There is a need for new systemic sclerosis subset criteria. A content analytic approach.

OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

[Nanna Svartz (1890-1986) : The first female professor of medicine in Sweden]. / Nanna Svartz (1890­1986) : Die erste Frau auf einem medizinischen Lehrstuhl in Schweden.

Nanna Svartz was a charismatic character who played a significant role in Swedish medicine in the mid-twentieth century. As one of five brothers and sisters, she escaped an early death from tuberculosis. She reached 96 years of age. Her diligence and sense of duty were legendary, along with her ambition to fully prove herself as "the first female professor". She inherited a certain insecurity from her father that led to her difficulty in taking criticism. Despite extensive academic obligations, she worked as a treating doctor for 55 years and always took her time with her patients, especially if they held important public positions. Nanna was honoured several times in her lifetime. Among others, she was a member of the Leopoldina, the National Academy of Germany, and received many honorary doctorates, for example, from Rockefeller College (USA) and the Åbo University (Turku, Finland). She was an honorary member of over 40 scientific societies. Underneath the new auditorium in the Karolinska Institute, a restaurant and a street in her home town of Västerås bear her name. An annual international Nanna Svartz Lecture is held by the Swedish Society for Rheumatology, and a Nanna Svartz Prize is awarded annually to a deserving young Swedish rheumatologist.

Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database.

OBJECTIVE: To determine the prevalence of and independent factors associated with joint involvement in a large population of patients with systemic sclerosis (SSc). METHODS: This study was cross-sectional, based on data collected on patients included in the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) registry. We queried this database to extract data regarding global evaluation of patients with SSc and the presence of any clinical articular involvement: synovitis (tender and swollen joints), tendon friction rubs (rubbing sensation detected as the tendon was moved), and joint contracture (stiffness of the joints that decreased their range of motion). Overall joint involvement was defined by the occurrence of synovitis and/or joint contracture and/or tendon friction rubs. RESULTS: We recruited 7286 patients with SSc; their mean age was 56 +/- 14 years, disease duration 10 +/- 9 years, and 4210 (58%) had a limited cutaneous disease subset. Frequencies of synovitis, tendon friction rubs, and joint contractures were 16%, 11%, and 31%, respectively. Synovitis, tendon friction rubs, and joint contracture were more prevalent in patients with the diffuse cutaneous subset and were associated together and with severe vascular, muscular, renal, and interstitial lung involvement. Moreover, synovitis had the highest strength of association with elevated acute-phase reactants taken as the dependent variable. CONCLUSION: Our results highlight the striking level of articular involvement in SSc, as evaluated by systematic examination in a large cohort of patients with SSc. Our data also show that synovitis, joint contracture, and tendon friction rubs are associated with a more severe disease and with systemic inflammation.

Aspects of science in Scandinavian rheumatology--the making of a specialty.

The five Scandinavian countries Denmark, Finland, Iceland, Norway, and Sweden have all contributed essential and unique knowledge to the science of rheumatology. The origins have varied between the countries. Bridges from basic science and international contacts have been essential for the quality and vitality of a small specialty in small countries. Inter-Scandinavian links as manifested in congresses and in the Journal are the visible superstructure of a far deeper and fertile common culture.

Classification of systemic sclerosis. Visions and reality.

Systemic sclerosis, scleroderma (SSc) is a disabling condition that shortens life expectancy. Disease heterogeneity and difficulties separating SSc from SSc-like conditions make classification an important issue. Limited cutaneous and diffuse cutaneous SSc, with different severity and survival, have been recognized for several years as distinct subsets. Some authors have suggested an intermediate cutaneous form with intermediate survival. This issue remains unsettled, however. The technique of capillaroscopy is helpful as an adjunct diagnostic tool to separate idiopathic Raynaud's phenomenon from SSc. Digitized video-capillaroscopy is developing as a powerful new method to assess individual capillaries over time. Using the simpler techniques of video-capillaroscopy, different patterns have been described and named 'early', 'active', 'late' and 'slow'. The value of nailfold video-capillaroscopy to distinguish different subsets or provide prognostic information for use in daily practice remains to be assessed. The features of CREST (calcinosis, Raynaud's, oesophagus dysmotility, sclerodactyly, telangiectasias) are not confined to single subsets of SSc. There is no convincing evidence of any advantage for distinguishing the limited, intermediate and diffuse forms of SSc rather than only the limited and diffuse forms.

A randomised placebo controlled 12 week trial of budesonide and prednisolone in rheumatoid arthritis.

OBJECTIVES: To compare budesonide, a locally acting glucocorticoid with minimal systemic exposure, with conventional glucocorticoid treatment and placebo in rheumatoid arthritis. METHODS: A double blind, randomised, controlled trial over 12 weeks in 143 patients with active rheumatoid arthritis, comparing budesonide 3 mg daily, budesonide 9 mg daily, prednisolone 7.5 mg daily, and placebo. Particular attention was paid to the pattern of clinical response and to changes in the four week period following discontinuation of treatment. RESULTS: There were improvements in tender joint count and swollen joint count on budesonide 9 mg compared with placebo (28% for tender and 34% for swollen joint counts, p<0.05). Prednisolone 7.5 mg gave similar results, while budesonide 3 mg was less effective. ACR20 response criteria were met by 25% of patients on placebo, 22% on budesonide 3 mg, 42% on budesonide 9 mg, and 56% on prednisolone 7.5 mg. A rapid and significant reduction in symptoms and signs in response to budesonide 9 mg and prednisolone 7.5 mg was evident by two weeks and maximal at eight weeks. There was no evidence that budesonide provided a different pattern of symptom control from prednisolone, or that symptoms became worse than placebo treatment levels after discontinuation of glucocorticoid treatment. Adverse effects attributable to glucocorticoids were equally common in all groups. CONCLUSIONS: The symptomatic benefits of budesonide 9 mg and prednisolone 7.5 mg are achieved within a short time of initiating treatment, are maintained for three months, and are not associated with any rebound in symptoms after stopping treatment.

Long term efficacy and safety of cyclosporin versus parenteral gold in early rheumatoid arthritis: a three year study of radiographic progression, renal function, and arterial hypertension.

OBJECTIVE: To compare the three year safety and efficacy of cyclosporin and parenteral gold in the treatment of early, active, severe rheumatoid arthritis (RA), and to study the reversibility of cyclosporin associated renal dysfunction in patients who discontinued cyclosporin treatment. METHODS: The patients continued to receive cyclosporin or parenteral gold in an 18 month open extension to an 18 month randomised, parallel group study. The main efficacy variable was blinded evaluation of radiographic progression of joint damage. Safety variables included serum creatinine, calculated creatinine clearance, and blood pressure. RESULTS: Radiographic progression during follow up was similar in both groups. About 60% of the patients in the intention to treat groups (n=272) and about half of the patients in the completer groups (n=114) had definite radiographic progression in joint damage (increases >6 in the Larsen-Dale score), and about one in three also had substantial progression (>18 increase in Larsen-Dale score). Both systolic and diastolic blood pressure were significantly increased in the cyclosporin group compared with the gold group, and 12/139 (9%) versus 3/139 (2%) (p=0.03) had notably raised blood pressure. The mean serum creatinine increased by 28% at the treatment end point in the cyclosporin group as compared with 7% in the gold group. The mean calculated creatinine clearance was reduced by 16% and increased by 1% in the cyclosporin and gold groups, respectively, at the end of the study. At the final follow up visit after discontinuation of cyclosporin (at least three months after treatment was stopped) the mean serum creatinine was increased by 15% and creatinine clearance reduced by 16%. Sustained increases in serum creatinine at this post-treatment end point were mostly seen in patients with a raised serum creatinine during treatment of at least 50%. CONCLUSION: Three year changes in radiographic damage during cyclosporin and parenteral gold were similar in patients with early, active RA. Abnormal renal function and raised blood pressure were often seen in the cyclosporin treated patients.

[Meager support for herbal therapy of rheumatoid arthritis]. / Klent underlag för att behandla reumatoid artrit med örtmedicin.

The Cochrane collaboration has recently published a systematic review of placebo controlled randomized trials of herbal therapies for rheumatoid arthritis. An extensive search including all languages screened 2500 hits, identified 47 trials and accepted 11 as meeting set quality criteria. Modest efficacy of gamma linolenic acid containing products was supported by 7 trials, 4 trials dealt with 4 different products, and no conclusions could be derived from these. Although it was stated in the review that safety was probably good, this is not apparent from the presented material.

Disease severity of 100 patients with systemic sclerosis over a period of 14 years: using a modified Medsger scale.

OBJECTIVE: To assess organ involvement according to a modified Medsger severity scale and its relation to outcome and prognosis in patients with systemic sclerosis. METHODS: One hundred consecutive patients observed in Lund with systemic sclerosis were followed up for a period of 14 years. The mean follow up time was 7.7 years. Initial assessment and an annual evaluation was performed for each patient, with a mean visit frequency of 5.6 per patient. RESULTS: Age at referral, high total skin score, truncal skin involvement, low vital capacity, low static lung compliance, low Cr-EDTA clearance, and ECG abnormalities at the initial assessment predict poor outcome. A severity scoring system for five organ systems indicates a slow progression of organ dysfunction after recruitment into the study. The female: male ratio was 2:1, the mean age at onset of symptoms was 42.3 (range 3-82), and the mean age at recruitment was 47.2 years (range 17-82). Thirty patients died during the follow up period at the mean age of 61.3 years (range 33-85). The causes of death were directly related to systemic sclerosis in at least 10 patients, infections in six, cancers in nine, and other causes in four patients. The standardised mortality ratio was 3.5 and 3.7 for men and women, respectively. CONCLUSION: A high severity score for function of vital organs was shown to predict shortened survival. In this study a severity score based on simple clinical assessment variables was able to predict poor outcome from extensive skin changes, ECG changes, and compromised lung and renal function. Organ dysfunction mainly became manifest during the first five years of the disease, whereafter organ function remained largely stable.

Enteropathic arthritis: how do the joints talk with the gut?

Enteropathic arthritis is a label for conditions in which gut pathology is believed to be of pathogenic importance for the developing joint disease. Impaired barrier function, as well as immunogenetic mechanism, are implicated. Recent publications have highlighted strong new support for the homing of lymphocytes from the gut mucosa to joint tissue, persistence of antigen- and cytokine-based immune deficiency. A convincing argument was made for the interesting observation that two distinct types of joint involvement with different class II HLA backgrounds occur in patients with inflammatory bowel disease. A new mechanism implicating dimeric HLA-B27 heavy chains in the pathogenesis of enteropathic arthritis is also presented. Despite evidence for persisting antigen presence, antimicrobial therapy seems ineffective in reactive arthritis.

Tumour necrosis factor microsatellites and HLA-DRB1*, HLA-DQA1*, and HLA-DQB1* alleles in Peruvian patients with rheumatoid arthritis.

OBJECTIVE: To study the association between rheumatoid arthritis (RA) and HLA and tumour necrosis factor (TNF) polymorphism in Peruvian mestizo patients in comparison with ethnically similar controls. METHODS: Seventy nine patients with RA and 65 ethnically matched healthy controls were genotyped for HLA-DRB1, HLA-DQA1, HLA-DQB1, and TNFalpha and TNFbeta alleles using PCR amplification. Clinical severity was assessed as mild, moderate, or severe in 35 of the patients. RESULTS: TNFalpha6 showed the strongest association with disease susceptibility. The TNFalpha6 allele was more common in patients than in controls (p<0.0076) and the proportion of patients with at least one copy of this allele was greater (p<0.015, relative risk 2.35). Among the HLA-DRB1* alleles with the shared epitope sequence, only the DRB1*1402 allele was significantly increased in patients compared with controls (p<0.0311), as was the proportion of patients with at least one copy of this allele (p<0.0232, relative risk 2.74). In contrast, the overall frequency of alleles with the shared epitope was not different in patients and controls. The haplotype HLA-DRB1*1402-DQB1*0301-DQA1*0401 was significantly more common in patients. TNFalpha6 was more common in patients whether or not they had this haplotype. None of the 11 patients lacking the TNFalpha6 allele had severe disease. CONCLUSIONS: This study shows for the first time that TNF gene polymorphism is associated with susceptibility to RA in a non-white population. TNFalpha6 and HLA-DRB1*1402 independently conferred significantly increased risk in Peruvian mestizo patients.

Approaches to rheumatoid arthritis in 2000.

The year 2000 was characterized by euphoria among clinicians based on the continued and consolidated success of tumor necrosis factor (TNF) inhibition but also by problems caused by the high cost of this therapy. Looking at the risks and adverse effects has only begun, and there is so far a remarkable lack of publications dealing with this topic. Leflunomide also emerges as an established disease-modifying antirheumatic drug (DMARD). Other therapies include the cyclooxygenase-2 (Cox-2) inhibitors, which are tolerated better by the gastrointestinal system but raise concerns regarding thromboembolism in patients at risk. The enthusiasm regarding Cox-2 inhibitors is somewhat tempered by recent reports of thromboembolic complications, although those have been rare. The advances in research regarding mechanisms of inflammation and pathogenesis continue to generate new therapeutic approaches, which, however, remain mostly experimental. The complexity of genetics has been emphasized by reports on susceptibility and severity relation to TNF, mannose-binding lectin, and gamma-interferon polymorphism. Epidemiologic studies focusing on prevalence, incidence and outcome continue to deliver conflicting messages. One major worry relates to chronic inflammation in RA and other rheumatic diseases as putative cause of accelerated atherosclerosis.

Cytokines, metalloproteinases, their inhibitors and cartilage oligomeric matrix protein: relationship to radiological progression and inflammation in early rheumatoid arthritis. A prospective 5-year study.

OBJECTIVE: To assess how serum concentrations of some cytokines, proteases and their inhibitors and cartilage oligomeric matrix protein (COMP) relate to the evolution of clinical disease and joint damage in early rheumatoid arthritis (RA). METHODS: Annual assessment was performed in 24 RA patients subdivided into three groups according to disease severity as determined by the radiological progression rate. All patients were followed for 5 yr after inclusion. Functional status, Larsen's radiographic index in hands and feet (joint damage score, JDS) and C-reactive protein (CRP) were assessed annually and compared with interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1Ra), promatrix metalloproteinase 3 (proMMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1) and COMP, which were determined by specific immunological tests. RESULTS: The median JDS was initially between 4.5 and 7. During the study time the progression of JDS was 1 (median) for patients with slow progression, 33 for patients with intermediate progression and 62 for patients with rapid progression. Changes in CRP and proMMP-3 concentrations over time differed significantly between the groups, but no significant difference was observed for IL-1Ra, TIMP-1 or COMP. ProMMP-3 was closely related to CRP at each time point. IL-6 correlated significantly with CRP at the last four annual follow-up examinations. CRP and proMMP-3 correlated with JDS at the last two or three examinations and the combined levels of these markers over 5 yr correlated significantly with joint damage progression (Spearman rank correlation 0.73 and 0.74 respectively). IL-1Ra showed a weak negative correlation with JDS, and COMP tended to correlate with JDS only at the start. The initial proMMP-3 concentration was the only significant variable predicting rapidly developing joint damage, but the predictive value was low. CONCLUSIONS: ProMMP-3 correlated closely at all time points with CRP, but gave little or no additional clinical information regarding inflammation or radiographic progression. IL-1Ra and TIMP-1 showed weaker, acute-phase-like variation, which may reflect pathogenic agonist/inhibitor imbalance in the evolution of RA. COMP, in contrast, did not reflect the inflammatory CRP-related component of the disease or the destructive aspect in this study.

Von Willebrand factor propeptide as a marker of disease activity in systemic sclerosis (scleroderma).

In 44 consecutive patients with systemic sclerosis (SSc), plasma concentrations of von Willebrand factor (vWf) were higher than those of the vWf propeptide, but the propeptide showed less variability within patient subgroups. Higher values of the propeptide were observed in patients with early pulmonary involvement. A closer correlation of the propeptide than of vWf to biochemical markers of activity was also evident. Our results suggest that the propeptide, despite a shorter circulating half-time and lower plasma concentrations than vWf, is more useful in the assessment of disease activity in SSc.