Rheumatoid Arthritis: Konttinen YT

Fedele S, Wolff A, Strietzel F, López RM, Porter SR, Konttinen YT. · UCL Eastman Dental Institute, London, United Kingdom. · J Rheumatol. · Pubmed #18671323 No free full text.

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Porola P, Laine M, Virkki L, Poduval P, Konttinen YT. · Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. · Ann N Y Acad Sci. · Pubmed #17894007 No free full text.

Abstract: Sjögren's syndrome is an autoimmune disease affecting the exocrine glands, most typically salivary and lacrimal glands. In Sjögren's syndrome, the acinar cells of these glands are damaged and destroyed, leading to diminished secretion of saliva and tear fluid. Accordingly, the current American-European criteria of Sjögren's syndrome include xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). In addition to these sicca symptoms and signs, the diagnostic criteria require autoimmune features in the form of Sjögren's syndrome SS-A and/or SS-B autoantibodies and lymphocyte infiltrates in labial salivary glands. Majority of patients with Sjögren's syndrome are women and the diagnosis is usually done when they are 40-50 years old. The cause of Sjögren's syndrome is unknown, but taking into account the female dominance and the late onset, our hypothesis is that sex steroids play a key role in the etiology of Sjögren's syndrome. More specifically, we believe that the driving factor behind Sjögren's syndrome could be lack of androgens. It has been shown that patients with Sjögren's syndrome have low concentrations of circulating dehydroepiandrosterone sulfate (DHEA-S) compared to age-matched healthy controls. Our hypothesis is that patients with Sjögren's syndrome suffer from an insufficient local androgen effect in the exocrine target tissues of the disease because of low systemic levels and/or ineffective local intracrine handling of DHEA-S prohormone. To further clarify the role of sex steroids and the eventual deficiency of androgens, salivary glands are studied using protein markers regulated by androgens or estrogens.

Konttinen YT, Porola P, Konttinen L, Laine M, Poduval P. · Department of Medicine, FIN-00029 HUS, Finland. · Autoimmun Rev. · Pubmed #17110311 No free full text.

Abstract: Sjögren's syndrome (SS) is characterized by keratoconjunctivitis sicca and xerostomia, which occur in an autoimmune lacrimal and salivary gland disease characterized by lymphocyte infiltrates of exocrine glands and/or Sjögren's syndrome autoantibody production. It has been reported that aquaporin-5 distribution is abnormal in SS, perhaps as a result of paracrine effect of TNF-alpha. Also the neurogenic regulation of the salivary gland is impaired in SS. Apart from functional changes, the syndrome is also characterized by structural abnormalities of the secretory acinar apparatus. The acinar basement membrane is abnormal as it lacks laminin alpha1 chain, which may impair its capability to induce the progenitor cells to differentiate to acinar cells. CRISP-3 and TMPRSS-2 can be used as androgen markers and LIV-1 and Cyr61 as estrogen markers to study the sexual dimorphism of the salivary glands. Patients with SS seem to have low concentrations of dehydroepiandrosterone, which may predispose women and the exocrine glands to this syndrome.

Konttinen YT, Seitsalo S, Lehto M, Santavirta S. · Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. · Acta Orthop. · Pubmed #16263606 links to  free full text

This publication has no abstract.

Laiho K, Kauppi M, Konttinen YT. · Rheumatism Foundation Hospital, Heinola, Finland. · Semin Arthritis Rheum. · Pubmed #15692956 No free full text.

Abstract: Rheumatoid involvement of the 24 joints of the cervical spine leads to prominent changes in the occipito-atlanto-axial area. Eight different subtypes of such changes are recognized, depicted, and defined. The frequencies of these 8 subtypes in rheumatoid arthritis and other arthritides are tabulated. A central role in these disorders is played by a small-size, heavy-duty fitting piece or adapter, atlas, between the occiput and C2. The history of the fate of Atlas, who led the fight of godlike titans against the new gods of Olympos, is recapitulated. In particular, for a short moment Atlas was released from his heavy physical ordeal by another strongman, the heavy-weight wrestler of his times, Heracles. The reasons for the current nomenclature and answer to the question "Why Atlas, why not Heracles" are provided.

Jonsson R, Gordon TP, Konttinen YT. · Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Armauer Hansen Building, NO-5021 Bergen, Norway. · Curr Rheumatol Rep. · Pubmed #14531959 No free full text.

Abstract: Sjögren's syndrome is a chronic autoimmune and rheumatic disorder of the mucous membranes caused by a lack of proper exocrine secretions, with prominent sicca complaints. The molecular mechanisms of the pathogenesis are virtually unknown, although progress has been made with regard to chemokines, B cell activating factor, and apoptosis. A large number of autoantibodies have been reported in Sjögren's syndrome, some of which relate to impairment of glandular function. Sjögren's syndrome is a female-dominant disease with a late age of onset; most patients contract the disease at the age of 40 to 50 years. Lately, attention has been drawn to the effects of adrenopause in Sjögren's syndrome and on dehydroepiandrosterone and its intracrine metabolism in target tissues. This can influence the maintenance and remodeling of exocrine glands and may explain, in part, another important disease symptom--fatigue.

Niissalo S, Hukkanen M, Imai S, Törnwall J, Konttinen YT. · Biomedicum Helsinki, Institute of Biomedicine/Anatomy, University of Helsinki, Finland. · Ann N Y Acad Sci. · Pubmed #12114296 No free full text.

Abstract: Classical symptoms of both inflammatory and degenerative arthritides may contribute to neurogenic responses like wheal, flare, edema, and pain. Rheumatoid arthritis (RA) is an autoimmune disease with an immunogenetic background. Neurogenic inflammation has been considered to play an essential role in RA, in part because of the symmetrical involvement (cross-spinal reflexes) and the predominant involvement of the most heavily innervated small joints of the hands and the feet (highly represented in the hominiculus). In contrast, osteoarthritis (OA) is considered to arise as a result of degeneration of the hyaline articular cartilage, which secondarily results in local inflammation and pain. However, it is possible that the age-related and predominant (compared to nociceptive nerves) degeneration of the proprioceptive, kinesthetic and vasoregulatory nerves can represent the primary pathogenic events. This leads to progressive damage of tissue with extremely poor capacity for self-regeneration. Inflammation, be it primary/autoimmune or secondary/degenerative, leads to peripheral sensitization and stimulation, which may further lead to central sensitization, neurogenic amplification of the inflammatory responses and activation of the neuro-endocrine axis. Neuropeptides serve as messengers, which modulate and mediate the actions in these cascades. Accordingly, many neuropeptides have been used successfully as experimental treatments, most recently VIP, which effectively controlled collagen-induced arthritis in mice. Therefore, it can safely be concluded that better treatment/control of disease activity and pain can be achieved by blocking the cascade leading to initiation and/or amplification of inflammatory process combined with effects on central nociceptive and neuroendocrine responses.

Konttinen YT, Käsnä-Ronkainen L. · Department of Medicine/Invärtes medicin, Helsinki University Central Hospital & ORTON Research Institute and the Orthopaedic Hospital of the Invalid Foundation, Finland. · Scand J Rheumatol Suppl. · Pubmed #12109538 No free full text.

Abstract: OBJECTIVE: To critically consider the public opinion/consensus on SS formulated by opinion leaders and textbook chapters. RATIONALE: Although our clinical work is based on evidence-based medicine, it is obvious that we do not have evidence-based solutions to the etiology and pathogenesis of autoimmune rheumatic diseases. In spite of this, consensus if often taken as a truth, which may hamper the production, funding and/or publication of new and original ideas and views. METHODS: Comparison of the classic view with one of the many other possible views. RESULTS: The consensus view states that 1) SS is initiated and/or caused by an exogenous agent, probably some type of retrovirus, and 2) after initiation, a straightforward sequence of events follows: a) salivary gland epithelial cells are disrupted, b) T lymphocytes migrate to and are activated in the glands, c) B cells get the help they need and start to produce SS and RF autoantibodies, which processes lead to structural destruction and loss of acinar cells and, thus, to sicca symptoms (an example of the linear, step-by-step "computer" logic). The problems inherent to this view include: 1) why women? (gender aspect), 2) why at the age of 50? (chronobiologic aspect), 3) is the normal immune system in SS only responding to normal (formely sequestrated) autoantigens? Is the loss of exocrine gland function really caused by "autoimmune" destruction? - or do the SS-autoantibodies and lymphocyte infiltrates only represent markers in an appropriate HLA background? (autoimmune aspect), 4) are the retroviral diseases really similar to SS? (exogenous rs endogenous causes), 5) is our current view compatible with unexpected, future findings? Is the textbook interpretation the final truth (evolutionary aspect of our view on pathogenesis). CONCLUSION: The tubuloalveolar exocrine glands may be seen as 1) locus minoris resistentiae for normal oral microbial flora and immune-inflammatory attacks at the normal environment-host interface. Apoptotic and/or necrotic cells are released into the intraluminal space and pass in normal glands through normal, immunologically competent lymphocyte foci and/or ectopic lymphatic tissue. Acinar cell degeneration/death may increase upon 2) aging and acinar cell renewal and well-being may be hampered by age-dependent deficiencies in the trophic 3) neuro-endocrine support. In a proper immunogenetic setting, a) marker autoantibodies (e.g. RF, SS-A/Ro, SS-B/La), useful in the diagnosis, are produced. However, sicca symptoms/SS develop only if muscarinic receptor or other b) pathogenetic autoantibodies disrupting the normal neuronal-to acinar cell communication are also produced. c) Systemic symptoms could be produced on neuroendocrine, chronobiologic and autoimmune basis. Other professionals are invited to entertain their own views on the pathogenesis of SS - make your own one!

Nordström DC, Konttinen YT. · HYKS:n sisätautien laitos Haartmaninkatu 4, 00290 Helsinki. · Duodecim. · Pubmed #11989008 No free full text.

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Konttinen YT, Valleala H, Honkanen V, Törnwall J, Tensing EK, Sorsa T, Nordström D. · · Duodecim. · Pubmed #11941814 No free full text.

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Valleala H, Mandelin J, Laasonen L, Koivula MK, Risteli J, Konttinen YT. · Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. · Eur J Endocrinol. · Pubmed #12720535 links to  free full text

Abstract: OBJECTIVE: To evaluate the role of serum osteoprotegerin (OPG) as a biochemical marker for disease activity assessment and drug monitoring in patients with rheumatoid arthritis (RA) treated with cyclical etidronate. DESIGN: Forty patients (35 women and 5 men) with RA of <5 years duration were randomized to receive intermittent cyclical etidronate therapy in conjunction with anti-rheumatic therapy or anti-rheumatic therapy alone (without etidronate) in a 2-year, open-label protocol. METHODS: Radiographs of hands and feet and serum samples for the determination of OPG, amino terminal propeptide (PINP), cross-linked C-telopeptide (ICTP) and amino terminal telopeptid of type I collagen were obtained at baseline and at 24 months. RESULTS: Etidronate treatment had no effect on circulating OPG levels, although the significant decline in PINP and ICTP (P=0.001 and P=0.04 respectively) reflected the efficacy of the anti-resorptive therapy. At baseline and at study termination, serum OPG correlated significantly with age (r=0.45; P=0.003 and r=0.56; P=0.0002 respectively). OPG was not related to biochemical markers of bone metabolism, indices of disease activity or radiographic disease progression. At baseline, the mean serum OPG was higher in patients receiving 5-10 mg/day prednisone (82.8+/-4.0 pg/ml, n=16) compared with those receiving <5 mg/day or with no prednisone (69.7+/-4.7 pg/ml, n=23) (P=0.05). CONCLUSIONS: Our results suggested that serum OPG measurement, perhaps because of the complexity of the regulation of the OPG, may be difficult to utilize in the evaluation of anti-resorptive therapy. Moreover, low dose corticosteroid-associated osteoporosis is probably not mediated by inhibition of OPG.

Valleala H, Laasonen L, Koivula MK, Mandelin J, Friman C, Risteli J, Konttinen YT. · Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. · J Rheumatol. · Pubmed #12610803 No free full text.

Abstract: OBJECTIVE: To investigate the effect of intermittent cyclical etidronate treatment on radiographic progression, bone collagen markers, and clinical disease activity in patients with rheumatoid arthritis (RA). METHODS: Forty patients with RA of less than 5 years' duration were randomized to receive intermittent cyclical etidronate therapy in conjunction with antirheumatic therapy or antirheumatic therapy alone (without etidronate) in a 2 year open-label protocol. Radiographs of hands and feet and serum samples for determination of aminoterminal propeptide (PINP), crosslinked C-telopeptide (ICTP), and aminoterminal telopeptides (NTx) of type I collagen were obtained at baseline and at 24 months. RESULTS: There was significant and similar worsening of the radiologic scores in both treatment groups. Both PINP, a marker of bone formation, and ICTP, an indicator of collagen degradation, declined in the etidronate group compared to the control group (p = 0.001 and p = 0.042, respectively). The groups did not differ for the change in serum NTx, a specific systemic marker of osteoclastic bone resorption. However, the change in serum NTx correlated significantly with the increase in erosion score in the total study population and in the control group (r = 0.41, p = 0.01 and r = 0.48, p = 0.034, respectively). CONCLUSION: Etidronate therapy did not prevent radiologic progression in patients with RA, but the decline in serum PINP and ICTP concentrations suggests a favorable effect on general bone metabolism. Correlation between the change in serum NTx and worsening of the erosion score provides biochemical evidence that osteoclast is the principal cell type responsible for focal bone resorption in RA.

Valleala H, Laitinen K, Pylkkänen L, Konttinen YT, Friman C. · Department of Medicine, Helsinki University Central Hospital, Finland. · Inflamm Res. · Pubmed #11822785 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy and tolerability of intravenous clodronate in patients with rheumatoid arthritis (RA). TREATMENT AND METHODS: Twenty-six patients with active RA were randomly allocated to receive either a single iv. infusion of placebo or 600 mg clodronate. Efficacy and safety were assessed weekly during the following three weeks by clinical and laboratory evaluations. RESULTS: Serum osteocalcin and carboxyterminal propeptide of type I procollagen (markers of bone metabolism) were significantly decreased in the clodronate group at the end of the study, whereas the indices of disease activity including number of swollen joints, number of tender joints, patient's and doctor's estimation of condition (visual analogue scale), erythrocyte sedimentation rate and serum C-reactive protein level were not affected by clodronate treatment. No serious adverse effects were observed. CONCLUSIONS: A single infusion of clodronate in patients with RA was safe and caused a decline in the markers of bone metabolism, but this short-term treatment did not suppress disease activity. Results from recent clinical and preclinical studies, however, suggest that the anti-inflammatory efficacy of clodronate requires liposome encapsulation.

Valleala H, Teronen O, Friman C, Sorsa T, Solovieva S, Konttinen YT. · No affiliation provided · J Rheumatol. · Pubmed #10852301 No free full text.

This publication has no abstract.

Takei I, Takagi M, Santavirta S, Ida H, Hamasaki M, Ishii M, Fukushima S, Ogino T, Konttinen YT. · Department of Orthopaedic Surgery, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan. · J Biomed Mater Res. · Pubmed #10397973 No free full text.

Abstract: The pseudojoint cavity formed in patients undergoing total hip arthroplasty (THA) is later remodeled to synovial membrane-like tissue, which produces pseudosynovial fluid. This pseudosynovium also is an important source of matrix metalloproteinases (MMPs). As it is widely speculated that synovial fluid MMPs may contribute to local tissue degradation in rheumatoid arthritis (RA) and osteoarthritis (OA), we hypothesize that locally produced MMPs are found in the pseudosynovial fluid, via which they have access to the implant-host interface, and that if they retain their proteolytic potential, they might contribute to aseptic loosening. Enzyme-linked immunosorbent assay (ELISA), immunoblotting, and zymography were used to analyze MMPs and tissue inhibitors of metalloproteinases (TIMPs) in synovial fluid in aseptic loosening, which was compared to RA and OA. Pseudosynovial THA fluid was characterized using low levels of MMP-1 but moderate levels of MMP-13 and MT1-MMP (MMP-14). Due to the lack of an appropriate assay, MMP-13 and MT1-MMP were not similarly assessed, but the immunoblotting indicated that they were in the 56 kD intermediate proteolytically processed forms. The MMP-9 level was intermediate between RA and OA. MMP-2 was on a significant level, but there were no differences among study groups. The THA group also was characterized using relatively high levels of TIMP-1 and TIMP-2. Accordingly, MMP-9 and MMP-2 were found to occur in the 92 kD and 72 kD proenzyme form, respectively, with full activity retained in all study groups. The data suggest that proMMP-2-TIMP-2 and proMMP-9-TIMP-1 complexes are formed in the pseudosynovial fluid due to the excess of TIMPs over MMPs in aseptic loosening of THA. TIMP-complexed MMPs are resistant to MMP-mediated proteolytic activation, which may explain their latency and proenzyme zymogen form. Thus, formation of stabilizing proMMP-TIMP complexes enable transportation of proMMPs far from their original site of production. Due to motion-associated cyclic changes of the intra-articular pressure, fluid-phase MMPs stabilized by TIMPs might be absorbed to implant surfaces and interface tissues and help to dissect the implant/cement-to-bone interface in situ. Consequently, they may contribute to local proteolytic/tissue destructive events and aseptic loosening.

Arborelius M, Konttinen YT, Nordström DC, Solovieva SA. · Department of Clinical Physiology, Malmö University Hospital MAS, Sweden. · Rheumatol Int. · Pubmed #10220832 No free full text.

Abstract: The aim of the present study was to examine if oral administration of Gly-X-Y repeat sequences alleviates disease activity in rheumatoid arthritis (RA). The study had a randomized, placebo controlled and double blind design with a wash-out/cross-over between the two 3-months long treatment periods. A total of 40 patients entered and 36 patients fulfilled the study, among them 16 started with the active drug and 20 with a placebo. Disease activity score (DAS) was used as the primary outcome measure with several secondary outcome variables. Type I or alpha error of 0.05 was accepted and the power (= 1-beta) was set to 80%, which according to the power analysis was also achieved. With active drug treatment, joint swelling score (54 count; P < 0.001), Ritchie's index (P < 0.01) and DAS (P < 0.001) improved. HAQ also improved (P < 0.05), but there was no improvement in the subjective condition of the patients as measured with the self-reported Pain Disability Index and Comprehensible Psychopathological Rating scale questionnaires. Apparently, 5/36 patients had a response of > or = 1.2 in DAS and 33/36 changed for the better; DAS impaired only in 3/36 patients during the active drug treatment When the stringent EU response criteria were applied and the results were compared to the placebo group, the response was not clinically significant. We conclude that Gly-X-Y repeat sequences are not effective as used in the present study. However, this does not definitely disprove the value of the Gly-X-Y repeat sequences, because confounding effects of dosage, concomitant medication and excessive degradation of the linear Gly-X-Y sequences in the stomach, gut or by phagolysosomes could not be adequately controlled. The discrepancy between the favourable effects in the preliminary, open pilot study and the controlled clinical trial emphasizes the value of the DAS, EU response criteria and adequately administered controlled clinical studies.

Caetano-Lopes J, Henriques R, Canhão H, Duarte J, Amaral PM, Vale M, Moura RA, Pereira PA, Weinmann P, Abdulghani S, Souto-Carneiro M, Rego P, Monteiro J, Sakagushi S, Queiroz MV, Konttinen YT, Graça L, Vaz MF, Fonseca JE. · Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. · Clin Exp Rheumatol. · Pubmed #19604441 No free full text.

Abstract: OBJECTIVES:Rheumatoid arthritis (RA) is associated with an increased risk of fragility fractures. In RA patients, the direct effect of inflammation on bone is difficult to study because their skeleton is also affected by medication with corticosteroids and other drugs as well as aging and menopause, which contribute to bone fragility. This study used an animal model of chronic arthritis to evaluate the direct impact of chronic inflammation on biomechanical properties and structure of bone.METHODS:In the SKG mouse chronic arthritis model three point bending tests were performed on femoral bones and compression tests on vertebral bodies. Collagen structure was analysed using second-harmonic generation (SHG) imaging with a two-photon microscope, ultramorphology by scanning electron microscopy (SEM) coupled with energy dispersive x-ray spectroscopy (EDS) and bone density using water pycnometer.RESULTS:Arthritic bones had poor biomechanical quality compared to control bones. SHG, SEM and pycnometry disclosed variable signs of impaired collagen organization, poor trabecular architecture and low bone density.CONCLUSION:Present data demonstrate for the first time that chronic inflammation per se, without confounding influence of drugs and aging, leads to impairment of bone biomechanics in terms of stiffness, ductility and ultimate strength (fracture).

Poduval P, Sillat T, Virtanen I, Porola P, Konttinen YT. · University of Helsinki, Helsinki, Finland. · Arthritis Rheum. · Pubmed #19333954 No free full text.

Abstract: OBJECTIVE: Sjögren's syndrome (SS) is characterized by atrophy and malfunction of the acinar cells. The aim of this study was to investigate whether type IV collagen alpha-chain composition of acinar cell compartments could be abnormal in diseased glands. METHODS: Messenger RNA (mRNA) from human submandibular gland (HSG) cells, cultured with or without growth factor-depleted Matrigel, was analyzed using quantitative reverse transcription-polymerase chain reaction (RT-PCR). Labial salivary glands were analyzed using quantitative RT-PCR and immunohistochemistry. RESULTS: HSG cells of both the ductal and acinar phenotypes synthesized all alpha-chain mRNA, in particular those of the alpha1 and alpha2 chains. Labial salivary glands (LSGs) contained alpha1/2 chains but also contained mRNA of all the other alpha-chains, although the mRNA copy numbers for the alpha3 and alpha4 chains were low, and the corresponding proteins were absent. Type IV collagen alpha1/2-chains were observed in all tubuloalveolar basement membranes. In healthy glands, alpha5 and alpha6 chains were continuous around ducts but discontinuous around acini. In SS glands, these chains were absent or patchy around the ducts and absent around the acini. CONCLUSION: Ductal and acinar epithelial cells are able to locally produce mRNA for all 6 different alpha-chains. Type IV collagen alpha1/2-chains seem to form the backbone in the tubuloalveolar basement membrane in salivary glands. Type IV collagen alpha3 and alpha4 chain mRNA were found in cultured salivary epithelial cells and LSG explants but were not translated to the corresponding alpha-chains in LSGs. Both alpha5 and alpha6 mRNA were observed in salivary epithelial cells and glands. In healthy glands, immunolabeling always disclosed corresponding alpha-chains around ducts, but their synthesis and/or degradation seemed to be locally regulated around acinar cells.

Forsblad-d'Elia H, Carlsten H, Labrie F, Konttinen YT, Ohlsson C. · Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, Göteborg S-413 46, Sweden. · J Clin Endocrinol Metab. · Pubmed #19318446 No free full text.

Abstract: CONTEXT: Serum levels of the sex steroid prohormones dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) decline upon aging and are reduced in primary Sjogren's syndrome. OBJECTIVE: Our aim was to investigate: 1) effects of 50 mg oral DHEA/day on changes in serum levels of DHEA and 12 of its metabolites; 2) relationships between steroid levels and disease characteristics; and 3) whether these parameters were influenced by DHEA. DESIGN: Twenty-three postmenopausal women with primary Sjogren's syndrome and subnormal levels of DHEA-S were included in a randomized, 9-month, controlled, double blind crossover study. Liquid chromatography/mass spectrometry (MS)/MS and gas chromatography/MS were used to measure the sex steroids. Anti-SS-A/Ro and/or anti-SS-B/La, salivary gland focus score, salivary flow rates, dry mouth and eye symptoms, and routine laboratory tests were assessed. RESULTS: Baseline erythrocyte sedimentation rate was inversely correlated with testosterone (Testo), dihydrotestosterone, and DHEA-S (rs = -0.42, -0.45, and -0.58, respectively). Dry mouth symptoms correlated with low Testo and androstenedione, whereas dry eyes correlated with low estrogens, most strongly estrone (rs = -0.63). Presence of anti-SS-A and/or anti-SS-B was independently associated with low estradiol (area under the receiver operating characteristic curve, 0.82). All metabolites increased during DHEA but not during placebo. The relative increases were less for estrogens and Testo compared to dihydrotestosterone and glucuronidated androgen metabolites. Dry mouth symptoms decreased during DHEA therapy. CONCLUSIONS: Disease manifestations in primary Sjogren's syndrome were associated with low sex hormone levels, dry mouth symptoms with low androgens, and dry eyes with low estrogens. Exogenous DHEA was preferentially transformed into androgens rather than into estrogens.

Honkanen PB, Kellomäki M, Konttinen YT, Mäkelä S, Lehto MU. · Department of Internal Medicine, Center of Rheumatic Diseases, Tampere University Hospital, Tampere, Finland. · J Hand Surg Eur Vol. · Pubmed #19282407 No free full text.

Abstract: This paper presents the results of a prospective study of 80 metacarpophalangeal joint arthroplasties, in which biodegradable polylactide 96/4 copolymer scaffolds were used. Twenty-three rheumatoid arthritis patients were assessed at an average of 59 months after operation, which exceeds the resorption time of P(L/D)LA 96/4 according to animal experiments. Palmar subluxation exceeded half of the bone thickness in 39 joints before operation and in nine at the last follow-up. Ulnar deviation decreased from 25 degrees to 5 degrees , extension deficit from 32 degrees to 15 degrees and active flexion from 76 degrees to 63 degrees . The results are comparable with published data on silicone implant arthroplasties. Implant resorption did not induce any significant osteolysis in the medium term and the restoration of the structure and function of the hand was maintained after implant resorption, probably as the guided fibrous tissues had replaced the dissolved implant.

Virkki LM, Konttinen YT, Peltomaa R, Suontama K, Saario R, Immonen K, Jäntti J, Tuomiranta T, Nykänen P, Hämeenkorpi R, Heikkilä S, Isomäki P, Nordström D. · Helsinki University, Finland. · Clin Exp Rheumatol. · Pubmed #19210870 No free full text.

Abstract: OBJECTIVE: We evaluated the cost-effectiveness of infliximab therapy in Finnish RA patients in a real-life clinical setting and identified factors influencing it, using the national register of biological treatment (ROB-FIN). METHODS: A cost-utility analysis was performed, derived from EQ-5D, and related to HAQ score and disease activity using multiple regression. QALYs were calculated based on these utilities, using patient-level data up to the last control registered. Cost-effectiveness analyses included costs per ACR50 responder, and costs per low DAS28 score (<3.2) achieved, in combination with a clinically significant improvement (>1.2). The costs considered were direct medical costs of infliximab and cost of intravenous infusion. Patient-level costs were calculated based on dose and dosage frequency, and were related to the difference in QALYs resulting from infliximab therapy. RESULTS: The 297 patients had been treated with infliximab for an average of 21 months. The HAQ score and patient's global assessment improved significantly on infliximab therapy. More than two-thirds of the patients achieved a clinically important improvement in HAQ. A QALY gain occurred in 76%. 35% of these had an incremental cost-effectiveness ratio of < or =40,000 Euro/QALY gained, the median cost being 51,884 Euro. The cost per QALY gained was significantly lower for patients achieving an ACR50 response at 3, 12 and 24 months. CONCLUSION: Treatment with infliximab and aiming at ACR50 response appears cost-effective, remembering the restrictions of an observational study set up. Current Care guidelines, which require sufficient disease control when deciding on continuing biological therapy, get support from these findings.

Vuorimaa H, Tamm K, Honkanen V, Konttinen YT, Komulainen E, Santavirta N. · Department of Rheumatology, Rheumatism Foundation Hospital, Heinola, Finland. · Clin Exp Rheumatol. · Pubmed #19032837 No free full text.

Abstract: OBJECTIVE: To investigate the relationship between children's arthritis self-efficacy, trait-anxiety, depression, clinical state of the disease (pain, disability, number of somatic complaints and active joints) and age of the child. METHODS: Trait anxiety and depression of JIA patients were measured by standardized scales (STAIC and CDI). For assessing self-efficacy CASE-scale was used. Pain, CHAQ and active joint count were used as indicators of the disease severity. The K-means cluster procedure was used to classify 145 consecutively recruited patients aged 8 to 15, regarding age, trait-anxiety and depression. One-way multivariate analysis of variance (MANOVA) followed by separate ANOVA's was used for comparisons between the cluster groups. Associations between the cluster groups and the children's self-efficacy were then evaluated using multivariate analysis of variance (MANOVA). RESULTS: Four cluster groups were identified based on the degree of depression and trait-anxiety. Clinical disease-related parameters differed significantly in the cluster groups. Pain was not necessarily related to the severity of the disease or to the diagnosis (oligoarthritis, oligoextended and polyarthritis). A higher level of self-efficacy was related to lower levels of depression, trait anxiety and pain. CONCLUSION: In JIA, the clinical classification of disease activity and severity did not directly correspond with depression and trait-anxiety in children with JIA. Instead, these were regulated by a self-efficacy, which was associated with less pain and somatic complaints.

Laine M, Virtanen I, Porola P, Rotar Z, Rozman B, Poduval P, Konttinen YT. · Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. · Clin Exp Rheumatol. · Pubmed #19032812 No free full text.

Abstract: OBJECTIVE:To analyze the epithelial cell-basement membrane attachment, in particular in the secretory end pieces (responsible for secretion of saliva) and in Sjögren's syndrome (SS) characterized by acinar cell failure.METHOD:Immunohistochemistry with laminin receptor chain-specific monoclonal antibodies to integrin (Int) subunits, Lutheran blood group antigen and alpha-dystroglycan.RESULTS:Only acinar cells contained Int alpha1 and alpha2 subunits. This staining was interrupted but strong in controls, but very weak in SS. Both acinar and ductal cells contained Int alpha3, alpha6, b1 and b4 and Lutheran blood group antigen and ductal cells also contained alpha-dystroglycan. These staining patterns were similar in SS and controls. CONCLUSIONS:Binding of the acinar and ductal cells to the basement membrane laminins seems to be mediated by Int alpha3b1, alpha6b1 and alpha6b4 integrin-receptors and Lutheran blood group antigen and alpha-dystroglycan non-integrin receptors. This structure-supporting system is intact in SS, compatible with the maintenance of the tubuloalveolar architecture of the SS glands. The irregular staining pattern of the acinus-specific Int alpha1b1 and alpha2b1 was compatible with a regulated signaling role, which was apparently impaired in SS. Indeed, their laminin counterparts (Lm -1/111 and -2/211) are also aberrant in SS revealing this as the central cell-matrix defect in the syndrome.

Porola P, Virkki L, Przybyla BD, Laine M, Patterson TA, Pihakari A, Konttinen YT. · Institute of Clinical Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. · J Rheumatol. · Pubmed #18843777 No free full text.

Abstract: OBJECTIVE: .We hypothesized that in addition to dehydroepiandrosterone (DHEA) depletion, Sjögren's syndrome (SS) is characterized by local androgen deficiency in salivary glands and defects in local processing of DHEA. METHODS: Sex steroid levels in serum and saliva were measured using enzyme immunoassays. Androgen effects on salivary gland cells were analyzed using the cysteine-rich secretory protein-3 (CRISP-3) androgen biomarker. RESULTS: Serum and salivary concentrations of androgens were low in SS. Substrate to end-product ratios and correlations suggest that in SS salivary glands DHEA is effectively converted to testosterone, but that there are defects in converting testosterone further to dihydrotestosterone (DHT). In healthy controls no such phenomenon was seen, but testosterone is effectively converted to DHT. Salivary glands contained type I 5-alpha-reductase, and its inhibition with dutasteride completely blocked the upregulating effect of DHEA, but not of DHT, on CRISP-3 in human salivary gland acinar cells. CONCLUSION: DHEA and DHT upregulate CRISP-3, which is reportedly low in SS. The effect of DHEA on CRISP-3 is indirect and is inhibited by dutasteride, showing that there is intracrine processing of DHEA in salivary glands. In healthy glands, but not in SS, DHEA is effectively taken up and converted to DHT. Sex steroid concentrations in saliva in part reflect glandular uptake of DHEA-sulfate and local intracrine DHEA metabolism, which seem to be defective in SS. Our study demonstrates a prominent androgen deficiency and a defect in intracrine production of active androgens in SS salivary glands, also suggesting that salivary DHT cannot be maintained at a normal level in this female-dominant autoimmune exocrinopathy.

Ainola M, Mandelin J, Liljeström M, Konttinen YT, Salo J. · Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. · Clin Exp Rheumatol. · Pubmed #18565244 No free full text.

Abstract: OBJECTIVE: To test if the pannus tissue is characterized by a high receptor activator of nuclear factor kappaB ligand to osteoprotegerin (RANKL:OPG) ratio, which could explain local osteoclastogenesis and formation of bony erosions. METHODS: Messenger RNA and protein expressions of RANKL and OPG in rheumatoid and osteoarthritic tissue samples were measured using quantitative real-time RT-PCR and Western blot/densitometry. Pannus and synovitis fibroblasts explanted from tissue samples were cultured in vitro without and with TNF-alpha, IL-1Beta or IL-17 and analyzed quantitatively for RANKL expression. The ability of pannus fibroblasts to induce formation of multinuclear osteoclast-like cells from human monocytes, with macrophage-colony stimulating factor (M-CSF) but without RANKL added, was tested. Histochemical staining was used to assess the eventual presence of RANKL and tartrate resistant acid phosphatase positive osteoclast-like cells at the pannus-bone interface. RESULTS: RANKL:OPG ratios of messenger RNA (p<0.05) and protein level were high in pannus (2.06+/-0.73 and 2.2+/-0.65) compared to rheumatoid (0.62+/-0.13 and 1.31+/-0.69) and osteoarthritis (0.62+/-0.32 and 0.52+/-0.16) synovial membranes. Resting and stimulated (p dependent on the cytokine used) pannus fibroblasts produced RANKL in excess (p=0.0005) and unstimulated pannus fibroblasts also effectively induced osteoclast-like cell formation from monocytes in vitro without any exogenous RANKL added. Compatible with these findings, multinuclear osteoclasts-like cells were frequent in the fibroblast- and macrophage-rich pannus tissue at the soft tissue-to-bone interface. CONCLUSION: The high RANKL:OPG ratio, together with close fibroblast-to-monocyte contacts in pannus tissue, probably favor local generation of bone resorbing osteoclasts at the site of erosion in rheumatoid arthritis.