Rheumatoid Arthritis: Wollheim FA

Wollheim FA. · Department of Rheumatology, Lund University Hospital, SE221 85 Lund, Sweden. · Expert Opin Investig Drugs. · Pubmed #12084005 No free full text.

Abstract: The introduction of TNF- alpha -inhibiting biologicals has been a major therapeutic breakthrough in rheumatoid arthritis therapy. Against a background of conventional disease-modifying antirheumatic drug experience, this review focuses on present experiences and possible future developments. TNF inhibition results in profound improvement in the majority of rheumatoid arthritis patients, but non-response and adverse effects need attention. Adalimumab is being filed for approval. Other monoclonal antibodies or receptor constructs are in late development. Small molecule inhibitors of TNF production or signalling are a hot topic. One emerging target is nuclear factor kappa B and selective inhibition has proved effective in animal models of arthritis. Synovial proliferation in rheumatoid arthritis is characterised by diminished apoptosis of fibroblasts, whereas bone marrow precursor cells undergo accelerated apoptosis in active rheumatoid arthritis. Both abnormalities are seemingly ameliorated by TNF inhibition. Anti-apoptotic strategies will soon go into development for control of unresponsive rheumatoid arthritis.

Wollheim FA. · Department of Rheumatology, Lund University Hospital, University of Lund, Lund, Sweden. · Curr Opin Rheumatol. · Pubmed #11333348 No free full text.

Abstract: 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.

Oliw E, Wollheim FA. · Klinisk farmakologi, Uppsala universitet. · Lakartidningen. · Pubmed #10900877 No free full text.

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Wollheim FA. · Department of Rheumatology, Lund University Hospital, Sweden. · Curr Opin Rheumatol. · Pubmed #10803749 No free full text.

Abstract: Substantial progress can be noted in the efforts to demonstrate the usefulness of tissue-related markers of disease in rheumatoid arthritis and other joint diseases. The most informative studies use longitudinal analyses of well-characterized patient groups. Emphasis should be on searching for markers which can be of prognostic significance. New markers need to be assessed in relation to existing ones, such as C-polysaccharide reacting protein and erythrocyte sedimentation rate, which, although not specific, are hard to beat as measures of inflammation. A newly identified matrix component, cartilage intermediate layer protein, has features which make it attractive as a potential cartilage specific marker. Many markers may not in the end prove clinically useful. They will, however, give important insight into pathogenic processes, and may help in evaluating new therapy. Finally, markers originally identified in humans have now proven their value in experimental arthritis.

Kvien TK, Zeidler HK, Hannonen P, Wollheim FA, Førre O, Hafström I, Kaltwasser JP, Leirisalo-Repo M, Manger B, Laasonen L, Prestele H, Kurki P. · Oslo City Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway. · Ann Rheum Dis. · Pubmed #12006323 links to  free full text

Abstract: 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.

Gazi H, Pope JE, Clements P, Medsger TA, Martin RW, Merkel PA, Kahaleh B, Wollheim FA, Baron M, Csuka ME, Emery P, Belch JF, Hayat S, Lally EV, Korn JH, Czirjak L, Herrick A, Voskuyl AE, Bruehlmann P, Inanc M, Furst DE, Black C, Ellman MH, Moreland LW, Rothfield NF, Hsu V, Mayes M, McKown KM, Krieg T, Siebold JR. · Division of Rheumatology, Department of Medicine, The University of Western Ontario, London, Ontario, Canada. · J Rheumatol. · Pubmed #17299843 No free full text.

Abstract: OBJECTIVE: To obtain a consensus on the minimal clinically relevant treatment effect in various scleroderma disease outcome measures to be used in future clinical trials. METHODS: A Delphi consensus building exercise using a survey was sent out to members of the Scleroderma Clinical Trials Consortium (SCTC). The 65 SCTC members were divided into 2 groups. Group 1 was informed, in a cover letter, of the usual American College of Rheumatology 20% response results in randomized trials using effective biologic treatments for rheumatoid arthritis, while Group 2 was not. The first round of the exercise presented the scleroderma experts with a survey composed of 95 questions/clinical scenarios divided into 8 categories. These included situations where the treatment group improved, or worsened, or where some outcome measures improved, while others worsened. From the responses of this first round, a mean, mode, median, and range of responses for each of the 95 questions was obtained. This information was sent out, in the second round of the Delphi exercise, only to those respondents who answered the first round. The respondent's previous answer and the mean and range from the first round were provided for each question. It gave respondents the option to change any of their initial responses. The median of their responses in the second round was used to calculate the values for the minimal clinically relevant treatment effect. RESULTS: Thirty-two of the 65 SCTC members returned the first round of the Delphi exercise. Twenty-eight members returned the second round. Intraclass correlation coefficients between responses to round 1 and 2 were calculated for the questions. These varied from 0.99 (excellent agreement) to 0.02 (poor agreement). The p value was under 0.09 for 9 questions and under 0.19 for 20 questions. Standard deviations (SD) were calculated and were found to be lesser for each of the questions in round 2 when compared to the SD in responses from round 1, thus indicating a movement towards a consensus by the second round. An average of 33% of the responses were changed by the respondents in the second round of the Delphi exercise to a value closer to the median/average of the first round's responses. A range in required values for the minimal clinically relevant treatment effect for Modified Rodnan skin score is 3 to 7.5 units, Health Assessment Questionnaire Disability Index (HAQ-DI) 0.2 to 0.25 units, HAQ pain 0.2 to 0.3 units, MD global (100 mm visual analog scale) 8 to 13, patient global assessment 10 to 12, and diffusing capacity (percentage predicted) 9 to 10. The scenarios were especially weighted towards overall disease modification, thus organ-specific measures, such as 6 minute walk time (which has been used in many pulmonary artery hypertension trials), forced vital capacity, and a dyspnea rating (which may be important in scleroderma lung trials), were not included in the survey. CONCLUSION: Our study begins to address the current deficiency in our knowledge of appropriate values for the minimal clinically relevant treatment effect in various scleroderma disease outcome measures. A consensus could be achieved, or at least a range of minimal clinically relevant treatment effect values could be found for several outcome measurements. Of course, this consensus statement will be modified by evidence as it accrues in each consensus area.

Wollheim FA. · Department of Rheumatology, Lund University Hospital, S-221 85 Lund, Sweden. · Curr Rheumatol Rep. · Pubmed #16973103 No free full text.

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Kirwan JR, Hickey SH, Hällgren R, Mielants H, Björck E, Persson T, Wollheim FA. · University of Bristol Academic Rheumatology Unit, Bristol Royal Infirmary, Bristol, UK. · Arthritis Rheum. · Pubmed #16645969 links to  free full text

Abstract: OBJECTIVE: To measure the effect of low-dose systemic glucocorticoid treatment on the adrenal response to adrenocorticotropic hormone (ACTH) in patients with rheumatoid arthritis (RA). METHODS: Patients with RA who took part in a randomized double-blind placebo-controlled trial of budesonide (3 mg/day and 9 mg/day) and prednisolone (7.5 mg/day) underwent a short (60-minute) test with injection of ACTH (tetracosactide hexaacetate) at baseline and the day after completing the 3-month treatment program. Plasma cortisol measurements at baseline and 3 months were compared within and between the treatment groups. Individual patients were classified as normal responders to ACTH or as abnormal responders if changes were >2 SD below the pretreatment value in the entire group of study patients. RESULTS: Short tests with ACTH injection were performed on 139 patients before beginning the study medication and on 134 patients after cessation of the medication. There were no changes in the placebo group. Mean plasma cortisol levels following treatment were reduced in all active treatment groups. In addition, mean values were significantly reduced for the 30-minute and 60-minute responses to ACTH. The maximum reduction (35%) occurred in the prednisolone group at 60 minutes. Following treatment, 34% of patients taking budesonide 9 mg and 46% of those taking prednisolone 7.5 mg failed to reach the normal maximum cortisol response to ACTH. Four patients failed to achieve the normal percentage increase in cortisol levels, but only 1 patient failed to meet both criteria. CONCLUSION: Low doses of a glucocorticoid resulted in depression of baseline and ACTH-stimulated cortisol levels after 12 weeks of therapy. Although the responsiveness of the hypothalamic-pituitary-adrenal axis in individual patients generally remained within the normal range, these changes should be investigated further.

Wollheim FA. · Department of Rheumatology, Lund University Hospital, S-221 85 Lund, Sweden. · Curr Rheumatol Rep. · Pubmed #12967512 No free full text.

This publication has no abstract.

Wollheim FA. · Reumatologiska kliniken, Universitetssjukhuset i Lund. · Lakartidningen. · Pubmed #11699249 No free full text.

Abstract: 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.

Castro F, Acevedo E, Ciusani E, Angulo JA, Wollheim FA, Sandberg-Wollheim M. · Hospital Central FAP, Lima, Peru. · Ann Rheum Dis. · Pubmed #11454644 links to  free full text

Abstract: 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.

Wollheim FA. · Reumatologiska kliniken, Universitetssjukhuset i Lund. · Lakartidningen. · Pubmed #11433990 No free full text.

This publication has no abstract.

Roux-Lombard P, Eberhardt K, Saxne T, Dayer JM, Wollheim FA. · Division of Immunology and Allergy, Department of Internal Medicine, University Hospital of Geneva, 1211 Geneva 14, Switzerland. · Rheumatology (Oxford). · Pubmed #11371663 links to  free full text

Abstract: 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.

Wollheim FA. · Reumatologiska kliniken, Universitetssjukhuset i Lund. · Lakartidningen. · Pubmed #11107747 No free full text.

Abstract: IL-18, originally identified as interferon-gamma inducing factor (IGIF), is related to the IL-1 family in terms of its structure as well as its processing, receptor, signal transduction pathway and pro-inflammatory properties. IL-18 is also functionally related to IL-12, as it induces the production of Th1 cytokines and participates in cell-mediated immune cytotoxicity. A summary is made of recent advances in the understanding of IL-18 structure, processing, receptor expression and immunoregulatory functions. It focuses on the role of IL-18 modulation in tumours, infections and autoimmune and inflammatory diseases.

Wollheim FA. · Department of Rheumatology, Lund University Hospital, Sweden. · Clin Exp Rheumatol. · Pubmed #10609062 No free full text.

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Saxne T, Wollheim FA. · No affiliation provided · Ann Rheum Dis. · Pubmed #14583582 links to  free full text

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Wollheim FA, Ciusani E, Acevedo E, Angulo J, Castro F, Wollheim MS. · No affiliation provided · Scand J Rheumatol. · Pubmed #12892262 No free full text.

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Wollheim FA. · No affiliation provided · Ann Rheum Dis. · Pubmed #12860743 links to  free full text

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Wollheim FA. · No affiliation provided · Scand J Rheumatol. · Pubmed #10898080 No free full text.

This publication has no abstract.