ABSTRACT
Isolated decreased serum-immunoglobulin (Ig)M has been associated with severe and/or recurrent infections, atopy and autoimmunity. However, the reported high prevalence of clinical problems in IgM-deficient patients may reflect the skewed tertiary centre population studied so far. Also, many papers on IgM deficiency have included patients with more abnormalities than simply IgM-deficiency. We studied truly selective primary IgM deficiency according to the diagnostic criteria of the European Society for Immunodeficiencies (ESID) (true sIgMdef) by reviewing the literature (261 patients with primary decreased serum-IgM in 46 papers) and analysing retrospectively all patients with decreased serum-IgM in a large teaching hospital in 's-Hertogenbosch, the Netherlands [1 July 2005-23 March 2016; n = 8049 IgM < 0·4 g/l; n = 2064 solitary (IgG+IgA normal/IgM < age-matched reference)]. A total of 359 of 2064 (17%) cases from our cohort had primary isolated decreased serum-IgM, proven persistent in 45 of 359 (13%) cases; their medical charts were reviewed. Our main finding is that true sIgMdef is probably very rare. Only six of 261 (2%) literature cases and three of 45 (7%) cases from our cohort fulfilled the ESID criteria completely; 63 of 261 (24%) literature cases also had other immunological abnormalities and fulfilled the criteria for unclassified antibody deficiencies (unPAD) instead. The diagnosis was often uncertain (possible sIgMdef): data on IgG subclasses and/or vaccination responses were lacking in 192 of 261 (74%) literature cases and 42 of 45 (93%) cases from our cohort. Our results also illustrate the clinical challenge of determining the relevance of a serum sample with decreased IgM; a larger cohort of true sIgMdef patients is needed to explore fully its clinical consequences. The ESID online Registry would be a useful tool for this.
Subject(s)
Diagnostic Errors/prevention & control , Immunoglobulin M/deficiency , Immunologic Deficiency Syndromes/epidemiology , Adult , Agammaglobulinemia , Aged , Child , Cohort Studies , Female , Humans , Immunologic Deficiency Syndromes/diagnosis , Male , Middle Aged , Netherlands/epidemiology , Retrospective StudiesSubject(s)
Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Epidemics , Immunocompromised Host , Opportunistic Infections/epidemiology , Q Fever/epidemiology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Adrenal Cortex Hormones/adverse effects , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/immunology , Etanercept , Female , Humans , Immunoglobulin G/adverse effects , Infliximab , Male , Methotrexate/adverse effects , Middle Aged , Netherlands/epidemiology , Opportunistic Infections/complications , Opportunistic Infections/immunology , Q Fever/complications , Q Fever/immunology , Receptors, Tumor Necrosis Factor , Risk FactorsABSTRACT
OBJECTIVES: To investigate the prevalence of cervical spine damage due to rheumatoid arthritis (RA) in the long term and to investigate which disease-specific factors are related to this damage. METHOD: Patients with early RA from the Nijmegen inception cohort with 6 to 12 years of follow-up were included. Conventional radiographs of the cervical spine were obtained at baseline, 3, 6, 9, and 12 years and scored for erosions of C1 and C2, anterior atlantoaxial subluxation (AAS) and atlantoaxial impaction (AAI). Disease-specific factors, such as disease activity, functionality, and peripheral joint damage, at baseline, 3, 6, and 9 years, were compared between patients with and without cervical spine damage at 9 years. RESULTS: A total of 196 patients were included, of whom 134 had radiographs at 9 years. Cervical spine damage was present in 16% (22/134) of the patients at 9 years. During the total 12 years of follow-up, AAS and erosions of C2 were observed most frequently. Erosions of C1 and AAI were very rare. Patients with cervical spine damage at 9 years had a higher number of erosions of the peripheral joints and failed more disease-modifying anti-rheumatic drugs (DMARDs) at 3, 6, and 9 years. Patients without peripheral erosive disease at 3 years were unlikely to develop cervical spine damage within 9 years of disease duration. CONCLUSIONS: The prevalence of cervical spine damage due to RA was 16% at 9 years. Patients without peripheral erosive disease at 3 years were unlikely to develop cervical spine damage at 9 years.
Subject(s)
Arthritis, Rheumatoid/epidemiology , Cervical Vertebrae/diagnostic imaging , Spinal Diseases/diagnostic imaging , Spinal Diseases/epidemiology , Adult , Age Distribution , Aged , Arthritis, Rheumatoid/diagnosis , Cervical Vertebrae/pathology , Cohort Studies , Comorbidity , Female , Follow-Up Studies , Humans , Male , Mass Screening/methods , Middle Aged , Netherlands/epidemiology , Prevalence , Radiography , Retrospective Studies , Risk Assessment , Severity of Illness Index , Sex Distribution , Spinal Diseases/physiopathology , Time FactorsABSTRACT
BACKGROUND: Detailed information is lacking on effectiveness of methotrexate (MTX) in sclerotic skin diseases, side-effects, and duration of remission after discontinuation. OBJECTIVES: To determine effectiveness, side-effects and period of remission gained by use of MTX in sclerotic skin diseases. METHODS: All patients with a sclerotic skin disease who were treated with MTX (group A) or MTX with corticosteroids (CS) (group B) between 1995 and 2007 were evaluated. Detailed information was collected on dosage and duration of MTX treatment, concomitant immunosuppressive medication and CS treatment, effectiveness, side-effects, duration of the remission period, and time until restart. RESULTS: Fifty-eight patients (A, n = 47; B, n = 11) were evaluated. Clinical assessment revealed that 38 patients (81%) treated with MTX and 11 patients (100%) treated with MTX + CS showed improvement of sclerotic skin. After one treatment course 51% of the patients treated with MTX and 73% treated with MTX + CS reached remission status with a median follow-up time of 55 and 58 months. Patients showing relapse still responded to a second and even to a third course of MTX. Patients who showed a relapse had received a lower cumulative dose, due to a shorter period of treatment with MTX in the first course. Serious side-effects were seen in six patients (10%). CONCLUSIONS: MTX was an effective treatment for various sclerotic skin diseases with a long period of remission and relatively low toxicity. Patients showing relapse still responded to a second and third course of MTX.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Methotrexate/therapeutic use , Scleroderma, Localized/drug therapy , Adolescent , Adult , Aged , Antimetabolites, Antineoplastic/adverse effects , Cohort Studies , Female , Humans , Male , Methotrexate/adverse effects , Middle Aged , Recurrence , Remission Induction , Time Factors , Young AdultABSTRACT
OBJECTIVE: To assess the effect of a functional polymorphism (676T>G, M196R) in the tumour necrosis factor receptor super family 1b (TNFSF1b) gene on disease activity, radiological joint damage and response to infliximab and adalimumab treatment in patients with rheumatoid arthritis (RA). METHODS: Two cohorts of patients with RA were genotyped for the 676T>G polymorphism (rs1061622) in exon 6 of the TNFSF1b gene by restriction fragment length polymorphism analysis. One cohort (n = 234) included patients from the Dutch Rheumatoid Arthritis Monitoring register with detailed information on their response to anti-TNF therapy (infliximab and adalimumab), the other cohort comprised patients from a long-term observational early inception cohort at our centre (n = 248). RESULTS: The 676T>G polymorphism was not associated with anti-TNF response after 3 or 6 months of treatment. Linear regression analysis showed no significant difference in the progression of radiological joint damage during the first 3 and 6 years of disease between the three genotype groups (TT, TG and GG). Additionally, no difference in mean disease activity between genotypes was seen after 3 and 6 years of disease. CONCLUSION: Despite its demonstrated functionality, the 676T>G polymorphism in the TNFSF1b gene does not have a major role in either the response to anti-TNF therapy or in the disease severity or radiological progression in RA.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Arthritis, Rheumatoid/genetics , Immunosuppressive Agents/therapeutic use , Polymorphism, Genetic , Adalimumab , Adult , Aged , Antibodies, Monoclonal, Humanized , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/immunology , Arthrography , Case-Control Studies , Female , Genotype , Humans , Immunoglobulin G/blood , Infliximab , Linear Models , Male , Middle Aged , Polymorphism, Restriction Fragment Length , Receptors, Tumor Necrosis Factor, Type I/genetics , Severity of Illness Index , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
Anti-tumour necrosis factor (TNF) therapy is associated with an increased risk of infection. There are sparse data and no evidence-based guidelines on how to deal with this problem in daily practice. However, recommendations can be made based on theoretical considerations and by extrapolating from recommendations for other types ofimmunodeficiency. Before starting anti-TNF therapy, screening for tuberculosis and other possible infections is indicated. During therapy, alertness is required to the increased risk of infection, infections with a more serious clinical course or unusual manifestations and opportunistic infections. Flu vaccination during anti-TNF therapy is indicated. Travel vaccinations with live microbial inocula should not be given.
Subject(s)
Opportunistic Infections/epidemiology , Opportunistic Infections/prevention & control , Tumor Necrosis Factor Inhibitors , Humans , Practice Guidelines as Topic , Risk FactorsABSTRACT
OBJECTIVES: To observe the course of the disease activity in rheumatoid arthritis (RA) patients treated with the standard infliximab dosing regimen and to adjust treatment guided by the pattern of disease activity. METHODS: All RA patients starting infliximab treatment were included and observed for at least 37 weeks. At infusion 4 (week 14), European League Against Rheumatism response was assessed. In moderate responders the dose was unchanged and the disease activity was carefully observed. In case of stable disease activity, the dose was increased at infusion 5 (week 22). In case of a temporary response the interval was reduced. Paired t-testing was applied to the disease activity score with 28-joint counts (DAS28) at week 22 and study endpoint. RESULTS: A total of 76 patients were included. Response after 14 weeks: good 22 (29%) patients, moderate 26 (34%) patients, and non-response in 21 patients. Seven patients (9%) dropped out before week 14 due to adverse events (5) or patients' initiative (2). In patients with moderate response, the following disease course between infusion 4 and 5 was observed: improvement to good response 6, temporary response 6, stable disease activity 6, drop out 8. In moderate responders, interval reduction and dose increase resulted in a decrease in mean DAS28 from 5.1 to 3.6 [P = 0.005, mean interval 5.6 weeks, mean infliximab dose 4.8 mg/kg/8 week (endpoint)] and from 4.1 to 3.6 [P = 0.04, mean infliximab dose 7.3 mg/kg/8 week (endpoint)], respectively. CONCLUSION: Three different patterns of disease activity were observed in moderate responders after 14 weeks of infliximab treatment, i.e. further improvement, no change in disease activity or a temporary response. Both interval reduction and dose increase significantly reduced disease activity, however, with different mean infliximab dosages. In good responders the response was often sustained over follow-up, whereas non-responders showed modest or no improvement despite dose adjustments.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antirheumatic Agents/antagonists & inhibitors , Arthritis, Rheumatoid/drug therapy , Adult , Aged , Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Drug Administration Schedule , Drug Monitoring/methods , Female , Humans , Infliximab , Male , Middle Aged , Patient Dropouts , Prospective Studies , Severity of Illness Index , Treatment Failure , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
OBJECTIVE: To develop and validate an extensive radiographic scoring system for ankylosing spondylitis (AS). METHODS: The Stoke Ankylosing Spondylitis Spinal Score (SASSS) was modified by adding a score for the cervical spine and defining squaring. This modified SASSS (mSASSS) is the sum of the lumbar and cervical spine score (range 0-72). 370 lateral views of the lumbar and cervical spine were used for development of the mSASSS, standardisation of observers, and for studying reliability. In a 48 week NSAID study of 57 patients, change over time and construct validity were studied. RESULTS: Interobserver correlations of the lumbar and cervical spine scores were good (r>0.95). The interobserver duplicate error was 0.55 in a range from 0 to 36. The mean change in the cervical and lumbar spine scores between weeks 0 and 48 of all patients was 1.45 (range 0-6.0) and 1.06 (0-5.0), respectively (paired t testing, p<0.001). Change in radiological score was seen in 36/57 (63%) patients (lumbar and cervical spine 11, cervical spine 12, lumbar spine 13 patients). CONCLUSION: The mSASSS is useful for assessing extensive radiographic damage in AS. It is reliable, detects changes over 48 weeks, and shows a satisfactory face and construct validity.
Subject(s)
Severity of Illness Index , Spondylitis, Ankylosing/diagnostic imaging , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Cervical Vertebrae/diagnostic imaging , Female , Humans , Lumbar Vertebrae/diagnostic imaging , Male , Observer Variation , Radiography , Reproducibility of Results , Spondylitis, Ankylosing/drug therapy , Treatment OutcomeABSTRACT
OBJECTIVE: To investigate the influence of previous and concomitant leflunomide on the efficacy and safety of infliximab therapy in rheumatoid arthritis (RA) and to compare it to infliximab in combination with other disease-modifying anti-rheumatic drugs. METHODS: RA patients starting infliximab therapy were prospectively followed from January 2000. Every 3 months data were collected regarding disease activity (DAS28), adverse events and treatment changes. In the primary analyses all patients were classified into a leflunomide group (LEF group) if they had used leflunomide during infliximab therapy or within 6 months prior to starting infliximab therapy, the latter because of the long half-life of leflunomide. All other patients were considered as controls (non-LEF group). Secondary drug survival analyses were performed with the LEF group consisting only of patients on active leflunomide at the start of infliximab (active LEF group). RESULTS: A total of 162 RA patients started infliximab therapy (57 in the LEF group, 105 in the non-LEF group). No statistically significant differences in baseline characteristics were observed between the groups. Maximum follow-up time was 46 months for both groups. No differences in drug survival, disease activity or adverse events were observed between the groups. In both groups an increase in patients positive for antinuclear antibodies (ANA) was seen. ANA positivity at start did not predict DAS28 or the occurrence of adverse events. Secondary drug survival analyses showed no differences between the active LEF group and the non-LEF group. CONCLUSION: The results indicate that the administration of infliximab after or simultaneously with leflunomide is safe and efficacious in RA patients.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Isoxazoles/therapeutic use , Adult , Aged , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antibodies, Antinuclear/blood , Antibodies, Monoclonal/adverse effects , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/immunology , Drug Administration Schedule , Drug Therapy, Combination , Epidemiologic Methods , Female , Humans , Infliximab , Isoxazoles/administration & dosage , Leflunomide , Male , Middle Aged , Severity of Illness IndexABSTRACT
OBJECTIVE: To determine which cut-off point in the RA disease activity score (DAS28) corresponds to fulfilment of the ARA criteria for clinical remission. METHODS: The disease activity of patients included in the Nijmegen RA inception cohort was systematically assessed every 3 months. For all visits, a modification of the ARA preliminary criteria for clinical remission was applied and the DAS28 was calculated. Receiver operating characteristic analysis was used to determine the cut-off point with maximum sensitivity and specificity in DAS28 corresponding with fulfilment of the modified ARA criteria. RESULTS: Three hundred and seventy-eight patients contributed 4378 visits. In 6.5% of the visits four of the five items and in 1.5% all five items of the modified ARA criteria were fulfilled. The optimal cut-off point for the DAS28 that corresponds to fulfilment of the modified ARA criteria was determined to be 2.66. CONCLUSION: DAS28 <2.6 corresponds to fulfilment of the preliminary ARA criteria for clinical remission in RA.
Subject(s)
Arthritis, Rheumatoid/physiopathology , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Cohort Studies , Female , Humans , Male , Middle Aged , ROC Curve , Remission Induction , Severity of Illness IndexABSTRACT
Tumour necrosis factor (TNF) blocking agents are an important advance in the clinical treatment of rheumatoid arthritis (RA). They were introduced into clinical practice while limited safety information was available. This means that intensive monitoring is needed early in the life cycle of these new drugs. Setting up large cohort studies to monitor efficacy, safety, and tolerability in long term use of these so-called biological agents will provide information about the consequences of using TNF blocking agents in chronic rheumatic disease like RA. Currently, a Dutch multicentre registry on biological agents in RA is being set up. This study aimed at investigating the efficacy and toxicity of TNF blocking agents in patients with RA at one participating academic centre by a drug survival analysis. Since 1997 230 patients with RA at the centre have been treated with TNF blocking agents for the first time (94 with adalimumab, 120 with infliximab, and 16 with etanercept). No differences in drug survival between the three TNF blocking agents were found despite the diversity in selection and patient numbers. Adverse events which occurred, leading to discontinuation, were similar to those from previous reports.
Subject(s)
Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Immunologic Factors/adverse effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/mortality , Etanercept , Female , Humans , Immunoglobulin G/adverse effects , Immunoglobulin G/therapeutic use , Immunologic Factors/therapeutic use , Infliximab , Male , Middle Aged , Opportunistic Infections/chemically induced , Prospective Studies , Receptors, Tumor Necrosis Factor/therapeutic use , Survival Analysis , Treatment FailureABSTRACT
OBJECTIVE: Anti-tumour necrosis factor alpha (TNF-alpha) therapy yields high response rates shortly after institution of therapy in patients with rheumatoid arthritis (RA), and on theoretical grounds large differences in the effective dose between patients can be expected. Together with the high costs, these differences warrant new approaches to the way patients are dosed. METHODS: We used the Disease Activity Score (DAS28), a composite disease activity index, to titrate the dose of anti-TNF-alpha (adalimumab, D2E7; Knoll) in 21 patients with low disease activity in an open extension study lasting 40 weeks. The dose of anti-TNF-alpha was reduced stepwise and dosing intervals were kept stable. Disease activity and flares were assessed using the DAS28. Patients who flared received the previous effective dose. RESULTS: Dose reduction was accomplished in 15 patients. The total amount of anti-TNF-alpha given to the patients was reduced by 67%. At the end of the study the mean DAS28 had not changed and no patients dropped out because of persistent worsening of the RA. CONCLUSION: Dose titration of anti-TNF-alpha treatment using the DAS28 is feasible and leads to overall dose reduction while maintaining clinical efficacy. This approach will save costs and possibly prevent long-term side-effects.