mean change in baseline of the modified Sharp score (a measure of joint damage assessed radiographically, based on joint space narrowing and erosions).
Percentage of patients achieving clinical remission (28 joint Disease Activity Score (DAS-28) <2.6), improvement in physical function measured by the health assessment questionnaire, and ACR20, ACR50, ACR70, and ACR90 responses at 2y.
• At 1y, 62% of patients receiving combination therapy exhibited an ACR50 response vs 46% receiving methotrexate alone or 41% receiving adalimumab alone (p=0.001). Similar effects on ACR20, ACR70, and ACR 90 response rates were observed at 2y.
• There was also significantly less radiographic progression among patients on combination treatment after 1 and 2y (1.3 and 1.9 Sharp units, respectively) when compared with patients on methotrexate alone (5.7 and 10.4 Sharp units) or adalimumab alone (3 and 5.5 Sharp units) (p≤0.002).
• 49% of patients on combination therapy displayed disease remission (DAS20<2.6) at 2y whilst only 25% displayed remission in the methotrexate alone or adalimumab alone groups.
This study provided evidence that early use of a TNF-A antagonist could induce remission in almost half the patients treated with adalimumab in combination with concomitant methotrexate.
• Further long-term data are required to establish the durability of remission on this drug combination as well as long-term cost-effectiveness.
• Despite impressive data from this study illustrating better outcomes in poor prognosis patients with RA treated early with combination therapy, the current UK National Institute for Health and Clinical Excellence (NICE) guidelines state that patients have to ‘fail’ with 2 DMARDs prior to anti-TNF-A therapy, thereby delaying the widespread introduction of TNF inhibitors.
Rheumatoid arthritis: comparison of TNF-α antagonists
TEMPO (Trial of Etanercept and Methotrexate with radiographic Patient Outcomes) study:
Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis.
Treatment with a combination of etanercept and methotrexate is superior in the treatment of rheumatoid arthritis (RA) than either agent alone.
Tumour necrosis factor-α (TNF-α) antagonists are now routinely used in the treatment of RA in patients who have active disease.
Etanercept is a human, soluble dimeric, TNF type II receptor fusion protein, linked to the IgG1-Fc fragment. It binds to and inactivates TNF. Both etanercept and methotrexate have previously been shown to be effective in the treatment of RA. This trial aimed to explore their effectiveness when used in combination.
• Diagnosis of RA (according to the 1987 American College of Rheumatology (ACR) criteria);
• Age ≥18y with disease duration 6 months to 20y;
• Active disease with ≥10 swollen joints and ≥12 tender joints plus one of: early morning stiffness for >45min; ESR>28mm/h; CRP>20mg/L;
• Failure of at least 1 disease-modifying anti-rheumatic drug (DMARD) other than methotrexate;
• Not treated with methotrexate in the previous 6 months.
• Immunosupressant therapy in the preceding 6 months;
• Previous treatment with any anti-TNF-α agent;
• Treatment with an investigational or biologic agent in the preceding 3 months;
• Treatment with DMARD or corticosteroid in the preceding 4wk;
• Active infections.
All patients received 5mg folic acid twice a week:
• Methotrexate 7.5mg weekly escalated to 20mg weekly within 8wk if patient had painful or swollen joints + SC placebo twice a week (n=228);
• Etanercept 25mg SC twice a week plus oral placebo tablet weekly (n=223);
• Methotrexate + etanercept (n=231).
Numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24wk. Radiographic endpoint was change in total joint damage score (modified total Sharp score=joint erosion + joint space narrowing score) over 52wk.
• ACR-N AUC at 24wk was greater for the combination group vs etanercept or methotrexate alone (18.3%-y [95% CI 17.1 to 19.6] vs 14.7%-y [13.5 to 16], p<0.0001, and 12.2%-y [11.0 to 13.4], p<0.0001, respectively).
• The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score –0.54 [95% CI –1.00 to –0.07] vs 2.8 [1.08 to 4.51], p<0.0001, and 0.52 [–0.1 to 1.15], p=0.0006, respectively).
• The number of patients reporting infections or adverse events was similar in all groups.
This study added another therapeutic option in the treatment of active RA. It showed that combination therapy with etanercept and methotrexate was superior to either agent alone. This observation emphasised the importance of co-prescribing methotrexate, when tolerated, even at modest doses, in order to achieve synergy with an anti-TNF-α agent such as etanercept.
• Use of anti-TNF-α agents is expensive (in the UK, costs are ≈£8000/y compared with methotrexate at ≈£20/y). Use of anti-TNF therapies has significant economic implications which may result in some degree of rationing.
• The study population comprised an unusually high proportion of patients in the established phase of disease without prior exposure to methotrexate. Such a population does not reflect the typical DMARD refractory patient considered for anti-TNF therapy in routine clinical practice.
Rheumatoid arthritis: infliximab
ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy):
Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) vs placebo in rheumatoid arthritis patients recei-ving concomitant methotrexate.
Treatment with infliximab and methotrexate is more effective than methotrexate alone in patients with uncontrolled active rheumatoid arthritis (RA).
Tumour necrosis factor-α (TNF-α) antagonists are now routinely used in the treatment of RA in patients who have active disease despite the use of conventional disease-modifying drugs.
Many patients with RA fail to respond to or are unable to tolerate conventional disease-modifying therapy such as methotrexate. This study aimed to investigate whether a chimeric human-mouse monoclonal antibody to TNF-α (infliximab) provided clinical benefit in patients with active disease.
• Diagnosis of RA (according to the 1987 American College of Rheumatology criteria);
• Active disease with ≥6 swollen joints, plus 2 of: early morning stiffness for >45min; ESR >28mm/h; CRP >2mg/dL;
• Stable dose of methotrexate (at least 12.5mg/week PO/IM);
• Stable dose of folic acid for at least 4wk;
• Receiving both drugs for at least 3 months;
• If oral corticosteroids (dose of 10mg/kg or less) or NSAIDs were used, then the dose must have been stable for 4wk prior to screening;
• Hb >5.3mmol/L, WBC >3.5x109/L, neutrophils >1.5x109/L, AST and ALP less than twice the upper limit of normal, creatinine <150micromol/L.
All patients received IV infusions at wk 0, 2, and 6:
• Infliximab 3mg/kg every 4wk (n=86) or 8wk (n=85);
• Infliximab 10mg/kg every 4wk (n=81) or 8wk (n=87);
• Placebo (n=88).
20% improvement as defined by the American College of Rheumatology (ACR20) at wk30.
• 50% and 70% improvement as defined by the American College of Rheumatology (ACR50 and ACR70);
• Reduction in individual measurements of disease severity;
• General health assessment.
Infliximab 3mg/kg every 8wk
Infliximab 3mg/kg every 4wk
Infliximab 10mg/kg every 8wk
Infliximab 10mg/kg every 4wk
Whilst conventional treatments such as methotrexate are effective, some patients develop adverse reactions and others maintain disease activity with resultant erosive destruction and deformation of joints. Uncontrolled RA also leads to an increase in mortality. TNF-α antagonists have revolutionised treatment of these patients, improving symptoms and inhibiting joint destruction. More recent studies (Arthritis Rheum (2003) 48, 35–45) have demonstrated the efficacy of the fully human anti-TNF-α monoclonal antibody, adalimumab. This has the advantage of being administered by subcutaneous injection.
• Although there was no difference in the number of serious adverse events between placebo and infliximab groups in this trial, subsequent experience indicates that infliximab may predispose to unusual infections, including reactivation of tuberculosis (TB).
• In this study, low levels of double-stranded DNA were induced in a small proportion of patients. Drug-induced lupus is rare, resolving with cessation of infliximab and treatment with steroids as required.
• Infliximab is contraindicated in patients with multiple sclerosis as it may precipitate demyelinating episodes.
• The efficacy of infliximab may decrease with repeated infusions over time because of the formation of human antichimeric antibodies.
Rheumatoid arthritis: early treatment
BeSt (‘BEhandel STrategieën’ – Dutch acronym for ‘best strategy’) study:
Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis.
Patients with early rheumatoid arthritis (RA) show faster improvement of function and inhibition of radiographic joint damage when treated with combination disease-modifying therapy, including either predniso-lone or infliximab.
The approach to RA management has changed from just symptom relief to prevention of long-term complications. This study aimed to establish whether combination drugs provided more clinical and radiographic benefit than single agents in the treatment of early RA. Additionally, it aimed to establish whether corticosteroids and tumour necrosis factor-α (TNF-α) agents should be part of this early aggressive treatment.
• Diagnosis of RA (according to the 1987 American College of Rheumatology (ACR) criteria);
• Age >18y;
• Disease duration ≤2y;
• Active disease: ≥6/68 tender joints and either ESR ≥28mm/h or global health score ≥20mm.
• Group 1 (sequential monotherapy): 1 drug at a time, starting with methotrexate, switching to other drugs if no improvement (sulfasalazine, leflunomide, then methotrexate with infliximab, if necessary) (n=126);
• Group 2 (step-up combination regimen): beginning on methotrexate, with more drugs added as necessary (sulfasalazine, then hydroxychloroquine, then prednisolone, then switching to methotrexate with infliximab) (n=121);
• Group 3 (combination therapy with prednisolone): started immediately on a combination of methotrexate, sulfasalazine, and tapered high-dose prednisolone (switching sulfasalazine for ciclosporin if necessary, and then to methotrexate with infliximab) (n=133);
• Group 4 (combination therapy with infliximab): combination therapy from the beginning with methotrexate and infliximab (and then, if necessary, leflunomide, sulfasalazine, ciclosporin, and prednisolone) (n=128).
Functional ability, measured by the Dutch version of the Health Assessment Questionnaire (D-HAQ) and radiographic damage according to the modified Sharp/Van der Heijde score. The latter was assessed on radiographs of the hands and feet obtained at baseline and 1y.
Mean D-HAQ score
1+2 vs 3+4; p<0.001
1 vs 3; p=0.01
1 vs 4; p=0.003
• In the first year of F/U, patients treated with initial combination therapy, including prednisolone (group 3) or infliximab (group 4), had less progression of radiographic joint damage.
Patients treated by initial combination therapy with either prednisolone or infliximab had more functional improvement than patients treated with sequential monotherapy or step-up combination therapy. Patients were less likely to progress to joint erosions after initial combination therapy with either prednisolone or infliximab. There were no benefits of step-up combination therapy over sequential monotherapy in terms of symptom improvement or inhibition of radiographic damage.
Rheumatoid arthritis: B cell targeted therapy
Efficacy of B cell targeted therapy with rituximab in patients with rheumatoid arthritis.
Treatment with the anti-CD20 monoclonal antibody, rituximab, is effective in patients with uncontrolled active rheumatoid arthritis (RA), despite treatment with methotrexate.
Rituximab is now approved in the treatment of severe uncontrolled active RA when tumour necrosis factor (TNF)-α antagonists have failed.
Rituximab is an anti-CD20 monoclonal antibody used in the treatment of CD20+ B cell non-Hodgkin’s lymphoma. CD20 is a B cell surface antigen that is expressed only on pre-B and mature B cells. The aim of this trial was to confirm previous (non-RCT) observations that selective depletion of B cells with the use of rituximab leads to sustained clinical improvements for patients with rheumatoid arthritis.
Active RA despite treatment with methotrexate:
• Diagnosis of RA (according to the 1987 American College of Rheumatology (ACR) criteria).
• Age >21y;
• Seropositive rheumatoid factor ≥20iu/mL;
• Active disease defined by ≥8 swollen joints, 8 tender joints on ≥10mg methotrexate, and ≥2 of the following:
• CRP level ≥15mg/L;
• ESR ≥28mm/h;
• Early morning stiffness >45min.
• Diagnosis of autoimmune disease other than RA;
• American Rheumatism Association functional class IV disease;
• Rheumatoid vasculitis; active infection; immunodeficiency; history of malignancy.
All patients received a 17d course of steroids and one dose of folinic acid:
• Methotrexate alone ≥10mg/wk (n=40);
• Rituximab alone 1g on d1 and 15 (n=40);
• Rituximab on d1 and 15 + cyclophosphamide 750mg on d3 and 17 (n=41);
• Rituximab on d1 and 15 + methotrexate ≥10mg/wk (n=40).
• 20% and 70% improvement defined by ACR20 and ACR70;
• Change in disease activity score (DAS28).
% attaining score at wk24
Change in score at wk24
Rituximab + cyclophosphamide
Rituximab + methotrexate
p values compared with methotrexate alone
This trial demonstrated that two doses of rituximab, alone or in combination with cyclophosphamide or methotrexate, provided a significant and enduring improvement in the symptoms of RA. Additionally, this effect was sustained for up to 48wk. The study also identified B cells as a key contibutor to the immunopathogenesis of RA.
Arthritis: cardiovascular outcomes with drug therapies
MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-term) programme:
Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis.
Rates of thrombotic cardiovascular events in patients with osteoarth-ritis or rheumatoid arthritis on the cyclooxygenase-2 (COX-2) inhibitor, etoricoxib, are similar to those in patients on long-term diclofenac.
Studies had shown increased rates of thrombotic cardiovascular complications with COX-2 inhibitors. However, comparable data for the use of non-steroidal anti-inflammatory drugs (NSAIDs) were not present. This study aimed to compare the relative risk of thrombotic cardiovascular events with etoricoxib and diclofenac using a non-inferiority trial design.
34,701 patients from 1,380 sites in 46 countries (patients combined from 3 trials: MEDAL, EDGE, and EDGE II).
• Diagnosis of rheumatoid arthritis according to the 1987 American College of Rheumatology;
• Diagnosis of osteoarthritis of the knee, hip, hand, or spine;
• Age ≥50y;
• Low dose aspirin was recommended for prophylaxis in patients with established cardiovascular, peripheral arterial, or cerebrovascular disease.
The hazard ratio of thrombotic events in the two groups was 0.95 (95% CI 0.81–1.11), showing non-inferiority of etoricoxib to diclofenac.
This large study showed no difference in the cardiovascular thrombotic rates of diclofenac and etoricoxib treatment in patients with osteoarthritis and rheumatoid arthritis.
• This study did not have a placebo group; hence, it was not possible to estimate absolute cardiovascular risks associated with etoricoxib and diclofenac.
• Increased cardiovascular risk has been demonstrated with other similar agents, including rofecoxib and valdecoxib. However, in the light of the findings in the MEDAL programme it cannot be assumed that this is a class effect.
• In the VIGOR study, the COX-2 inhibitor, rofecoxib, was compared with naproxen when more cardiovascular events were observed in the rofecoxib group. The explanation for this could be 3-fold. Firstly, rofecoxib promotes intravascular thrombosis. Secondly, naproxen is protective against these thromboses, or thirdly, both the previous considerations might apply. It would be interesting to compare etoricoxib with naproxen in terms of cardiovascular outcomes.
Ankylosing spondylitis: TNF-α antagonists
Treatment of active ankylosing spondylitis with infliximab: a randomised, controlled, multicentre trial.
Infliximab improves the disease activity index in patients with active anky-losing spondylitis despite treatment with non-steroidal anti-inflammatory drugs.
The first trial to show the effectiveness of tumour necrosis factor-α (TNF-α) antagonists in the treatment of ankylosing spondylitis, providing a therapeutic option for patients with uncontrolled pain and inflammation.
There are few treatment options for ankylosing spondylitis. Infliximab, a monoclonal antibody to TNF-α, had already been used with great success in other chronic inflammatory conditions such as rheumatoid arthritis. This trial aimed to assess the role of infliximab in the treatment of ankylosing spondylitis.
• Diagnosis of ankylosing spondylitis as defined by New York criteria (1984);
• Bath ankylosing spondylitis disease activity index (BASDAI) ≥4;
• Spinal pain as assessed on 10cm visual analogue scale.
• Active tuberculosis within the previous 3y;
• Specific chest X-ray changes;
• Serious infections in the previous 2 months;
• History of malignant disease in the previous 5y.
Improvement in visual analogue score for spinal pain, Bath ankylosing spondylitis functional index (BASFI), Bath ankylosing spondylitis metrology index (BASMI), short form (SF)-36, CRP, and ESR.
50% BASDAI improvement at wk12
• BASFI and BASMI showed similar differences.
There have been very few randomised studies of disease-modifying drugs in the treatment of ankylosing spondylitis. This study showed infliximab to significantly reduce disease activity, and improve function and quality of life in patients who were chronically ill and partly disabled by ankylosing spondylitis.
• This was a short-term trial. Therefore, long-term effectiveness of infliximab and its effects on radiographic progression of disease could not be assessed. Subsequent studies show sustained improvement in function although TNF blockade does not arrest progression of radiographic axial damage.
Gout: NSAIDs and COX-2 inhibitors
Safety and effectiveness study:
Randomised, double-blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis.
The cyclooxygenase-2 (COX-2) inhibitor, etoricoxib, is comparable to indometacin in the effective and rapid treatment of gouty arthritis.
Etoricoxib is now used in the treatment of gout where classical non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated.
The NSAID, indometacin, had been established as the most commonly used treatment for gout, despite limited studies demonstrating its efficacy. COX-2 inhibitors had been proposed to have efficacy in treating acute inflammatory conditions without some of the gastrointestinal side effects of NSAIDs. This study aimed to assess the safety and efficacy of a selective COX-2 inhibitor compared with the gold standard treatment, indometacin, in the treatment of acute gouty arthritis.
• Age ≥18y;
• Diagnosis of acute gout (onset within 48h) associated with moderate or severe pain;
• Sum score ≥5 for pain (0–4 point scale), tenderness (0–3 point scale) and swelling (0–3 point scale);
• No clinically significant abnormalities of blood count, chemistry, and urinalysis.
• Polyarticular gout involving more than 4 joints;
• Concurrent medical or arthritic disease;
• Unstable medical condition;
• Cerebrovascular accident or myocardial infarction in the preceding year;
• Patients on antiplatelet or anticoagulant therapy, digoxin, or corticosteroids (1 month previously).
Patient’s assessment of pain in the study joint (0–4 point scale: none/mild/moderate/severe/extreme) 4h after initial dose on d1, and then 4h after the first dose on d2 to 8.
Investigator’s assessment of the study joint on the basis of palpation or passive movement, swelling and erythema, and the patient’s and investigator’s global assessment of response to treatment.
• Patient’s assessment of pain in the study joint over d2 to 5 showed a mean change from baseline of –1.72 (95% CI –1.9 to –1.55) for etoricoxib and –1.83 (–2.01 to –1.65) for indometacin.
• Etoricoxib showed efficacy similar to indometacin for all secondary efficacy endpoints.
This was the largest controlled trial in gout reported to date. It found that the efficacy of etoricoxib was comparable to that of indometacin with significantly less drug-related adverse effects in the etoricoxib group. In practice, it may be more convenient for patients to take a once-daily formulation, and etoricoxib is likely to be a popular choice in the treatment of acute gout. The study was well designed because emphasis was placed on drug effects during the initial days of the acute gouty attack. This is important because acute gout is usually a self-limiting condition.
• One limitation of the study was that patients with polyarticular gout were excluded. Therefore, it is difficult to conclude whether the efficacy of the COX-2 inhibitor, etoricoxib, was equivalent to indometacin in this patient population.
• Many patients with gout are also at risk of cardiovascular complications, and such patients were excluded from this study. Given the concern about COX-2 inhibitors’ association with thrombotic events, further safety evaluation studies should be undertaken.
Scleroderma lung disease: cyclophosphamide
Cyclophosphamide vs placebo in scleroderma lung disease.
Oral cyclophosphamide has some beneficial effect on lung function, dyspnoea, skin thickening, and health-related quality of life in patients with symptomatic scleroderma-related interstitial lung disease.
Cyclophosphamide is used to improve quality of life in the treatment of scleroderma-related lung disease.
Cyclophosphamide had been the only treatment to date to show promise in the treatment of scleroderma-related interstitial lung disease in a number of retrospective studies. This study aimed to provide definitive evidence regarding cyclophosphamide’s efficacy, toxicity, and risk-benefit ratio in sclerodermalung disease.
• Diagnosis of limited or diffuse systemic scleroderma with evidence of active alveolitis on examination of bronchoalveolar lavage fluid or high resolution CT;
• Forced vital capacity (FVC) between 45% and 85% of predicted;
• Grade 2 exertional dyspnoea (according to the baseline instrument of the Mahler Dyspnoea Index).
• Single breath carbon monoxide diffusion capacity less than 30% predicted;
• History of smoking in preceding 6 months;
• Clinically significant pulmonary hypertension requiring treatment;
• Patients taking prednisolone more than 10mg/d, previous cyclophosphamide treatment and previous potentially disease-modifying treatment.
• Oral cyclophosphamide (1mg/kg/d, increased monthly up to 2mg/kg/d) (n=79);
• Placebo (n=79).
• 145 patients completed at least 6 months of treatment.
• The mean absolute difference in adjusted 12 months FVC percent predicted between the cyclophosphamide and placebo groups was 2.53% (95% CI, 0.28 to 4.79%), favouring cyclophosphamide (p<0.03).
• There was no effect on measures of gas transfer, but there was a significant improvement in dyspnoea, skin thickening, and HAQ disability index in the cyclophosphamide-treated group.
Whilst the effect of cyclophosphamide was modest in scleroderma-related interstitial lung disease, there was a marked improvement in quality of life. Therefore, this double-blinded study concluded that this agent should be considered in the treatment of inflammatory lung disease secondary to scleroderma.
Painful shoulder: corticosteroid injection vs physiotherapy
Effectiveness of corticosteroid injection vs physiotherapy for treatment of painful stiff shoulder in primary care
Intra-articular corticosteroid injections are superior to physiotherapy in the treatment of painful stiff shoulder syndromes.
Corticosteroid injections could be used as an early treatment in the management of painful shoulder syndrome.
Painful stiff shoulder (or capsular) syndrome is characterised by painful restriction of passive motion, particularly lateral rotation and abduction. With limited comparative data, this trial aimed to compare two common interventions in the treatment of this syndrome: intra-articular steroid injection and physiotherapy.
• Age ≥18y;
• Painful passive glenohumeral mobility with limited lateral rotation more restricted than abduction and medial rotation.
• Bilateral symptoms;
• Positive painful arc or resistance tests or loss of power;
• Corticosteroid or physiotherapy in the preceding 6 months;
• Contraindications to treatment;
• Type 1 diabetes.
• Physiotherapy (n=56);
• Corticosteroid injection (40mg triamcinolone acetate via the posterior approach) (n=53).
Outcome at 3 and 7wk as assessed by patient on a 6-point Likert scale and 100mm visual analogue scale (100=very severe pain). Functional disability was evaluated with a shoulder disability questionnaire (a 16-item scale consisting of common situations that might cause shoulder pain).
An independent observer scored the overall clinical severity of the disorder on a visual analogue scale after a physical examination of the patient.
• At 7wk, 77% treated with injections were deemed to be improved compared with 46% treated with physiotherapy.
• However, by 52wk, the differences between the two interventions were relatively small.
Intra-articular steroid injections may be preferable to physiotherapy in the initial treatment of painful stiff shoulder because they provide comparatively quick relief of symptoms. However, long-term effects of the two treatments were demonstrated to be similar.