Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: a multicentre randomised controlled trial.

OBJECTIVES: To assess the effect of sulfasalazine (SSZ) on inflammatory back pain (IBP) due to active undifferentiated spondyloarthritis (uSpA) or ankylosing spondylitis in patients with symptom duration <5 years. METHODS: Patients with IBP and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >3 from 12 centres were randomly assigned to 24 weeks' treatment with SSZ 2 g/day or placebo. The primary outcome variable was the change in BASDAI over 6 months. Secondary outcomes included measures of spinal pain, physical function and inflammation. RESULTS: 230 patients (50% men, age range 18-64 years, 67% human leucocyte antigen B27 positive) were treated with either SSZ 2x1 g/day or placebo for 6 months. Enthesitis was found in 50%, and peripheral arthritis in 47% of the patients. The mean (SD) BASDAI dropped markedly in both groups: by 3.7 (2.7) and 3.8 (2.4), respectively, as did most secondary outcome measures. No noticeable difference in treatment was observed between groups. Patients with IBP and no peripheral arthritis had significantly (p = 0.03) more benefit with SSZ (BASDAI 5.1 (1.3) to 2.8 (2.3)) than with placebo (5.2 (1.6) to 3.8 (2.4)). Spinal pain (p = 0.03) and morning stiffness (p = 0.05) improved with SSZ in these patients, but other secondary outcomes were not markedly different. CONCLUSION: SSZ was no better than placebo for the treatment of the signs and symptoms of uSpA; however, SSZ was more effective than placebo in the subgroup of patients with IBP and no peripheral arthritis.

[Necrotizing keratitis in chronic polyarthritis. Combined immunosuppressive and surgical therapy]. / Nekrotisierende Keratitiden bei chronischer Polyarthritis. Kombinierte immunsuppressive und chirurgische Therapie.

INTRODUCTION: Areactive forms of keratitis in patients with seropositive rheumatoid arthritis are inflammations threatening the visual acuity and integrity of the eye. They commonly occur in a rheumatologically inactive interval and have a poor prognosis. A retrospective evaluation of medicamentous and surgical strategies for a curative therapy with optical rehabilitation is necessary to optimise the treatment of patients with necrotic sclerokeratitis. PATIENTS AND METHODS: A total of 27 eyes of 22 patients (14 women and 8 men, ranging in age at the time of operation from 40 to 88 years; mean 68.7 years) with seropositive rheumatoid arthritis and secondary Sjögren's syndrome were reviewed retrospectively. There were 17 eyes with necrotic keratitis and 9 eyes with necrotic sclerokeratitis. In one eye, necrotic sclerokeratitis with bacterial transmigrating keratitis and hypopyon occurred. OPERATIONS: In 8 cases we performed a perforating mini-keratoplasty, in 16 cases a tectonic and optical perforating keratoplasty, in 3 cases a tectonic sclerokeratoplasty, in 9 patients a combined keratoplasty and cataract extraction with posterior chamber lens implantation and in 1 case a partial conjunctival plasty. Follow-up ranged from 7 months to 4 years (average 2.8 years). RESULTS: In all eyes, a sufficient tectonic and primary curative effect was achieved only under cyclophosphamide immunosuppression. In 3 cases, a rekeratoplasty had to be performed because of recurrent keratitis after changing the systemic cyclophosphamide therapy to methotrexate, glucocorticosteroids or non-steroid antiphlogistic agents. Visual acuity outcome was depending on the eccentricity of the keratoplasty and earlier affections of the eye. Postoperatively, the visual acuity improved in 23 eyes. In 3 cases, no change of visual acuity was achieved. Visual acuity deteriorated in one case from counting fingers to hand motions. Peri- and postoperative complications during the follow-up period were corneal infiltration around sutures in 4 eyes, graft rejecting reactions in 3 cases, and sicca syndrome in 6 cases. CONCLUSIONS: The intensive cooperation of ophthalmologists and rheumatologists enables the successful treatment of apparently hopeless situations in necrotic sclerokeratitis in patients with seropositive rheumatoid arthritis. The rate of complications under an immunosuppressive therapy with cyclophosphamide was found at average 2.8 years follow-up to be low. The indication for the combined therapy depends on the ophthalmological findings; rheumatologists and ophthalmologists should decide on the appropriate dosage for the systemic cyclophosphamide therapy. Topical glucocorticosteroid therapy alone is contra-indicated.

Middle and long latency somatosensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome.

Ten female patients with fibromyalgia syndrome (FS) were investigated with laser evoked potentials (LEPs) after hand stimulations and compared with 10 female pain-free and age-matched control patients. FS patients exhibited significantly lower heat pain thresholds than controls (P < 0.05) and had higher amplitudes of LEP components N170 (P < 0.01) and P390 (P < 0.05) in response to intensities of 20 W (beam diameter 5 mm, duration 20 msec, wavelength 10.6 microns). N170 additionally appeared with a broader distribution over bilateral central, vertex and fronto-central leads which contrasted to the control group and studies in healthy subjects where N170 was much more restricted to central and midtemporal positions contralateral to the stimulated hand. Auditory stimuli interspersed between laser impulses that served to announce subjects to rate the perceived pain elicited auditory evoked potentials that were not different between groups indicating no differences of general vigilance level to account for observed LEP effects. P390 amplitude enhancement might indicate greater attention and cognitive processing of nociceptive stimuli in FS subjects. Effects upon N170 rather point to exogenous factors like peripheral and spinal sensitization or reduced cortical or subcortical inhibition of nociception.

[Combination therapy in chronic polyarthritis]. / Kombinationstherapie bei chronischer Polyarthritis.

Long-term effects of disease-modifying antirheumatic drugs are not at all satisfactory. Therefore combinations of different substances have long been studied. But no convincing recommendations could be derived from those results. Some combinations seem to be more effective than the single substances, but often have more side-effects. First of all, those types of rheumatoid arthritis must be defined which require an aggressive therapy. These may profit from combinations with sulfasalazine, methotrexate or azathioprine. But such questions may only be answered by long-term studies which can be statistically evaluated.

Treatment of psoriatic arthritis with auranofin and gold sodium thiomalate.

Forty-two patients with psoriatic arthritis were included in a multicenter, double-blind trial comparing auranofin and gold sodium thiomalate (GST) for 6 months, followed by a 6-month open treatment. Fifty-two percent of the patients on auranofin and 33% on GST were able to complete the 1-year course of therapy. As a result of the study we conclude that both gold compounds are effective agents in the treatment of psoriatic arthritis. Degree of improvement of arthritis was better in the GST group, but the number of improved patients was greater in the auranofin group. Two patients on auranofin were withdrawn for side effects (one diarrhoea, one worsening of psoriasis) and 5 on GST (rash 2, total loss of appetite 1, exacerbation of psoriasis 2). Comparing the side effects of both compounds, auranofin is less likely to aggravate the psoriatic condition or result in withdrawal of patients for adverse reactions.

[The treatment of ankylosing spondylitis with auranofin (Ridaura)]. / Zur Behandlung der Spondylitis ankylosans mit Auranofin (Ridaura).

Auranofin has no influence on axial skeleton manifestation of ankylosing spondylitis, neither on clinical complaints, nor on function and inflammatory parameters. Peripheral arthritis is possibly influenced positively, but this cannot be stated definitely because of the low number of cases in this study. This question must be analyzed in larger collectives, as alternatives to conventional therapy are needed for the treatment of peripheral joint involvement of ankylosing spondylitis.

[D-penicillamine--side effects, pathogenesis and decreasing the risks]. / D-Penicillamin--Nebenwirkungen, Pathogenese und Risikominderung.

D-penicillamine (DPA) leads to side effects in different ways: collagen and elastin crosslinking are inhibited, which results in thin and vulnerable skin, cutis laxa, elastosis perforans serpiginosa, wound healing defects and embryopathy. Toxic influences effect thrombo- and leukocytopenia (incidence 5-15%), gastrointestinal disturbances (10-30%), changes or loss of taste (5-30%), loss of hair (1-2%), and partly proteinuria (5-20%). Acute hypersensitive reactions include DPA-allergy (2-10%). Severe adverse effects are autoimmune phenomena such as pemphigus, DPA-induced lupus erythematosus, polymyositis/dermatomyositis, membranous glomerulopathy and hypersensitivity pneumonitis (like Good-pasture's syndrome) and myasthenia (all less than 1%). In addition there are a number of rare side effects, often single observations. Risk factors include a genetic disposition (especially HLA-B8 and -DR3), poor sulphoxidizers and, to a certain degree, higher age. During pregnancy and in clinically relevant disturbances of bone marrow, liver and renal function DPA is contraindicated. The total incidence of side effects amounts to 30-60%, the withdrawal rate is 20-30%; therefore clear indications and a regular survey of DPA therapy are necessary.

[Diagnostic and prognostic significance of serologic studies in Yersinia arthritis]. / Diagnostische und prognostische Bedeutung serologischer Untersuchungen zur Yersinia-Arthritis.

Commonly-used serological methods for the determination of Yersinia antibodies are based on the presence of agglutinins, which are frequently absent or of low titer when arthritis begins. Stool cultures are usually negative at that time, so many Yersinia infections are underdiagnosed. On the other hand, significant agglutinin titers, of diagnostic value, become frequently minimised because of cross reactivity with Yersinia and other gram-negative bacteria. With the immunoblot-technique, using specific virulence-associated antigens and the detection of class-specific antibodies, clear statements are possible about whether there is a recent or an old Yersinia infection. As Yersinia arthritis may have an acute start and a protracted course over months, an exact diagnosis is essential for therapy and prognosis, as well as for answering the question of whether there is acute exacerbation of a preexisting rheumatoid illness of an additional infectious arthritis.

[Skin changes in advanced age--biochemical findings corresponding to morphology?]. / Hautveränderungen im hohen Lebensalter--korrespondieren biochemische Befunde zur Morphologie?

The clinically relevant morphological changes of the skin during aging can be summarized by the term "senile atrophy". The changes are a diminished thickness of epidermis with a reduced mitosis rate of epidermal basal cells, shortened and attenuated rete ridges, reduction of epidermal appendages, and a decreased number of fibroblasts and capillaries in the dermis. Corresponding to these morphological findings regarding the cell number in the senile skin (cutis) we found a slight decrease in the DNA concentration of human and rat cutis. The specific DNA activity (3H-thymidine incorporation rate related to DNA concentration) decreased in presenile versus adult animals. The mesenchymal changes in the dermis have been morphologically described by the term "senile elastosis" or "elastoid collagen degeneration", but in fact they correspond to a progressive collagen denaturation with aging. The total collagen concentration, here determined as the hydroxyproline concentration in the human cutis, shows almost constant values from the 3rd until the 9th decade of life in both sexes. This is also true for the skin of two different rat strains. The insoluble collagen fraction shows a relative increase to the disadvantage of the soluble collagen fractions, which can be interpreted as an indicator of a decelerated collagen turnover. In spite of the decelerated turnover, i.e. a prolonged half-life of the collagen metabolism in the skin, the indicators of the collagen neosynthesis (14C-proline incorporation rate, specific hydroxyproline activity, prolyl-hydroxylase activity) are significantly elevated in the cutis of presenile versus adult rats. Any connection of these findings with a possible change in the distribution of collagen types in the senile skin (e.g. pericapillar fibrosis with increase of collagen type I as well as changes in the distribution of type I, III, IV and V) can only be discussed at present. The glycosaminoglycans in the cutis show a minimal increase of the total content of hexosamines and uronic acids with a significant shift in the ratio of the glycosaminoglycan components in favour of dermatan sulfate and keratan sulfate and to the disadvantage of hyaluronic acid and partly also of chondroitin-4-sulfate and -6-sulfate. The neosynthesis of sulfated glycosaminoglycans (indicator method: 35S-sulfate incorporation rate) is only slightly increased whereas the enzyme activities being specific for the glycosaminoglycan catabolism (beta-glucuronidase, beta-N-acetyl-glucosaminidase) are significantly decreased with aging of the skin.(ABSTRACT TRUNCATED AT 400 WORDS)

[Age-dependent changes in connective tissue]. / Alternsbedingte Veränderungen des Bindegewebes.

Alterations of the various connective tissues with aging are investigated by combined morphological and biochemical methods. The aging of connective tissues depends on aging of informational- and structural-macromolecules. Aging-dependent alterations of proteoglycans/GAG and collagen can be caused by changes in genetic information or in the cellular information-coded synthesis, but also by changes in the controls of the various metabolic processes of connective tissue cells. The activities of enzymes involved in the anabolism and the catabolism of proteoglycans/GAG and collagen show reductions with aging, but do not show age-specific variations. The aging of connective tissues is rather a dynamic process (with measurable metabolic parameters of the various connective tissue cells and their products) than a passive or so-called degenerative connective tissue process. The bradytrophy concept of connective tissue cannot be accepted any longer, because connective tissue cells partly have metabolic rates at the same level as parenchymal cells. Furthermore, parenchymal cells can synthesize and degrade mesenchymal structural macromolecules. Connective tissue aging is demonstrated on 3 organ groups: 1. on typical mesenchymal organs: aorta, cartilage and skin, 2. on organs, which are mainly composed by connective tissue: heart and lung, 3. on connective tissues of parenchymal organs: liver and kidney. These various organs exhibit some common basic processes but also differences in connective tissue aging, which are due to the different composition of proteoglycans/GAG and collagen types, and on structure and function. The aging of connective tissues is of special importance for the aging of organs. Besides alterations of cells and GAG, the very important aging fibrosis in several mesenchymal and parenchymal organs is demonstrated and discussed. The connective tissue aging of organs is one of the reasons why the frequency of diseases increases with aging and diseases are grafted more strongly on aging cells, tissues, organs and organisms.

Aging of liver: morphological and biochemical changes.

Light-microscopically there are no significant age-dependent changes in the liver, due to the slight increase in biochemically determined connective tissue components. Electron-microscopical comparison of young and old animals show a larger size and decreased numbers of liver cell mitochondria in older animals. Collagen synthesis in liver is accelerated during growth, as demonstrated by assay of the [3H] proline incorporation rates and of the specific activity of hydroxyproline, corresponding to a decrease in the prolyl hydroxylase activity with age. The neutral salt-soluble collagen fraction may be regarded as a parameter for collagen synthesis, which is activated during the growth period and then remains constant without age and sex differences. Not much is known about the significance of these changes with increasing age or about their initiating factors, although there are parallel findings for liver intoxication and inflammation.

[The effect of sulfur compounds (N-acetylhomocysteine-thiolactone and penicillamine) on liver collagen metabolism in chronic thioacetamide poisoning]. / Der Einfluss von Thio-Verbindungen (N-Acetylhomocysteinthiolakton und Penicillamin) auf den Kollagenstoffwechsel der Leber bei chronischer Thioacetamid-Intoxikation.

The influence of N-acetyl-homocysteine-thiolactone (AHCT) and penicillamine on experimental thioacetamide (TAA)-induced liver fibrosis was investigated. TAA causes an increase in liver collagen content, which can partly be prevented by penicillamine and AHCT. This prevention is most effective, when the TAA-intoxication started earlier than the therapy with these two substances. The therapeutic effect of penicillamine is achieved by an inhibition of collagen biosynthesis and cross-linking (with an increase in the easily soluble collagen fractions). In the case of AHCT the inhibition of pathological collagen synthesis in experimental liver fibrosis cannot be explained by disturbed collagen cross-linking or increased collagen solubility. Whether collagen synthesis is inhibited and/or other influences of AHCT are present has still to be analyzed.

[The value of morphology in the diagnosis of chronic polyarthritis]. / Der Stellenwert der Morphologie in der Diagnostik der chronischen Polyarthritis.

The clinician's question concerning the value of morphological findings in diagnosis of rheumatoid arthritis is answered by the pathologist. After a short discussion of clinical problems and the ARA-criteria, at first the diagnostic importance of synovial cytology in RA is dealt with. The patient's history, biopsy technique and methods are the most important prerequisites of an optimal assistance of the pathologist to a definite diagnosis; they are reviewed in short paragraphs. These data are the bases of the morphological evaluation which is discussed in detail. This is the most important part of the answer to questions of the clinician; the pathologist is not only able to verify the clinical diagnosis of rheumatoid synovitis or of RA but often he may decisively judge the course and activity of the disease and the therapeutic success.

[Autoradiographic studies on the mitotic and productive metabolism of the articular cartilage in mouse genetic arthritis]. / Autoradiographische Untersuchungen zum Teilungs- und Leistungsstoffwechsel des Gelenkknorpels bei genetisch bedingter Arthrose der Maus.

With suitable radioactively labelled precursors the mitotic (using 3H-thymidine) and the productive metabolisms (using 3H-proline and 35S-sulphate) were investigated on various kinds of joint- etc. cartilage from mice with genetically caused arthrosis. The autoradiographic analyses were performed using 3H-thymidine-, 3H-proline- and 35S-sulphate-indices and the statistical evaluation of the findings led to the following results: the synthesis level of sulphated glycosaminoglycans (GAG) in the cartilage ground substance is lower for 5--6 month-old mice than for the 16--17 month-old animals of this genetic arthrosis strain. This is most distinct in the 3rd (= basal) zone of the knee-joint cartilage which increased to double the comparable value in this period. In all 3 zones of the knee-joint cartilage GAG-synthesis is considerably greater than the collagen synthesis according to these autoradiographic analyses. These findings can be detected before any histologically or histochemically demonstrable cartilage alterations and represent therefore the earliest signs of a so-called "pre-arthrosis". Collagen synthesis decreases thereby, and the same holds for DNA-synthesis and the mitotic metabolism of the cartilage cells - according to the findings to date. However the question is still under investigation whether arthrosis (like atherosclerosis) also starts with an increase in cell-turnover. This question is not only of theoretical interest, it has practical clinical consequences, even for the treatment. These investigations also serve this clinically relevant question because arthrosis is the most common human joint disease.