Peter Oxholm

Immunohistological detection of interleukin 1‐like molecules and tumour necrosis factor in human epidermis before and after UVB‐irradiation in vivo

Skin biopsies from five healthy subjects, taken before and after UVB irradiation, were examined using immunohistological techniques for the cytokines interleukin‐1 (IL‐1) and tumour necrosis factor (TNF). Using polyclonat specific antibodies against IL‐1 and TNF, the two cytokines appeared identically located on the epidermal cell membranes of the stratum granulosum and stratum spinosum in unexposed skin. After UVB‐exposure, the staining intensity for both IL‐1/epidermal cell derived thymocyte‐activating factor (ETAF) and TNF was markedly increased, and the epidermal staining included the basal cell layer.

A new model for classification of disease manifestations in primary Sjögren's syndrome: evaluation in a retrospective long-term study.

Objectives. The clinical features of 80 patients with primary Sjögrens syndrome (PSS) were revised in order to evaluate the descriptive and analytical facilities of a newly proposed model for classification of the exocrine and nonexocrine disease manifestations in PSS.

Patients with Primary Sjögren's Syndrome Treated for Two Months with Evening Primrose Oil

Twenty-four female and 4 male patients, all fulfilling the Copenhagen criteria for primary Sjögrens syndrome (primary SS), were treated for 8 weeks with evening primrose oil (Efamol). Efamol is a seed oil which consists primarily of the n-6 essential fatty acids (EFA): cis-linoleic acid and gammalinolenic acid (GLA). The investigation was carried out as a randomized, double-blind, placebo-controlled, cross-over trial in order to determine whether long-term treatment of patients with primary SS with Efamol would improve the ocular and oral clinical status, and whether the levels of EFA in plasma and erythrocytes increase during Efamol treatment. The objective ocular status, evaluated by a combined ocular score, including the results from Schirmer-I test, break-up time and van Bijsterveld score, improved significantly during Efamol treatment when compared with Efamol start-values (p less than 0.05), but not when compared with placebo values (p less than 0.2). The GLA metabolite and prostaglandin-E1 (PGE1) precursor dihomogammalinolenic acid (20: 3n6, DGLA) increased both in plasma (p less than 0.001) and in erythrocytes (p less than 0.001) during treatment with Efamol. No correlations between objective ocular and oral status and DGLA values in plasma or erythrocytes were found.

Epidermal tumour necrosis factor α and interleukin 6-like activities in AIDS-related Kaposi's sarcoma

Biopsies from 6 patients with AIDS and Kaposis sarcoma (KS) in the tumour stage, and 6 healthy controls, were immunohistologically examined for the presence of tissue‐bound tumour necrosis factorα (TNFα) and interleukin 6 (IL‐6) in the skin. TNFα was demonstrated using specific polyclonal antiserum to human recombinant TNFα. IL‐6 was visualized indirectly using a polyclonal antiserum to partially purified human crude supernatants of activated human blood monocytes, followed by absorption with recombinant human IL‐6. The cytokines were found identically located in epidermal cell membranes in stratum granulosum and spinosum of the epidermis from unaffected skin in both AIDS patients and in controls. Biopsies from KS elements showed markedly increased epidermal staining for both TNF δ and IL‐6. It was not possible to detect TNFα or IL6 in the endothelial cells of the tumour. The observation of increased amounts of epidermal‐bound TNFα and IL‐6 in AIDS‐related KS elements suplements previous studies indicating that the skin plays an active immunoinflammatory role in patients with AIDS.

Pulmonary function in patients with primary Sjögren's syndrome

SummaryIn 43 women and 3 men suffering from primary Sjögrens syndrome pulmonary function was correlated to various clinical, haematological and serological disease activity parameters. Primary Sjögrens syndrome was defined as the presence of keratoconjunctivitis sicca and xerostomia, in the absence of other well-defined chronic inflammatory connective tissue diseases. Only objective tests were used in the evaluation of the patients [2]. Total lung capacity, residual volume, vital capacity, functional residual capacity and ventilatory capacity were normal. The diffusion capacities measured for CO were significantly reduced compared with the predicted values. This indicates that pulmonary interstitial disease is a common feature of primary Sjögrens syndrome. There was a statistically significant negative correlation between reduced diffusion capacity and previous pneumonia, previous pleurisy, tiredness, dyspnoea, ESR and p-orosomucoid. No correlation was found to certain other clinical disease parameters, the duration of disease or tobacco smoking.

A follow-up study of pulmonary function in patients with primary Sjögren's syndrome.

SummaryTwenty-seven patients (25 women, 2 men) with primary Sjögrens syndrome, previously reported to have reduced pulmonary diffusing capacities were reexamined in a 7-year follow-up in order to evaluate longitudinal alterations in pulmonary function. Primary Sjögrens syndrome was diagnosed according to the Copenhagen criteria. The present examination revealed normal and unchanged values for vital capacity, forced expiratory volume in 1 s, maximal expiratory flow at 50% of expired vital capacity (MEF50), and diffusing capacity per liter alveolar volume. Total diffusing capacity (P<0.01) and MEF75 (P<0.05), were, however, significantly reduced compared with the predicted values, indicating pulmonary involvement primarily affecting the small airways. The longitudinal examination, furthermore, showed increasing values for total diffusing capacity (P<0.02), diffusing capacity per liter alveolar volume (P<0.001), and MEF75 (P<0.02), suggesting an improvement in lung status in the course of time. No correlation was found between MEF75 and diffusing capacities, nor between alterations in pulmonary function and complaints of dyspnoea, tiredness, cough, expectoration, tobacco smoking, or medical treatment with bromhexine, glucocorticosteroids, essential fatty acids, or nonsteroid antiinflammatory drugs.

Rational drug therapy recommendations for the treatment of patients with Sjögren's syndrome.

The aetiology of Sjögrens syndrome (SS) is unknown, and consequently curative treatments are not available. The immunopathogenesis of SS is partly clarified and immune-regulating drugs (IR) may therefore be of therapeutic value. However, the present understanding of SS is still too unclear to allow an exact and evidence-based algorithm for therapeutic decision making. Rational drug recommendations for the therapy of SS must, therefore, rely mostly on empirical data.Several IR drugs have been shown to be able to downregulate the immunopathological activity of primary SS, but it is not certain whether the diagnostic and cardinal manifestations from the eyes and mouth can be improved. In primary SS the disease-modifying qualities of IR and cytotoxic drugs, therefore, largely apply to the treatment of severe internal organ involvement, inflammatory vascular disease and malignant B lymphocyte disease. In secondary SS the IR therapy is directed against the basic immunoinflammatory connective tissue disease. Symptom-modifying therapies include drugs to stimulate and substitute for exocrine functions, and drugs to treat complications of the exocrine disease manifestations and to improve the various nonexocrine disease manifestations.The main drugs available for increasing lacrimal and salivary gland output are bromhexine and pilocarpine, respectively. However, exocrine substitutes, and in particular eye drops, are still the most important means of alleviating the sicca symptoms. They are also indispensable local treatment measures which may help to prevent mucosal complications.

Quantitative Assessment of Clinical Disease Status in Primary Sjögren's Syndrome

Quantitative and qualitative assessment of the clinical disease manifestations in 41 primary Sjögrens syndrome (pSS) patients was performed according to a new classification model. Frequencies of subgrouped disease manifestations were as follows: 1) surface exocrine disease: 100%, 2) internal organ exocrine disease: 63%, 3) monoclonal B lymphocyte disease: 5%, 4) inflammatory vascular disease: 71%, 5) non-inflammatory vascular disease: 59%, 6) mediator induced disease: 98%. Summary scores for severity of surface exocrine disease correlated to the summary scores of all other disease manifestations (p = 0.02), to the summary scores of internal organ exocrine disease (p = 0.003), and to the summary scores of mediator induced disease (p = 0.03). Blood leucocyte counts showed significant negative correlations to levels of plasma IgG, serum IgA-RF, IgM-RF, anti-SSA/SSB antibodies, IL-6, and IL-1Ra. We conclude that the model made detailed analysis of the clinical presentation of pSS possible, and thus may assist in elucidating important pathobiological aspect of the disease.

Keratoconjunctivitis sicca in patients with primary Sjögren's syndrome. A longitudinal study of ocular parameters.

Abstract Thirty‐four patients, all fulfilling the Copenhagen criteria for Primary Sjögrens Syndrome, were examined retrospectively in order to evaluate possible longitudinal alterations in Schirmer‐1‐test results, Rose‐bengal score, break‐up time and level of ocular score. Twenty‐three of the patients were characterized as Bromhexine responders according to their intially positive response to systemic treatment (16 mg × 3 daily) and 11 patients were Bromhexine non‐responders. All patients were treated with tear substitutes during the entire observation period. The patients were followed over a period of 27 to 76 months (mean 53 months), and all eye examinations were carried out by the same ophthalmologist. The responder group had, both in the start as well as at the end of the observation period, a better ocular status compared to the non‐responder group. The latter group had a significantly (P < 0.02) lower Schirmer‐1‐test at the start and at the end of the period, and a significantly (P < 0.02) higher Rose‐bengal score at the end of the period. Moreover, the responder group improved in Rose‐bengal score (P < 0.001), whereas the non‐responder group improved both in break‐up time (P < 0.05) and Rose‐bengal score (P < 0.05). The use of a score combining results from all three tests, i.e. the ocular score, seems to be a useful tool when evaluating longitudinal variations i dry eye states. Considerable variation was seen between successive results of each ocular test, also in the periods without systemic treatment.

Circulating IgA- and IgM-rheumatoid Factors in Patients with Primary Sjögren Syndrome: Correlation to Extraglandular Manifestations

IgM- and IgA-rheumatoid factors (RF) were determined by ELISA technique in 40 consecutive patients with primary Sjögren syndrome (primary SS), all fulfilling the Copenhagen diagnostic criteria. Increased concentrations of IgM-RF were found in 25 patients (63%) (median concentration: 85 IU/ml, range 11-302 IU/ml). Increased concentrations of IgA-RF were found in 22 of the patients (55%) (median concentration: 100 AU/ml, range 25-255 AU/ml). The levels of IgM- and IgA-RF were closely correlated (r = 0.82, p less than 0.001). IgM-RF (p = 0.037), but not IgA-RF (p = 0.17), was significantly correlated to the presence of antinuclear antibodies (ANA). In contrast, IgA-RF (p = 0.002), but not IgM RF (p = 0.068), was significantly correlated to the presence of hypergammaglobulinemia. The most common extraglandular manifestations were: arthralgia/synovitis (60%), myalgia/myositis (28%), Raynauds phenomenon (20%) and pulmonary manifestations (15%). Concentrations of both IgM-RF (r = 0.43, p less than 0.01) and IgA-RF (r = 0.57, p less than 0.001) were correlated to the number of extraglandular manifestations present in each patient.