Revista Romana de Reumatologie 2008 NR 4

Revista Romn de
REUMATOLOGIE
Volumul XVII Nr. 4 An 2008 ISSN 1843-0791 Cod CNCSIS 378 Redactor ef: Horaiu D. BOLOIU Redactori onorifici: tefan UEANU Eugen POPESCU Secretar General de Redacie: Laura DAMIAN
COLEGIUL DE REDACIE Geza Balint (Budapest) Mioara Banciu (Timioara) Rodica Chiriac (Iai) Paulina Ciurea (Craiova) Ctlin Codreanu (Bucureti) Constantin Dumitrache (Bucureti) Lia Georgescu (Trgu Mure) Philippe Goupille (Tours) Walter Grassi (Ancona) Laszlo Hodinka (Budapest) Ruxandra Ionescu (Bucureti) Nicolae Iagru (Bucureti) Marco Matucci (Firenze) Nicolae Miu (Cluj-Napoca) Sarah Nica (Bucureti) Gyula Poor (Budapest) Simona Rednic (Cluj-Napoca) Zoltan Szekanecz (Debrecen) Maria ua (Constana) Coman Tnsescu (Bucureti) Francesco Trotta (Ferarra) Jean-Pierre Valat (Tours) Sjef van den Linden (Maastricht)
CONSILIUL TIINIFIC: Codrina Ancua (Iai) Andra Blnescu (Bucureti) Mihai Bojinc (Bucureti) Violeta Bojinc (Bucureti) Tatiana Bratu (Timioara) Dorica Crstei (Brila) Anca Cozo (Trgu Mure) Lucia Cucu (Oradea) Daniela Fodor (Cluj-Napoca) Constantin Gaube (Piatra Neam) Daniel Grigorie (Bucureti) Bogdan Jante (Bucureti) Victoria Jugravu (Bucureti) Radu Miclu (Deva) Mihaela Micu (Cluj-Napoca) Claudia Mihailov (Constana) Mariana Mihailov (Bile Felix) Gavril Mirea (Braov) Eugenia Mociran (Baia Mare) Corina Mogoan (Timioara) Laura Muntean (Cluj-Napoca) Dan Neme (Timioara) Ioan Parasca (Cluj-Napoca) Horaiu Popoviciu (Trgu Mure) Denisa Predeeanu (Bucureti) Alina Rdulescu (Bucureti) Florin Rdulescu (Bucureti) Elena Rezu (Iai) Sio-pin Simon (Cluj-Napoca) tefni Tnseanu (Bucureti) Maria Vaida-Voevod (Arad) Editura Medical AMALTEA
Editori: Dr. M.C. Popescu Dr. Cristian Crstoiu Director executiv: George Stanca Redactori: Oana Cristina Plcint, Alina-Nicoleta Ilie Prepress: AMALTEA TehnoPlus Tehnoredactor: Gabriela Cpitnescu DTP: Petronella Andrei, Gabriela Cpitnescu Producie: Mihaela Conea Distribuie: Mihaela Stanca ________________ CONTACT: AMR@medica.ro ABONAMENTE: redactia@amaltea.ro TIPAR: EMPIRE Print RomExpo, Pavilion T, Bucureti tel.: 021 / 316 96 40, 031 / 405 99 99 email: office@empireprint.ro
EDITORIAL
Cuprins
EDITORIAL H.D. Boloiu Serendipitate i tratamentul reumatologic __________________________________________ 187 ARTICOLE DE ORIENTARE T. Dorner, G.R. Burmester No B cells-no RA? Advances in B cell depletion in rheumatoid arthritis-repeated therapy under conditions of clinical practice ________________________________________ 189 N.G. Schenker, A.S.M. Jawad Bisphosphonates and osteonecrosis of the jaw _______________________________________ 193 M. Inanc Very early rheumatoid arthritis cohorts: limited by selection ________________________ 197 D.J. Armstrong Celecoxib and cardiovascular risk lessons from APC and PreSAP studies ______________ 201 LUCRRI ORIGINALE I. tefan, C. Vertan, H.F. Jelinek, R. Badea Modificarea texturii trabeculare la populaia feminin vrstnic, evideniat prin analiza fractal pe radiografia calcaneului _____________________________________ 203 Carolina Negrei, D. Bllu, Andra Blnescu, Mihaela Ilie, Denisa Margin, Daniela Baconi, Denisa Predeeanu, Violeta Bojinc. F. Berghea, Daniela Opri, Ruxandra Ionescu Influena tratamentului cu leflunomid i metotrexat asupra unor parametri de stress oxidativ la pacieni cu poliartrit reumatoid _______________________________________ 208 tefania Marinea, C. Cernescu, Denisa Predeeanu, Andra Blnescu, Violeta Vlad Evaluarea stilului de via al pacienilor cu poliartrit reumatoid _____________________ 212 Mariana tefan Consideraii asupra terapiei cu etanercept la copii cu artrit idiopatic juvenil _________ 218 CAZUISTIC INSTRUCTIV Adriana Sarah Nica, Anca-Magdalena Melia, L. Macovei, Camelia Brileanu Probleme de tratament la un bolnav cu spondilit anchilozant i status post-hemoragie cerebral ________________________________________________ 221 Cristina Pamfil, Maria-Magdalena Tamas, Ana Petcu, Bianca Gusho, Ileana Nicoara, Siao-pin Simon, Simona Rednic Reactivare tuberculoas la un pacient cu spondilit anchilozant n tratament biologic o ansa spulberat __________________________________________ 225
EDITORIAL
SERENDIPITATE I TRATAMENTUL REUMATOLOGIC

Uneori oamenii se mpiedic de adevr, dar trec mai departe n grab, fr ca nimic s se ntmple. Winston Churchill
Serendipitatea, un termen intraductibil derivat dintr-un nume propriu, a fost pentru prima dat utilizat de Sir Horace Walpole n anul 1754, pornind de la titlul unei istorioare persane Cei trei prini din Serendip. La vremea respectiv, Serendip era numele arab al Ceylonului, astzi Sri Lanka. Ori de cte ori cei trei prini plecau ntr-o cltorie, gseau din ntmplare lucruri preioase pe care nu le cutaser. Noiunea este utilizat n teoria cercetrii tiinifice ca descoperirea mai mult sau mai puin ntmpltoare a unor fapte de interes. Exemple clasice de serendipitate sunt descoperirea Americii de ctre Cristofor Columb, inventarea fonografului i a telefonului de ctre Thomas Alva Edison, respectiv Alexander Graham Bell, i a radioactivitii naturale de ctre Henri Bequerel, ca s citm exemple din domenii diferite ale cunoaterii. n medicin, sunt larg cunoscute ntmplrile care au condus la descoperirea de ctre Louis Pasteur a microorganismelor i de ctre Alexander Flemming a penicilinei. Mai puin celebre sunt accidentele fericite care s-au concretizat ulterior n tratamentele cu care operm astzi n reumatologie, i aici exemplele nu sunt puine. n anul 1890, Robert Koch a observat ntmpltor c srurile de aur sunt capabile s inhibe creterea Mycobacterium tuberculosis n culturile sale i de aici pn la utilizarea acestora pentru tratarea tuberculozei nu a fost dect un pas. Istoria medicinii atribuie lui Laude i Forestier ntmplarea de a fi observat cazul unui bolnav ftizic, suferind concomitent de ceea ce n epoc se numea poliartrit cronic evolutiv, n care cel puin a doua boal sa ameliorat substanial dup acest tratament. Mult vreme, poliartrita reumatoid a fost considerat ca fiind determinat de infecia tuberculoas. Nici astzi nu se cunoate modul exact n care acioneaz chrisoterapia n aceast boal, dar cu siguran nu prin efectul antimicrobian.
REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008
Nu este singurul caz din reumatologie n care un medicament corect a fost indicat pentru motive incorecte, iar virtuile sale terapeutice au fost confirmate de statistici. n anul 1972, Nanna Svarz credea c poliartrita reumatoid este declanat de infecia digestiv cu Streptococcus agalactiae i a preconizat tratamentul acestei boli cu sulfasalazin, o sulfamid recent descoperit. Premisa a fost fals, dar beneficiile evidente. De fapt, aproape toate medicamentele remisive cu molecul mic - Dpenicilamina, antimalaricele, metotrexatul i leflunomidul au fost descrise ca atare dup ce mai nti au fost recomandate de puin serendipitate (a bit of serendipity). Leflunomidul a fost sintetizat la Hoechst de ctre G. Heubach n cadrul unui program de cercetare pentru pesticide. Un alt chimist, E. Wolff, a bnuit (?) c substana ar putea avea proprieti antiinflamatoare i l-a convins pe un biolog s o testeze pe modelul de artrit experimental indus la obolan cu ajutorul adjuvantului Freund. Acesta nu putut dovedi aciunea antiinflamatoare, dar a semnalat-o pe cea imunodepresoare. Serendipitatea a jucat un rol i n descoperirea corticoterapiei. n anul 1929, Phillip Hench a avut geniul s considere c ameliorarea inflamaiei articulare a unuia dintre bolnavii si cu ocazia episoadelor intermitente de icter sau n sarcin la femei, nu se datoreaz unei coincidene. Urmarea a fost c i-a dedicat toat viaa studiului acestui fenomen i rezultatele au fost ncununate de succes exact acum 60 de ani. Pentru c femeile cu icter se ameliorau mai frecvent dect brbaii, autorul a crezul c ceea ce numea substana antireumatic X ar putea fi un hormon. Din ntmplare, colegul su de la Mayo Clinic, Edward Kendall, tocmai se dedicase studierii hormonilor suprarenali i din colaborarea celor doi a fost izolat compusul E, care administrat la 21 septembrie 1948, a produs ameliorarea spectaculoas a unui caz cu poliartrit
187
188
reumatoid. S ne reamintim aseriunea conform creia ntmplarea favorizeaz minile pregtite!. Ar mai trebuie poate menionat c efectele osoase ale bisfosfonailor au fost descoperite n cadrul unor studii care au fost urmarea utilizrii acestor substane ca detergeni sau ca ageni antitartru pentru instalaiile sanitare i c, poate anec-
dotic, rituximabul a fost introdus pentru tratarea poliartritei reumatoide dup ce un caz care suferea concomitent de un limfom cu celule B i-a vzut ameliorate ambele boli. Astfel de situaii invit la completarea paradigmei evidence-based practice cu reversul su practicebased evidence . Horaiu D. Boloiu
ARTICOLE DE ORIENTARE
NO B CELLSNO ACTIVE RA? ADVANCES IN B CELL DEPLETION IN RAREPEATED THERAPY UNDER CONDITIONS OF CLINICAL PRACTICE
T. Dorner, G. R. Burmester Charite Universitatsmedizin and Deutsches Rheumaforschungszentrum, Berlin, Germany. Early observations in 1999 by Jo Edwards group at University College London, UK [1] provided evidence that using a B-cell depleting antibody licensed for non-Hodgkin lymphoma was able to significantly reduce signs and symptoms of RA with an acceptable safety profile during a single treatment course of induced B-cell depletion and subsequently led to clinical development of this drug based on large randomized clinical trials (proof of concept/IIa, DANCER, REFLEX) and finally to approval in the US, Switzerland and the EU for this indication. This is the first cell-directed therapy for the treatment of RA arriving in the clinics after studies of T-cell directed therapy using anti-CD4 antibodies opened this area more than 10 yrs ago [2]. Importantly, it offers alternative treatment options to severe RA patients inadequately responding to TNF blockers. The breath-taking pace of this clinical development with inducing a clinical response for several months in individual patients confronts the rheumatology community with a number of issues and questions that need to be addressed under nonstudy conditions, such as (i) what is the best retreatment schedule, (ii) what are the most frequently occurring side effects outside clinical trials, (iii) do certain subsets of patients preferentially benefit from this therapy as compared to a profile of non-responders. These burning clinical questions will be answered soon by expanding daily experiences as well as by further trials. Right at the time of international approval of anti-CD20 therapy with rituximab in RA after failing TNF blockers, the update report of the largest experiences of recurrent B-cell depletion of the UCL RA cohort provides
us with additional information of 37 RA patients by the pioneers in the field, published in this issue of Rheumatology [3]. Patients with moderate to severe RA were chosen for this treatment after failing other DMARDs and TNF blockers. Most importantly, they had co-morbidities, such as secondary amyloidosis, psoriasis, a history of MALT lymphoma, etc. This heterogeneity reflects a realistic patient population under daily clinical practice. Most importantly, this study contributes to our understanding of long-term efficacy and safety of repeated B-cell depletion.
RETREATMENT
So far, retreatment data have not been published based on clinical trial data but we have learned from DANCER [4] and REFLEX [5] as compared with the early proof of concept phase IIa study [6] that patients with previous inadequate responses to TNF blockers achieve lower ACR responses than patients who have failed methotrexate only. Despite clear evidence of an overall robust response to repeated cycles of B-cell depletion in RA, Popa et al. [3] report an average duration of response of 15 months and time to retreat of 20 months. These data set out the task for the future! How can we minimize the gap of about 5 months between flaring disease and re-treatment or is this the best way forward. In order to answer this question, we believe that combined evaluation of clinical data (i.e. DAS28 parameters) and identifying reliable biomarkers is needed for professional retreatment. In this study [3], simply measuring peripheral blood B cells did not correlate with the clinical course in the experiences of the UCL group. About 50% of cases showed a relapse before B cells returned,
189
190
the remaining 50% showed relapse on average after 2.5 yrs. This is likely related to the fact that not recurrence of B cells per se is important but more dependent on early recurrences of memory B cells [7,8]. To which extent this applies to larger populations needs further analyses. Although reoccurring B cells apparently do not necessarily indicate relapse of RA, Popa et al. [3] nicely demonstrate in their Fig. 1 that relapse did not occur without peripheral B cell. This implicates two major, apparently interrelated aspects. First, the dogma no B cellsno RA relapse was confirmed by retreatment analyses. Secondly, there is an intimate role of B-cells in the pathogenesis of RA that cannot be substituted by other mechanisms of the immune system. Consistent with that, one patient even had a response for up to 43 months after a single cycle of rituximab treatment indicating that the time of response varies and precludes regular retreatment as we practice with TNF blockers and other small molecule DMARDs. Subsequent cycles of Rituximab treatment in the current article was apparently based on clinical judgement and raised CRP levels. We believe that clinical judgement with DAS28 is currently the best way to define the requirement of retreatment after successful previous administration of this drug as recommended by an international consensus [9]. Another biomarker for a potential relapse identified earlier by this very same group [10] was an increase in one of the autoantibodies (IgG, IgM, IgA RF, anti-CCP antibodies). The possibility of antibody profiling over time has not been explored in re-treatment studies but would be of utmost interest for daily practice because of its feasibility.
into psoriasis arthropathy which may indicate exclusion of B-cell depletion as potential therapy. Consistently, patients with psoriasis lacked response to B-cell depletion independently of RF. This is an interesting distinction to what we learned by TNF blockade. If these clinical observations will be confirmed and robust, differential therapy with biologics becomes reality. The presence of certain autoantibody profiles in RA and their potential relation to the efficacy of B-cell depletion has not been investigated thoroughly. Despite follow-ups of RF titre, very limited data are available for anti-CCP antibodies [10] after B-cell depletion in RA. Previous studies demonstrated that at least one autoantibody increases prior to a flare [10] and underscores the role of B cells and humoral imprinting in RA.
MOST FREQUENTLY OCCURRING SIDE EFFECTS

A major strength of the report by Popa et al. [3] reflects safety aspects of re-treatment. Patients with RA represent usually a multimorbid cohort with early cardiovascular events and a higher rate of Bcell non-Hodgkins lymphoma [11,12]. Therefore, development of new drugs for RA patients is very challenging to ensure improved risk/benefit ratios but otherwise taking into account the underlying genuine risks of RA, such as cardiovascular complications, enhanced risks for infections and cancer. The three available randomized controlled trials comprising about 1035 patients did not indicate significant safety signal for any infection or other adverse event when treatment groups were compared with placebo. These patients usually had also very severe rheumatoid arthritis, a history of several previous DMARDs and longstanding disease (usually over 10 yrs). The study by Popa et al. [3] observed an increased rate of lower respiratory infections under daily practice conditions. Moreover, no relation to hypogamaglobulinaemia and infections was seen. This is of interest for wider use in severe RA if confirmed. Patients with humoral immunodeficiency have a higher risk of airway infections. In this regard, IgM was reduced after B-cell depletion as expanded by the data of the study [3]. If this predisposes to the reported enhanced rates for lower respiratory infections, is uncertain. To some surprise, even in patients with five cycles of rituximab treatment, IgA and IgG levels do not decline as one may have
SUBSETS OF PATIENTS
Experiences of the efficacy of rituximab in RF patients are still limited, given that in phase IIa only RF+ patients were considered and in DANCER RF+ patients were the primary study population. A total of 79% patients enroled in the REFLEX trial were RF+. Although RF patients were included in an exploratory analysis, the available data are still limited and RF patients in DANCER had a high placebo response with 52%. In the report by Popa et al. [3], five patients did not respond to B-cell depletion, four of them (80%) were RF. Reconsideration of the RF patients classified them
191
expected. This confirms that retreatment is feasible in RA without unforeseen declines in protective immunity even in the very severe patients usually immunocompromised. Ig levels under repeated cycles of rituximab are of great interest with regard to potential (and expected) disturbances in protective Igs. Data of individual patients can vary even between different cycles of B cell depletion as demonstrated by Popa et al. Although we do not have direct comparisons with methylprednisolone, which is able to inhibit Ig synthesis in plasma cells [13] with effects within a few days on IgG, B-cell depletion has apparently only an effect via turnover of plasma cells. As discussed before, the potential role of follow-up measurements of Ig levels needs to be explored (i) in terms of efficacy of repeated B-cell depletion as well as (ii) as surrogate marker for safety aspects. Consistent with the RCTs, there was no relation with certain infections seen.
depletion seen in individual patients. However, the underlying factors leading to prolonged B-cell depletion are interesting, not solely dependent on the presence of the anti-CD20 antibody [15] and significantly longer than the period of B-cell reconstitution after bone marrow transplantation. Moreover, involvement of TB interaction, Tcell activation, precursors of (auto)antibody producing cells, production of pro-inflammatory cytokines do not fully explain all the clinical observations after B-cell depletion. A striking feature is the time of clinical effectiveness which is delayed for 612 weeks after B-cell depletion which occurs within hours. Although some B cellsmay remain in tissues [16], it may not necessarily explain this time course in the clinics.
CONCLUSION
Overall, the first fully published study on repeated treatment cycles with rituximab in RA patients reports robust and comparable efficacy in subsequent treatments but also points our interest toward the needs for biomarkers (B-cell subsets, autoantibody profile, Ig levels etc.) that allow improved patienttailored therapy. Although declines in Ig levels occur, they are not necessarily related to infections. Registries for this additional biologic [17] are needed to provide a large database for the safety profile for potentially less frequent adverse events. Conflict of interest: T.D. and G.R.B. received speakers honoraria, less than 10, 000 USD and served at advisory boards of Roche Ltd.
MECHANISM OF ACTION
After experiences with TNF blockers as the first biologics used on large scales in rheumatology, we learned that they usually led to rapid clinical improvements and require re-treatment after specific time intervals. Selective B-cell depletion has a different timing of repeated treatment and the mechanisms of repletion within 68 months in RA are quite remarkable. It is not clear whether some pre-B cells can also be depleted [14] potentially contributing to a longer period of peripheral B-cell
REFERENCES
1. Protheroe A, Edwards JCW, Simmons A, Maclennan K, Selby P. Remission of inflammatory arthropathy in association with anti-CD20 therapy for non-Hodgkins lymphoma. Rheumatology 1999;38:11502. Horneff G, Burmester GR, Emmrich F, Kalden JR. Treatment of rheumatoid-arthritis with an anti-Cd4 monoclonal-antibody. Arthritis Rheum 1991;34:12940. Popa C, Leandro MJ, Cambridge G, Edwards JCW. Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 years. Rheumatology 2007;46:711715. Emery P, Szczepanski L, Szechinski J et al. Sustained efficacy at 48 weeks after single treatment course of rituximab in patients with rheumatoid arthritis. Arthritis Rheum 2003;48:S439. Cohen SB, Emery P, Greenwald MW et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793806. Edwards JCW, Szczepanski L, Szechinski J et al. Efficacy of Bcell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:257281. Roll P, Palanichamy A, Kneitz C, Dorner T, Tony HP. Regeneration of B cell subsets after transient B cell depletion using
2.
3.
4.
5.
6.
7.
anti-CD20 antibodies in rheumatoid arthritis. Arthritis Rheum 2006;54:237786. 8. Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JCW. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 2006;54:61320. 9. Smolen JS, Keystone EC, Emery P et al. Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2006; Dec 20 [Epub ahead of print]. 10. Cambridge G, Leandro MJ, Edwards JCW et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 2003;48:214654. 11. Baecklund E, Ekbom A, Sparen P, Feltelius N, Klareskog L. Disease activity determines lymphoma risk in patients with rheumatoid arthritis. A nested case-control study. Arthritis Rheum 1997;40:1696. 12. Baecklund E, Sundstrom C, Ekbom A et al. Lymphoma subtypes in patients with rheumatoid arthritis - Increased proportion of diffuse large B cell lymphoma. Arthritis Rheum 2003;48:154350. 13. Butler WT, Couch RB, Rossen RD, Hersh EM. Methylprednisolone fails to inhibit primary and secondary antibodyresponses but causes marked suppression of on-going antibodyformation in man. J Clin nvest 1974;53:A14.
192
14. Leandro MJ, Edwards JCW, Ehrenstein MR, Cambridge G, Isenberg DA. Follow up study of B-lymphocyte depletion in the treatment of patients with systemic lupus erythematosus. Rheumatology 2005;44:I25. 1 5. Silverman GJ. Therapeutic B cell depletion and regeneration in rheumatoid arthritis Emerging patterns and paradigms. Arthritis Rheum 2006;54:235667.

16. Gong Q, Ou QL, Ye SM et al. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immuno 2005;174:81726. 17. Scott DL, Kingsley GH. Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med 2006;355:70412.
(Articol publicat n parteneriat cu Rheumatology 2007;46:10491051)
n actualitate Amiloidoza n poliartrita reumatoid
Prevalena amiloidozei AA n poliartrita reumatoid (PR) nu este cunoscut cu exactitate. Acest studiu s-a bazat pe reexaminarea esuturilor obinute de la autopsiile consecutive a 369 pacieni decedai i de la 370 cazuri cu deces de alte cauze, corespunztori ca
vrst i sex. Fa de rezultatele iniiale ale autopsiilor, examinatorii au gsit amilodoza cu 30% mai frecvent n esuturile poliartriticilor, fa de 4% la martori. n PR, amiloidoza cardiac a fost mai frecvent dect cea renal. La acetia, boala a fost mai nde-
lungat i mai sever. Numai 56% dintre poliartriticii cu amiloidoz avuseser proteinurie n timpul vieii. Concluzia este c amiloidoza este subdiagnosticat la bolnavii cu PR.
Sursa: Koivuniemi R, Paimela L, Suomalainen R et al, Amyloidosis in frequently undetected in patients with rheumatoid arthritis, Amyloid, 2008, 15, 262-268
Vizitai site-ul
SOCIETII ROMNE DE REUMATOLOGIE www.srreumatologie.ro
BISPHOSPHONATES AND OSTEONECROSIS OF THE JAW

N. G. Shenker, A. S. M. Jawad Department of Rheumatology, The Royal London Hospital, Bancroft Road, London E1 4DG, UK
There are concerns regarding osteonecrosis of the jaw (ONJ) in patients who take aminobisphosphonates. This is a relatively newly recognized complication of a therapy from which hundreds of thousands of patients in the UK currently benefit, a number which is currently increasing. What is the evidence linking these drugs with ONJ? Which bisphosphonates are implicated? What patients are at risk? And finally, what are the implications of this new insight for the management and safety of patients under the care of rheumatologists? ONJ is a rare but often intractable disease. Patients with ONJ present with exposed bone related to the oral cavity which is necrotic and often complicated by secondary infection with the bacteria that typically cause periodontitis, including actinomycetes [1]. Patients usually present in pain which is sometimes severe although a significant proportion, up to a third, have no pain at all [2]. Other manifestations include loose teeth or a draining fistula. It more commonly involves the mandible rather than the maxilla and lesions are non-healing, or slow to heal. Histological appearance reflects this underlying avascular necrosis usually with superadded infection [2]. ONJ has previously been associated with osteopetrosis and phosphorous poisoning (phossy jaw). The main risk factors already known to be associated with ONJ are corticosteroids, dental surgery, radiotherapy and poor oral hygiene. Other risks that have been recognized include alcohol abuse, smoking, poor nutrition, infection, chemotherapy, hormonal treatments, anaemia, thalidomide and previous organ transplant [15]. Currently, there are no effective treatments for ONJ. It is important to note that surgical debridement can make the condition worse and
patients should avoid this if at all possible [3]. Should surgery be contemplated, then a referral should be made to an experienced oral and maxillofacial surgeon. Patients may be treated noninvasively with antibiotics (such as penicillin or clindamycin) and antimicrobial mouth rinses (such as chlorhexidine or hydrogen peroxide) to limit the extent of the damage. Because of the recent association it is recommended that any bisphosphonate should be stopped when ONJ has been identified although the long half-life of such treatment precludes an immediate impact on the course of the disease. Hyperbaric oxygen has not been shown to be effective. Sadly, most lesions are non-healing or show only slow improvements and close follow-up should be made [2, 3]. ONJ is hypothesized to occur as the direct result of microtrauma on bone that is both hypovascular and hypodynamic and thus less able to meet an increased demand for repair and remodelling. The jaw is particularly prone to ONJ as it is regularly exposed to physiologic stress (e.g. mastication), iatrogenic damage (e.g. tooth extraction or denture injury) or tooth infection. The anti-angiogenic properties of some coexisting risk factors contributes to this hypothesis. These include medications (glucocorticoids, thalidomide and bortezomib in patients with myeloma), diabetes mellitus, irradiation of the jawbone, peripheral vascular disease and hyperviscosity syndromes. Bisphosphonates are synthetic analogues of cellular inorganic pyrophosphates. The first generation of bisphosphonates (etidronate, tiludronate and clodronate) are not nitrogen containing and these compounds have not been considered to cause ONJ [3]. Multiple mechanisms effect their actions on bone but the primary mechanism of action is
193
194
likely to be a direct osteoclastic cytotoxicity once they are converted to a non-hydrolysable adenosine triphosphate analogue. Alendronate, risedronate, pamidronate, zoledronic acid and ibandronate all contain nitrogen within a side chain. These aminobisphosphonates, as well as inducing apoptosis via another adenosine triphosphate analogue, also inhibit farnesyl diphosphonate synthase which is part of the mevalonate pathway of cholesterol synthesis [6]. This has the effect of disrupting osteoclast function. All bisphosphonates also appear to reduce the recruitment of osteoclasts, and aminobisphosphonates in particular have been demonstrated to have anti-tumour effects and have therefore become standard therapy for patients with multiple myeloma and bone metastases [7]. Aminobisphosphonate usage in post-menopausal osteoporosis has gradually superseded the older bisphosphonates as they are more efficacious with respect to bone mineral density and fracture prevention, and the weekly and intravenous preparations are better tolerated. Other indications for their rheumatological use include Pagets disease and steroid-induced osteoporosis and they are used in other diseases associated with altered bone turnover including ankylosing spondylitis, childhood disorders of bone metabolism and complex regional pain syndromes [8]. The nitrogen-containing bisphosphonates, and especially the intravenous forms (zoledronate and pamidronate) have been associated with ONJ. At oncological doses the incidence ranges from 4 13%, with a median onset of between 22 and 39 months from the first administration [5]. Oral bisphosphonates given to rheumatology patients however carry an ONJ incidence <0.1% and likely to be about 1 in 100 000 [9]. Twenty-two cases of ONJ occurred in patients who were taking oral bisphosphonates for either osteoporosis or Pagets disease, a further six cases being associated with the intravenous forms. This is dwarfed by more than 900 cases occurring in patients with cancers who were treated with intravenous bisphosphonates which are given at doses up to 12 times greater than those for osteoporosis or Pagets disease. In 2003, Marx [10] reported that there may be an association between ONJ and aminobisphosphonate use. In a recent review, 368 published cases of ONJ in relation to the use of bisphosphonates were identified although the true number of cases is much higher [3]. Novartis, at an FDA
review in 2005, reported 875 cases of jaw osteonecrosis out of 2.9 million patients treated with intravenous bisphosphonates. Six cases (4056 patients) had previously been identified in all controlled clinical trials and the first post-marketing report was made in December 2002. From the published cases, 94% are related to intravenous zoledronate and/or pamidronate for the treatment of metastatic or bony cancers [3]. Sixty percent of all cases occurred following dental procedures. Despite this, some cases occurred spontaneously and were associated with oral bisphosphonates. Alendronate was implicated in 13 cases compared to one case involving risedronate. Novartis data broadly support Woo et als summary although are restricted to oncology patients. The majority of cases had hadrecent dental surgery and most (74%) had another risk factor aside from cancer and aminobisphosphonate prior to developing ONJ. These included corticosteroids, chemotherapy, radiotherapy, hormonal treatments, anaemia, thalidomide and previous organ transplant. Novartis has already circulated memoranda to all doctors in the US in 2005 advising on the risk of ONJ in patients about to start zoledronate or pamidronate infusions and who have cancer or other risk factors. They have changed the medication information leaflet to reflect this risk. They recommend that patients about to commence such treatment for bone cancers should be considered to have a dental examination with appropriate preventive dentistry and, once commenced, should avoid invasive dental procedures. Woo et al. recommended in their review that all patients (including those with osteoporosis) prior to starting aminobisphosphonate treatment (alendronate and risedronate included) should have oral infections actively treated; should have routine restorative care of carious teeth and should have invasive procedures for nonsalvageable teeth. In addition, biannual oral examinations with dental cleaning should be performed. Both of these recommendations would appear heavy handed when applied to patients about to start bisphosphonate treatment for osteoporosis and Pagets disease. Grey and Cundy [11] highlighted the distinction between patients with cancer who receive much higher bisphosphonate doses and have multiple other risk factors for ONJ (chemotherapy, radiotherapy, poor nutrition) and those with osteoporosis. They emphasized that the
195
recommended approach runs the risk of denying potentially beneficial treatments for patients with osteoporosis and Pagets disease with poor dentition as well as potentially beneficial dental surgery for those patients already on treatment [11, 12]. More recent advice from the American Dental Association concerning patients who are about to start an oral bisphosphonate are perhaps more appropriate [9]. This report recommends that the benefits of treatment should be emphasized but the patient should also be informed of the very low risk of ONJ. A screen for oral risk factors should be performed (e.g. poor dental hygiene, oral infection, recent and proposed dental surgery). A risk-benefit analysis should then be performed for each patient. Should there be significant doubt, then a referral to an appropriate dental professional might be considered and alternative treatments, including bisphosphonate therapy with the non-amino category of bisphosphonates, can be considered. What advice should be given to non-cancer patients already taking bisphosphonates? It is important that patients who are at high risk, especially those who are to undertake dental surgery whilst on therapy, should be made aware of the risk of ONJ. Following this there is uncertainty and little guidance exists. The American Dental Associations advice is still pertinent to this group of patients. Vigilance, education and good oral care with the avoidance of unnecessary dental surgery would be appropriate take-home messages. ONJ is the latest in a number of new side effects associated with bisphosphonates. Nephrotic syndrome, renal insufficiency and ophthalmic inflammation have also been described as well as the well-recognized upper gastrointestinal symptoms, hypocalcaemia and the myalgic self-limiting illness that occurs around the time of intravenous administration [13]. Further areas for discussion include the role of a drug holiday. Does the ONJ-bisphosphonate association affect the risk-benefit analysis when considering the implementation of a drug holiday? There is animal evidence to suggest that micro fractures increase and may accumulate as a result of the hypodynamicity of the bone caused by bisphosphonates [14]. This is controversial, however, and not generally accepted at this point. The delayed development of ONJ adds further evidence to the suggestion that continued
bisphosphonate administration may be harmful. More work is needed to see if ONJ incidence peaks at any one time, or the medians quoted above are artefactual due to patient factors. Studying populations longitudinally over many years will provide the answer to this question. With respect to a bisphosphonate holiday, the major benefit in terms of fracture risk reduction occurs in the first year following treatment and then tails off, although it is clear that fractures remain at a lower level for at least 5 yrs since starting treatment with alendronate. Interestingly this reduction is maintained for the following 5 yrs when the alendronate is stopped, although bone turnover markers and BMD are seen to drop when compared with patients who continue to take the alendronate [15]. Bone mineral density is preserved 1 yr after stopping chronic alendronate use before then diminishing in subsequent years. Presumably BMD may be preserved for longer in patients exposed to the bisphosphonates with longer half-lives such as zoledronic acid. The benefits and risks of a bisphosphonate holiday will continue to be debated and the information concerning ONJ and its relationship to these drugs will influence this. We recommend that patients about to start oral and intravenous bisphophonates should have an oral inspection by the rheumatologist, and if there are any doubts then the patient should be referred to an appropriate dental surgeon for further advice. Secondly, we recommend that patients who are already taking oral bisphosphonates should not stop these when they go for dental surgery as the risk of ONJ is very small and the half-life of the bisphosphonates long. Thirdly, we recommend that in patients who are already having intravenous bisphosphonates and who have planned dental surgery, the administration of the bisphosphonates should be delayed until after healing has been completed. In conclusion, ONJ has been linked with highdose intravenous bisphosphonate use in patients with bony cancers and the observation has been extended at a much lower incidence to patients on oral bisphosphonates taken for rheumatological conditions. The benefit-risk ratio is still heavily weighted towards therapy but rheumatologists need to be aware of this link. The risk is greatest in those with poor oral health who are undergoing dental urgery.
196
If there is doubt, then a review by an experienced oral surgeon is appropriate. Finally, given the paucity of NHS dentists in the UK, there is a role for a wider debate on the links between
rheumatology and oral surgeons in the management of this potentially disabling, costly and increasingly common problem.
REFERENCES
1. Badros A, Weikel D, Salama A et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 2006;24:94552. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonateinduced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63:156775. Woo SB, Hellstein JW, Kalmar J. Systematic review: bisphosphonates and osteonecrosis of the jaw. Ann Intern Med 2006;144:75361. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:52734. Capsoni F, Longhi M, Weinstein R. Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologists role. Arth Res Ther 2006;8:219. Kavanagh KL, Guo K, Dunford JE et al. The molecular mechanism of nitrogencontaining bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci 2006;13:782934. Ross JR, Saunders Y, Edmonds PM, Patel S, Broadley KE, Johnston SRD. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. Br Med J 2003;327:46972. 8. Silverman SL, Maricic M. Recent developments in bisphosphonates therapy. Semin Arthritis Rheum 2007;36:34145. 1050 Editorial American Dental Association Council on Scientific Affairs. Expert panel recommendations: dental management of patients receiving oral bisphosphonate therapy. J Am Dental Assoc 2006;137:114450. Marx RE. Pamidronate (Aredia) and zoledronic acid (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:111517. Grey A, Cundy T. Letter: bisphosphonates and osteonecrosis of the jaw. Ann Intern Med 2006;145:791. Bilezikian JP. Osteonecrosis of the jaw do bisphosphonates pose a risk? New Engl J Med 2006;355:227881. Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol 2006;17:897907. Mashiba T, Mori S, Burr DB et al. The effects of suppressed bone remodelling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab 2005;23(Suppl):3642. Black DM, Schwartz AV, Ensrud KE et al. Effects of continuing or stopping alendronate after 5 years of treatment: the fracture intervention trial long-term extension (FLEX): a randomized trial. JAMA 2006;296:292738. (Articol publicat n parteneriat cu Rheumatology 2007;46:563564)
2.
9.
10.
3.
11. 12. 13.
4.
5.
14.
6.
7.
15.
n actualitate Artrita lui Gaudi Antoni Gaudi I Cornet, arhitectul catalan i unul dintre cei mai importani artiti vizuali ai secolelor 19 i 20, suferea de un sindrom articular recurrent i adesea persistent, nc de la vrsta de 6 ani. Diagnosticul su era incert, dar cel mai probabil fusese vorba de artrit juvenil idiopatic. Artistul a suportat bine boala de-a lungul vieii sale i se crede chiar c l-ar fi avantajat sub aspectul a dou dintre marile sale caliti: capacitatea de observare i analiza naturii.
Sursa: Azevedo VF, Diaz-Torne C, The arthritis of Antoni Gaudi, J Clin Rheumatol, 2008, 14: 367-369
VERY EARLY RHEUMATOID ARTHRITIS COHORTS: LIMITED BY SELECTION

Murat Inanc Istanbul University, Istanbul Medical Faculty, Department of Internal Medicine, Division of Rheumatology, Istanbul, Turkey
The heterogeneous course and prognosis of early arthritis (EA) patients continues to be a major challenge for clinicians involved in the management of these patients. A variable proportion of EA patients can be classified under rheumatoid arthritis (RA) or another disease (e.g. spondylarthritis and lupus) during the follow-up, while others remain undifferentiated or resolve spontaneously. In cohort studies of EA, the cumulative prevalence of RA varied significantly and was reported between 7 and 42%, which indicates that selection factors may influence the outcome of such cohorts [1]. Identifying EA patients at risk for developing persistent and/or erosive arthritis is mandatory for selecting a treatment strategy according to the current early aggressive treatment approach [2]. It has been widely discussed that the current ACR 1987 classification criteria for RA is not an appropriate tool for treatment purposes in the very early phase of the disease mainly because of low sensitivity and lack of exclusions [3]. Instead of classifying a subset of disease with an already proven persistent and destructive nature, a need for a criteria to guide clinicians about selecting treatment strategies in very early patients is apparent [3]. Propensity of arthritis to become persistent and/ or destructive would be the focus of these efforts [2, 4]. Recently,an The European League Against Rheumatism (EULAR) expert panel formed a set of recommendations based on evidence-based literature review, including the early referral of patients with arthritis within 6 weeks and the early start of disease-modifying anti-rheumatic drugs (DMARDs), mainly methotrexate, in patients at risk of developing persistent and/or erosive arthritis [4]. In this issue of Rheumatology, Machold et al. [5] report the outcome of patients classified as RA
during the follow-up from Austrian Early Arthritis Action, which included patients with arthritis of no longer than 12 weeks. They included 314 patients into the cohort in 5 yrs starting from 1996, and among the regular 229 patients they identified 138 cases of RA. More than half of this cohort was lost to follow-up. They present here the radiological outcome of 55 patients who completed 3 yrs of follow-up. Clinical and serological variables that were collected from this very early stage as predictive factors of erosive disease were analysed. This cohort has many patients lost to follow-up and the analysis is restricted only to the remaining patients with follow-up data, which limits the validation of the results. Nevertheless, from the data of the remaining patients, their findings and conclusions might have important implications for practising rheumatologists and researchers. For this report, their specific aims were to determine: (i) the frequency of erosive arthritis among patients followed up from a very early stage to the end of early stage, (ii) the features of patients who did and did not develop radiological erosions, (iii) the pace of erosive changes during the 3 yr period and (iv) prognostic factors for the development of erosive disease. Their results showed that almost two-thirds of the patients developed erosive disease in 3 yrs despite being followed up by a specialized arthritis clinic. In almost half of the patients erosions became manifest in the first year of the disease. In a real-life-like situation (treatment was not predefined), most patients started DMARD monotherapy (87%) at median 19 weeks from the onset of the symptom. During the observation period,
197
198
many patients had switched to other DMARDs. Most of the patients used steroids, and continuous use was more frequent in erosive patients. Owing to the avaliability, tumour necrosis factor (TNF)blockers started in only 11% of the erosive patients. In this patient group, none of the baseline clinical parameters and acute-phase responses could identify patients who developed erosions, but 91% of patients with rheumatoid factor (RF) positivity and 96% of patients with anti-cyclic citrullinated peptide (anti-CCP) positivity ended up with erosive disease. The authors pointed out that based on a regression model >60% of radiological progression can be explained by RF, anti-CCP, c-reactive protein (CRP), cumulative swolen joint count and total time in low disease activity/remission. On the other hand, onefourth of the patients who developed erosive disease did not have any positive serology. Strikingly for the core set parameters, the difference between the erosive and non-erosive groups became apparent only during the second or third year. Long-standing clinical (DAS28) remission as an ultimate target was reached in only 29% of the patients who were either in the non-erosive group (69%) or who had initial erosions without progression (31%). The study by Machold et al. [5], tried to answer very important questions but also raised important issues to be discussed.
from one data set to another is recommended to test the generalizability of the data [7]. It is crucial to develop methods to keep the patients in the cohorts, to understand the reasons of subject loss and finally to describe the characteristics of those lost to follow-ups to avoid left/right censorship bias.
USE OF RA CLASSIFICATION CRITERIA IN EA COHORTS

Machold et al. [5] have chosen the term very recent onset RA for their title (instead of VERA) to clearly differentiate their patients from undifferentiated EA. Their key words and running title include VERA, which reflect the difficulty in the terminology. Sixty percent of their EA cohort (with follow-up data, 138 out of 229 patients) consisted of patients fulfilling ACR criteria for RA during the follow-up. The prevalence of RA is one of the highest among similar cohorts, and possibly reflects the effect of their entry criteria plus the longer and regular follow-ups with retaining severe patients [1]. Although the general consensus is <3 months of the symptoms for a the window of opportunity in early rheumatoid arthritis (ERA), most of the patients do not meet the ACR criteria in this period. If the criteria is not applied cumulatively, patients might fulfill the criteria temporarily during the course of the disease and some patients satisfy the requirements as late as 5 yrs [8]. The literature on ERA is more difficult, and trials include patients with 624 (up to 5 yrs) months of symptom duration [9]. Fulfilling the ACR criteria seems to be a function of time and does not help in predicting patients with persistent and/or erosive arthritis [10, 11]. It should be considered that patients fulfilling ACR criteria with different combinations of individiual cirterion at some point may represent a heterogeneous patient population with different course and outcome.
THE EFFECT OF PATIENT RECRUITMENT AND LOST-TO FOLLOW-UPS IN EA COHORT STUDIES

The rationale for cohort studies of EA are wellestablished, and the information gained from these studies on the outcome of these patients is an essential part of our current understanding of RA [6]. However, despite all efforts, fulfilling the reporting requirements for longitudinal studies is difficult [7]. In some of these observational studies, such as the present one [5], treatment before and after the entry to the cohort is not standardized and the assessment of the effect of treatment on the outcome is limited and uncontrolled. The difficulty of keeping the patients in the cohorts is increasing with the longer follow-ups. The statistical analysis of data from observational cohorts needs a multivariate approach considering the use of all relevant data and decreasing number of patients with time. Ideally, methods appropriate for longitudinal analysis should be used, and the validation of results
ANTI-CCP TEST IN GUIDING THE MANAGEMENT OF ERA

A recent systematic review revealed that antiCCP antibody positivity with a second-generation test is a more specific marker for the diagnosis of RA than RF with comparable sensitivity [12]. A combined analysis of publications concerning more than 2000 patients with early undifferentiated arthritis showed a prevalance of 23% for anti-CCP2
199
antibodies. The prevalence increased to 51% in more than 1000 patients who fulfilled RA classification criteria after a median follow-up of 18 months. The mean odds ratio was reported to be 25 (confidence interval, 1835) for the development of RA [12]. It was previously reported that the clinical presentation of anti-CCP-positive and anti-CCP-negative patients were similar, but the anti-CCP-positive patients had more severe radiological destruction during the disease course [13]. The study by Machold et al. [5] also confirms the importance of baseline anti-CCP2 serology in ERA and they reported stable titres during the follow-up. There is a possibility of bias that patients retained in this cohort were selected by their antiCCP status because of the close association with severe disease. In a study of consecutive patients, in which they showed the importance of the antiCCP test in predicting radiological and functional outcome, Quinn et al. [14] found a sensitivity of 60% for anti-CCP antibodies in RF-negative RA. In our multicentre study designed to compare antiCCP status in patients with RF-positive and RFnegative RA, we found that only 20% of our patients were anti-CCP2-positive among established RFnegative RA patients [15]. If positive, the anti-CCP test is an important surrogate marker for especially RF-negative RA and predictive of radiological progression [14, 15]. Additionally, accumulating data indicate that there is a clear difference in genetic background between anti-CCP-positive and anti-CCP-negative patients with RA, and the presence of these autoantibodies is associated with shared epitope exclusively [16]. Cytokine profiles of anti-CCP-positive EA patients anti-CCP-negative patients also showed significant differences [17]. On the other hand, several studies including ours [15] confirmed the existence of seronegative (both for RF and anti-CCP) patients who developed erosive disease.
third year. On the contrary, it was previously reported that first erosions may develop after 2 yrs or even longer from the disease onset [18]. It should be noted that several different types of radiological progression have been reported including linear or non-linear developments (reviewed in [6]). The relationship between treatment choices and radiological damage in EA is complex, and TNF antagonists might have important influence on the development of these lesions. We do not know how the advent of imaging techniques and the use of MRI and ultrasonography will effect future data. Early aggressive treatment is expected to improve radiological outcome in EA cohorts at least in patients who could be identified as pro-erosive.
CONCLUSION
Austrian Early Arthritis Action is one of the important efforts that aims to form an inception cohort of EA patients to investigate the long-term outcomes and predictive factors for bad prognosis of these patients. These observational studies have been productive and have resolved many issues in EA. It is important to understand that EA cohort studies have limitations in terms of recruiting target population, retaining patients in the study, data collection and analysing treatment effects. These limitations may be different among countries and health systems, which makes extrapolations of data difficult, and hence should be studied further. The emerging concept of anti- CCP-positive patients as a distinct patient population with some similarities to other EA patients, but poor outcomes and different pathogenesis may improve clinical management of those. On the other hand, there exist pro-erosive patients without any clinical or serological clue during the course of the disease with varying patterns of joint destruction reflecting the heterogeneity of RA patients fulfilling current classification criteria.
RADIOLOGICAL OUTCOME OF PATIENTS WITH EA

There is a significant variation in the recruitment criteria and methods for the assessment of radiological damage in EA inception cohorts, which may have an impact on the erosion risk. As with similar to the present study [5], erosions may be present in the first year, peak during the second year and increase by almost 70% at the end of the
ACKNOWLEDGEMENT
The author is grateful to Professor Alan Silman for his helpful suggestions and comments on the manuscript. The author received honoraria/ sponsorship for consultancies, scientific meetings, educational and research purposes from Abbot laboratories, Sanofi-Aventis, Schering Plough and Wyeth Laboratories.
200
REFERENCES
1. Hitchon CA, Peschken CA, Shaikh S, El-Gabalawy HS. Early undifferentiated arthritis. Rheum Dis Clin N Am 2005;31:60526. Smolen JS, Aletaha D, Machold KP. Therapeutic strategies in early rheumatoid arthritis. Best Practice & Research Clinical Rheumatology 2005;19:16377. Aletaha D, Breedveld FC, Smolen JS. The need for new classification citeria for rheumatoid arthritis. Arthritis Rheum 2005;52:33336. Combe B, Landewe R, Lukas C et al. EULAR recommendations for the management of early arthritis. Report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006 (e-pub). 186 Editorial Machold KP, Stamm TA, Nell VPK et al. Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology 2006 (in press). Symmons DP, Hazes JM, Silman AJ. Cases of early inflammatory polyarthritis should not be classified as having rheumatoid arthritis. J Rheumatol 2003;30:9024. Silman A, Symmons D. Reporting requirements for longitudinal observational studies in rheumatology. J Rheumatol 1999;26:4813. Symmons DPM, Silman AJ. Aspects of early arthritis. What determines the evolution of early undifferentiated arthritis and rheumatoid arthritis? An update from the Norfolk Arthritis Register. Arhritis Research & Therapy 2006;8:214. Sokka T, Hannnen P, Mo tto nen T. Conventional disease modifying antirheumatic drugs in early rheumatoid arthritis. Rheum Dis Clin N Am 2005;31:72944. 10. Young A. Early rheumatoid arthritis. Rheum Dis Clin N Am 2005;31:65979. 11. Visser H, le Cessie S, Vos K et al. How to diagnose rheumatoid arthritis early: a prediction model for persistant (erosive) arthritis. Arthritis Rheum 2002;46:35765. 12. Avouac J, Gossec L, Dougados M. Diagnostic and predictive value for anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis 2006; 65:84551. 13. van der Helm-van Mil AHM, Verpoort KN, Breedveld FC, Toes REM, Huizinga TWJ. Antibodies to citrullinate proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Therapy 2005;7:R94958. 14. Quinn MA, Gough AKS, Green MJ et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology 2006;45:47880. 15. Inanc N, Dalkilic E, Kamali S et al . Anti-CCP antibodies in rheumatoid arthritis and psoriatic arthritis. Clin Rheumatol 2006 (e-pub). 16. de Vries RRP, Huizinga TWJ, Toes REM. Redefining the HLA and RA association: to be or not to be anti-CCP positive. J Autoimmune 2005;25:215. 17. Hitchon CA, Alex P, Erdile LB et al. A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis. J Rheumatol 2004;31:233646. 18. Bukhari M, Harrison B, Lunt M, Scott DGI, Symmons DPM, Silman AJ. Time to first occurrence of erosions in inflammatory polyarthritis. Arthritis Rheum 2001;44:124853. (Articol publicat n parteneriat cu Rheumatology 2007;46:185187)
2.
3.
4.
5.
6.
7. 8.
9.
n actualitate Glucocorticoizii i antiinflamatoarele n atacul acute de gut Antiinflamatoarele nesteroidiene (AINS) sunt frecvent utilizate pentru sistarea atacului acut de gut. Acest studiu a fost realizat pentru a afla dac AINS, cu cunoscutele lor efecte adverse digestive, nu ar putea fi nlocuite cu glucocorticoizi n acest scop. O sut douzeci de pacieni examinai n ambulator pentru gut acut au primit 35 mg prednison n doz cotidian unic sau naproxen 2 x 500mg/zi pentru 5 zile. Nu au fost constatate diferene de evoluie a bolii ntre cele dou tratamente. Interpretarea autorilor a fost aceea c glucocorticoizii sunt alternativa terapeutic a atacului acut de gut la pacienii vrstnici cu numeroase comorbiditi.
Sursa: Gaffo AL, Saag KG, Nat Clin Pract Rheumatol 2008, ahead of print
CELECOXIB AND CVS RISKLESSONS FROM THE APC AND PRESAP STUDIES
D. J. Armstrong Department of Rheumatology, University Hospital of North Durham, North Road, Durham
Since the return of Robin Goodfellow to the land of the faeries, we mortal rheumatologists have had to scan the general medical press ourselves for items of arthritic interest. One wonders what Robin might have made of the two large trials of celecoxib for the prevention of colonic adenomatous polyps recently published in the New England Journal of Medicine [1, 2], and of the generally negative view of the accompanying editorial [3] with respect to balancing risks and benefits. If coxibs are too dangerous to use to prevent pre-malignant polyps (he might have asked), can one safely assume they are too dangerous to prescribe for sore knees? A total of over 3000 patients who had previously had at least one colorectal adenoma removed took part in the Adenoma Prevention with Celecoxib (APC) and Prevention of colorectal Sporadic Adenomatous Polyps (PreSAP) studies, designed to examine the effect of daily celecoxib use on the recurrence of polyps. In APC [1], 2035 patients were randomized to receive placebo, 400mg daily or 800mg daily of celecoxib. Thirty per cent of each group also took low dose aspirin. Colonoscopy was performed 1 yr and 3 yrs after randomization, and patients were closely monitored for serious cardiovascular complications. Recurrence of adenomata over 3 yrs was reduced from 60.7% in placebo to 43.2% and 37.5%, respectively in the two celecoxib groups, but with an odds ratio for CVS events of 2.6 (1.16.1) and 3.4 (1.57.9). As a result of interim analysis suggesting increased CVS events in the celecoxib arms, the study was discontinued early [4]. However, when patients receiving celecoxib at either dose were divided into those with established coronary or cerebrovascular disease and those without, the findings were noticeably different8.8% of patients with
established atherosclerotic disease had a CVS event compared with only 2.1% of those without. The figure of 2.1% was higher than placebo (0.7%) in the healthy group, but still lower than placebo in those with established CVS disease (3.0%). Notably, the incidence of CVS events was considerably lower than that of gastrointestinal ulceration or haemorrhageover 11% in all three groups. In the PreSAP study [2], 1738 patients were enrolled, and randomized to receive either celecoxib 400 mg daily or placebo. Aspirin use was less than in the APC project (around 17% in both groups), but endoscopic and CVS surveillance was similar. Although an interim analysis did not show any statistically significant increase in CVS events, the study was ended prematurely at the same time as the APC research. In terms of efficacy for prevention of adenoma recurrence, the results confirmed those of the previous studycumulative rate of adenoma recurrence fell from 49.2%2.2 in the placebo group to 33.7% 4.1 in the celecoxib arm, and indeed the incidence of advanced adenomas was almost halved. The picture for development of serious CVS events was also similar, but not statistically significant1.9% of the placebo group compared with 2.5% of the celecoxib arm, an odds ratio of 1.30 (0.652.62). Although it is more difficult to tease out the effect of previous CVS history within the placebo and celecoxib arms from the figures, in the groups together, the arrow was pointing in the same direction as the previous study6.1% of those with a CVS history suffered a serious CVS event, compared with 1.7% of those without. The conclusions of the editorialists are unarguable. Regular colonoscopy and removal of polyps is associated with negligible CVS risk, while
201
202
taking regular celecoxib is associated with a (small) risk. Although the studies confirm that coxibs significantly reduce the risk of polyp recurrence, patients will need regular endoscopic monitoring anyway, at which polyps will be removed, therefore, the routine use of celecoxib is not recommended. Indeed, their hypothetical riskbenefit analysis confirmed one would be better taking aspirin, which will be good for the heart as well as the bowel. What can the jobbing rheumatologist learn from this? Several points stand out. In the first instance, patients taking 800 mg of celecoxib a day had no more gastrointestinal ulcers or haemorrhages than placebo (in fact they had marginally fewer), and even those also taking aspirin had only a small and non-significant increase over placebo. In the absence of CVS worries, one imagines this would be regarded as a major finding from the studies. Secondly, for patients without IHD taking 400 mg celecoxib daily (the absolute maximum recommended dose), while the incidence of serious CVS events is greater than placebo, it is still at the 12% level (compared with over 10% who will have an ulcer or bleed). Even in patients with established IHD at entry (a group in whom most doctors would not now consider prescribing a coxib), and who received 800 mg of celecoxib daily for 3 yrs (a sustained and substantial overdose), more than 91% suffered no serious CVS side effect. Finally, many rheumatology prescriptions of celecoxib are for 200 mg daily or on a PRN basis, which the studies do not directly address. Evidence for an increased cardiovascular risk with long-term use of coxibs (and almost certainly other NSAIDs) is substantial, but these studies go some way towards properly quantifying it, and should be viewed with the perspective they deserve. Few outside the rheumatology community appre-
ciate the substantial improvements in pain control and quality of life that an effective anti-inflammatory can make in both rheumatoid and osteoarthritis, even in patients on quantities of immunosuppressive or corticosteroid therapy. Most of us have patients who still rue the withdrawal of Vioxx, which appeared almost unparalleled in efficacy. The use of NSAIDs is contra-indicated in patients with active peptic ulcer disease. Even in those in whom there is no known history, 3.5% will develop a symptomatic ulcer in the first year of taking the full dose regularly, rising to 6.0% in patients who also take aspirin [5]. We therefore ask patients specifically about ulcer disease, and may consult their past records, before considering the use of an NSAID. In exactly the same way, with a well-quantified risk, we can enquire about a patients CVS history, and involve the patient in the discussion of the risks and benefits of using a coxib. Some areas require clarification; for example, the influence of CVS risk factors (as opposed to established disease) remains open to debate, although most physicians would be reluctant to prescribe a high dose of anti-inflammatory to an obese middle-aged smoker with hypertension, even if there was not yet established disease. Nevertheless, knowledge is power, and the more knowledge we gain about COX-2 inhibitors (and we await the results of the MEDAL study into the effects of etoricoxib with interest), the better able we are to prescribe them with confidence to the correct patients. In many ways, these are remarkably safe and effective drugs, and correctly prescribed, deserve their place in the formulary for the foreseeable future. I hope Robin would agree. ... D.J.A. has received honoraria, speakers fees and unrestricted educational grants from MSD, Pfizer and Novartis.
REFERENCES
1. Bertagnoli MM, Eagle CJ, Zauber AG et al. Celecoxib for the prevention of colorectal adenomas. N Engl J Med 2006;335:87384. Arber N, Eagle CJ, Spicak J et al. Celecoxib for the prevention of adenomatous polyps. N Engl J Med 2006;355:88595. Psaty BM, Potter JD. Risks and benefits of celecoxib to prevent recurrent adenomas. N Engl J Med 2006;355:9502. 4. Soloman SD, McMurray JJ, Pfeffer MA et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:107180. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:124755. (Articol publicat n parteneriat cu Rheumatology 2007;46:561562)
2. 3.
5.
LUCRRI ORIGINALE
MODIFICAREA TEXTURII TRABECULARE LA POPULAIA FEMININ VRSTNIC, EVIDENIAT PRIN ANALIZ FRACTAL PE RADIOGRAFIA CALCANEULUI
I. tefan 1, C. Vertan 2, H.F. Jelinek 3, R. Badea 4 1 Secia Traumatologie, Spitalul Judeean de Urgen,, Baia Mare 2Laboratorul de Analiza i Prelucrarea Imaginilor, Universitatea Politehnica, Bucureti 3 School of Community Health, Charles Sturt University, Australia 4 Catedra de Imagistic Medical, Universitatea de Medicin i Farmacie Iuliu Hatieganu Cluj-Napoca
Rezumat
Textura trabecular osoas a fost studiat pe radiografii de profil a calcaneului provenind de la femei, cu scopul de a detecta modificri ale microarhitecturii osului spongios datorate vrstei avansate, raportate la perioada peri- i postmenopauz. S-au comparat dou seturi a cte 12 radiografii digitizate prin fotografiere cu o camer digital, folosindu-se analiza multifractal pe imagini binarizate i 4 dimensiuni fractale (DF) diferite, calculate pe imagini n tonuri de gri. Rezultatele au fost comparate folosindu-se analiza ROC (Receiver Operating Characteristic) prin determinarea ariei de sub curb (Area Under the Curve - AUC). S-a ncercat clasificarea radiografiilor prin algoritmuri de clasificare supervizat k-vecinii cei mai apropiai (k-nearest neighbor, k-nn). S-au gsit valori mai mici semnificativ statistic ale DF prin ambele metode, la grupul cu vrsta egal sau peste 70 ani. Analiza fractal pe imagini n tonuri de gri i analiza ROC au avut un randament mai bun n identificarea radiografiilor. Cuvinte cheie: osteoporoza senil, radiografia calcaneului, analiz fractal.
Summary Cancellous bone texture of the calcaneus in elderly women measured by fractal analysis on radigraphs
Cancellous bone texture was studied on calcaneus's radiographs from women in order to identify trabecular micro-architecture changes attributable to advanced age, compared to the peri- and postmenopausal period. Two sets of 12 X-rays, digitalized with a digital camera, were compared using multifractal analysis on binarized images and 4 different fractal dimensions (FD) computed on greyscale images. The results were subjected to ROC (Receiver Operating Characteristic) analysis, by measuring AUC (Area Under the Curve). Classification of the X-rays was attempted, using k-nn (k-nearest neighbour) supervised classification algorithms. Statistically significant lower values of FD, were found with both methods for the advanced age group. Fractal analysis applied to greyscale images and ROC analysis proved more successful in identifying the X-rays. Key words: senile osteoporosis, calcaneus's radiograph, fractal analysis.
INTRODUCERE
Rezistena osului este determinat de densitatea mineral osoas (DMO) i calitatea osului (1). n timp ce DMO este evaluat cu mare precizie i acuratee utiliznd osteodensitometria cu fascicul dual de raze X (DXA) (2), calitatea osului rmne o noiune complex, greu de cuantificat. Microarhitectura trabecular reprezint o component esenial a calitii osului spongios. Deteriorarea microarhitecturii trabeculare caracteristice vrstei avansate la femei, este rezultatul unui
proces lent, dependent de vrst, n care se produce o subiere treptat a trabeculelor osului spongios, cu meninerea ns a conectivitii intertrabeculare (3). Acest proces se suprapune i succede perioadei postmenopauz, caracterizat printr-o pierdere osoas accelerat, asociat unui turnover osos ridicat i avnd ca rezultat perforarea i apoi ntreruperea unor trabecule cu diminuarea interconectivitii trabeculare (3, 4). n acest studiu ne propunem s aflm n ce msur modificarea microarhitecturii trabeculare dup vrsta de 70 ani poate fi evideniat cu ajutorul
203
204
analizei fractale, aplicat radiografiei de profil a calcaneului. Acest tip de analiz computerizat, reprezint una dintre metodele neinvazive utilizate frecvent, n prezent pentru investigarea arhitecturii osului spongios (5). Interesul pentru acest subiect este justificat i n contextul apariiei osteoanabolicelor, al cror reprezentant, teriparatidul, stimuleaz formarea osului, crete volumul osos spongios i conectivitatea, amelioreaz morfologia trabecular, cu creterea numrului trabeculelor lamelare (6, 7), deschiznd astfel perspectiva aplicrii unor medicaii cu impact direct asupra microarhitecturii osoase.
Figura 2. ROI 0 binarizat
MATERIAL I METODE
Studiul s-a efectuat pe dou seturi a cte 12 radiografii de profil ale calcaneului, primul provenind de la femei cu vrsta ntre 50 i 55 ani (vrsta medie = 53 ani, DS = 1,6 ani) iar al doilea, de la femei cu vrsta mai mare sau egal cu 70 ani (vrsta medie = 77 ani, DS = 6,2 ani). Radiografiile au fost digitizate prin fotografiere cu o camer 2.0 Mpixel Fuji FinePix 2600 Zoom, apoi transformate n imagini n tonuri de gri. Pe fiecare radiografie au fost selectate 3 regiuni de interes (Region of Interest = ROI) de 150/150 pixeli: ROI 0 suprapus regiunii talamice, ROI 1, triunghiului lui Ward i ROI 2, interseciei grupurilor de trabecule plantar posterior i talamic (figura 1). Imaginile obinute au fost prelucrate i analizate urmndu-se doua protocoale.
http://www.csu.edu.au/faculty/sciagr/eis/fractop/). S-a calculat dimensiunea generalizat D(q) pentru valori ntregi ale lui q de la -5 la +5. Deoarece D(q) nu e definit pentru q = 1, pentru fiecare imagine sa obinut un set de 10 parametrii, a cror reprezentare grafic este spectrul multifractal (figura 3). Valorile corespunztoare D(q), pentru cele dou seturi diferite de radiografii, au fost comparate statistic utilizndu-se analiza ROC (Receiver Operating Characteristic) prin determinarea ariei de sub curb (Area Under the Curve = AUC). Prin aceast metod s-au determinat gradul de semnificaie P, sensibilitatea i specificitatea metodei de investigaie.
Figura 3. Spectru multifractal
Figura 1. Dispunerea celor 3 ROI.
Protocolul I. Imaginile n tonuri de gri au fost binarizate (figura 2), folosind un procedeu de segmentare dinamic ( software : ImageJ - www. gcsca.net/IJ/Dynamic.html) apoi au fost supuse analizei multifractale bazat pe metoda numrrii cutiilor (box-counting) (software: FracTop v0.3b -
Aceleai valori D(q) au fost utilizate pentru a clasifica radiografiile ntr-unul din cele 2 grupuri. Pentru aceasta s-a utilizat algoritmul de clasificare supervizat k-vecini cei mai apropiai (k-nearest neighbor - k-nn), pentru k=1 i k=3, cu determinarea numrului de clasificri eronate la cross-validare prin metoda Leave-One-Out (8). Protocolul II. Imaginile in tonuri de gri au fost analizate direct cu ajutorul unui software Gwyddion (http://gwyddion.net/), fr a mai fi necesar
205
segmentarea lor. Acesta permite calcularea a patru tipuri diferite de dimensiuni fractale (DF): prin metodele cube- counting (FDCC), triangulaiei (FDT), varianei (FDV) i power spectrum (FDPS). Aceste rezultate au fost de asemenea comparate cu ajutorul analizei ROC i folosite pentru ncercarea de clasificare a radiografiilor, cu ajutorul algoritmului k-nn.
REZULTATE
Analiznd rezultatelor obinute urmndu-se protocolul I, am gsit diferene semnificative ntre valorile D(q), pentru q = 0,2,3,4,5 i ROI 0 (tabelul 1). Acurateea unui test diagnostic prin msurarea AUC, este excelent pentru AUC = 0.9-1, bun pentru AUC = 0.8-0.9, acceptabil pentru AUC = 0.7-0.8, slab pentru AUC = 0.6-0.7, eec pentru AUC = 0.5-0.6.
Tabelul 1 Rezultatele analizei ROC pentru valorile D(q), pentru q = 0,2,3,4,5 i ROI 0
Clasificarea 1-nn pentru aceleai valori D(q) calculate pe ROI 0, a identificat un numar minim de 8 clasificri eronate, avnd o sensibilitate de 75% i specificitate de 58,33%.
Analiza rezultatelor obinute n urma protocolului II, a evideniat diferene semnificative statistic ntre valori DF, conform tabelului 2.
Tabelul 2. Rezultatele analizei ROC, pentru DF i ROI la care s-au gsit diferene semnificative statistic
Clasificarea 3- nn n care fiecare radiografie a fost caracterizat prin trei parametrii, FDPS calculat pe ROI 0, FDV i FDT calculai pe ROI 1, a identificat un numar minim de 7 clasificri eronate, avnd o sensibilitate de 75% i specificitate de 66,67%.
DISCUII
Vrsta a fost identificat ca cel mai bun predictor clinic al fracturilor oldului la femei postmenopauz (9). Dup vrsta de 70 de ani la femei, incidena fracturilor oldului crete exponenial (10). Tot dup aceast vrsta se poate constata prezena osteoporozei senile. Aceasta e caracterizat printro pierdere proporional de os cortical i spongios. Implic o proporie important din populaia feminin i ntr-o mai mic msur populaia masculin i e asociat cu producerea fracturilor oldului i corpilor vertebrali.
Constatarea fcut de Resnick i Greenspan (11), care subliniaz discrepana ntre consecinele devastatoare ale osteoporozei senile i efortul de cercetare, concentrat cu precdere asupra osteoporozei peri- i postmenopauz, rmne valabil i astzi. Exist puine studii dedicate investigrii modificrilor microarhitecturii osului spongios n cadrul osteoporozei senile sau la o vrst avansat. Dintre acestea, majoritatea se bazeaz pe analiza unor piese bioptice (12, 13, 14, 15). Metodele de investigaie ale unora dintre aceste studii, se bazeaz pe tehnici sofisticate, precum achiziii de micro-tomografie computerizat urmate de reconstrucie tridimensional (13) sau microradiografie (15), rezervate deocamdat cercetrii. n comparaie cu aceast abordare, analiza computerizat a texturii osului spongios pe radiografii reprezint o alternativ creia i se recunosc cteva avantaje. Metoda nu este invaziv. Obiectul investigaiei l reprezint radiografii
206
obinute n cursul activitii obinuite n ambulator. Digitalizarea este efectuat prin fotografiere cu o camer digital uzual, iar analiza digital se poate face pe un calculator personal folosind programe libere (gratuite). Metoda are un potenial intrinsec de mbuntire, prin utilizarea unor metode mai elaborate de digitizare a filmului radiografic (16) sau prin utilizarea direct a unor radiografii digitale. Dimensiunea fractal a fost frecvent utilizat pentru a caracteriza i clasifica imagini i texturi. Ea reprezint o msur a complexitii i neregularitii unei texturi sau a rugozitii (roughness) unei suprafee (17).
Figura 4. Reprezentarea tridimensional a unei ROI 0.
Reprezentarea tridimensional a texturii trabeculare (figura 4), aa cum apare pe radiografia calcaneului, e similar cu reprezentarea reliefului terestru prin modele de elevaie digital. Ambele suprafee rezultate au fcut obiectul a numeroase studii n care s-a folosit analiza fractal. Rugozitatea acestor suprafee si premiza autosimilaritii la diferite scale, le pun n poziia de candidate ideale pentru acest tip de analiz. Aplicnd protocolul I, am putut diferenia cele 2 grupuri de radiografii prin valorile rezultate din analiza ROI 0, corespunznd regiunii talamice. Valorile D(q), pentru q>0, la care diferena a fost semnificativ statistic (p<0,05), reflect contribuia subregiunilor din ROI cu textur mai dens (18). Acurateea metodei n a identifica radiografiile a fost acceptabil (AUC n intervalul 0.7-0.8). Numrul minim de rezultate fals pozitive i negative (sensibilitate = 83.33%, specificitate = 66.67%) s-a gsit pentru valorile D(q=0). D(q) pentru cazul
particular q=0, este denumit dimensiunea capacitii i este egal cu dimensiunea fractal box-counting . Aplicarea protocolului II a produs rezultate semnificativ diferite statistic (p<0,05), avnd ca surs toate cele 3 ROI studiate. Acurateea de identificare a radiografiilor a fost bun (AUC n intervalul 0.8-0.9) pentru valorile FDPS provenite de la ROI 0 i acceptabil pentru valorile FDV i FDT provenite de la ROI 1 i FDV de la ROI 2. Numrul minim de rezultate fals pozitive i negative (sensibilitate = 83.33%, specificitate = 75%) s-a gsit pentru valorile FDPS provenite de la ROI 0 i FDV provenite de la ROI 1. Randamentul mai bun al protocolului II n identificarea corect a radiografiilor poate fi explicat prin faptul c programul menionat (Gwyddion) calculeaz cele patru dimensiuni fractale direct pe imagini n tonuri de gri. Se evit astfel procedeul de binarizare, care ar conduce la o pierdere de informaie. Pentru toate situaiile mentionate mai sus, n care compararea valorilor DF a evideniat diferene semnificative statistic, media valorilor pentru grupul cu vrsta mai mare sau egal cu 70 ani a fost mai mic dect la grupul cu vrsta ntre 50 i 55 ani. De aici se poate deduce c textura trabecular pe radiografia calcaneului, dup vrsta de 70 ani prezint o complexitate i neregularitate mai mic dect cea din perioada peri- si postmenopauz. Aplicarea algoritmului de clasificare predictiv k-nn, a condus la un numr mai mare de erori de clasificare dect cele obinute prin analiza ROC prin determinarea AUC, neconfirmnd ipoteza c prin caracterizarea unei imagini prin mai muli parametrii s-ar putea obine mai puine erori de clasificare. Rmne de dovedit dac metodele descrise unt suficient de sensibile pentru a evidenia modificri de tipar trabecular la femei cu sau fr fracturi pe os osteoporotic, dup vrsta de 70 ani sau modificri induse prin aplicarea unui tratament antirezorbtiv osos sau osteoanabolizant. Apreciem ca relativ mic numrul de cazuri luate n studiu, dar suficient pentru a susine concluziile formulate. Poziionarea manual a ROI, poate influena rezultatele obinute. ntr-un studiu anterior, am constatat ns robusteea clasificrii, la modificri ale poziiei ROI, cu pn la 25% din dimensiunea acestora (19). Pentru a minimaliza efectul pertur-
207
bator al alegerii ROI, poziionarea acestora s-a efectuat de ctre acelai autor. Poziionarea automat a ROI pe suprafaa calcaneului, realizabil cu ajutorul unui software, ar putea nltura inconvenientele seleciei manuale.
CONCLUZII
1. Analiza fractal poate evidenia modificri ale texturii trabeculare, pe radiografia calcaneului, la femei cu vrsta egal sau mai mare de 70 ani. 2. Valorile medii ale DF au fost mai mici pentru grupul cu vrsta egal sau mai mare de 70 ani. 3. Acurateea maxim n identificarea apartenenei radiografiilor la unul din grupurile studiate
corespunde unei sensibiliti de 83,33% i unei specificiti de 75%. 4. Dimensiunile fractale calculate direct pe imagini n tonuri de gri i analiza ROC confer o acuratee mai mare dect analiza multifractal efectuat pe imagini binarizate, respectiv algoritmii de clasificare supervizat, n identificarea corect a radiografiilor. 5. Este important s se studieze textura trabecular pe radiografia calcaneului pe mai multe ROI, atta timp ct nu a putut fi identificat o ROI ideal. 6. Metodele utilizate n acest studiu, nu necesit o tehnic sofisticat i sunt reproductibile n toate etapele.
BIBLIOGRAFIE
Seeman E, Delmas PD, Bone Quality, The material and structural basis of bone strength and fragility, N Engl J Med, 2006, 354: 22502261 2. Boloiu CR, Densitometria osoas cu fascicul dual de raze X: Standardul de aur in evaluarea osteoporozei. Aspecte tehnice, Clujul Medica l, 2004, 4: 668-675 3. Rubin R, Strayer DS, Rubin E, McDonald JM, Rubin's pathology: Clinicopathologic Foundations of Medicine, Ediia a 5-a, Lippincott Williams & Wilkins, 2007 4. Riggs BL, Overview of osteoporosis, West J Med, 1991, 154: 6377 5. Link TM, Majumdar S, Current diagnostic techniques in the evaluation of bone architecture, Curr Osteop Rep, 2004, 2: 47-52 6. Jiang Y, Zhao JJ, Mitlak BH etc, Recombinant human parathyroid hormone (31-34) (teriparatide) improves both cortical and cancellous bone structure, J Bone Miner Res 2003, 18:1932-1941 7. Manuele S, Sorbello L, Puglisi N etc, The teriparatide in the treatment of severe senile osteoporosis, Arch Gerontol Geriatr 2007, 44 Suppl 1: 249-58 8. Elisseeff A, Pontil M, Evgeniou T, Leave-one-out error, stability, and generalization of voting combination of classifiers, Mach Learn, 2004, 55: 71-97 9. Robbins J, Aragaki AK, Kooperberg C etc, Factors associated with 5-year risk of hip fracture in postmenopausal women, JAMA 2007, 298: 2389-2398 10. Cooper C, Melton LJ, Epidemiology of osteoporosis, Trends Endocrinol Metab 1992, 3: 224-229 1. 11. 12. Resnick NM, Greenspan SL, 'Senile' osteoporosis reconsidered, JAMA 1989, 261:1025-1029 Chappard D, Alexandre C, Riffat G, Spatial distribution of trabeculae in iliac bone from 145 osteoporotic females, Acta Anat 1988, 132:137-142 Ding M, Hvid I, Quantification of age-related changes in the structure model type and trabecular thickness of human tibial cancellous bone, Bone 2000, 26: 291 - 295 Rupprecht M, Pogoda P, Mumme M etc, Bone microarchitecture of the calcaneus and its changes in aging: A histomorphometric analysis of 60 human specimens, J Orthop Res, 2006, 24: 664-74 Jakubas-Przewlocka J, Sawicki A, Przewlocki P, Assessment of trabecular bone structure in postmenopausal and senile osteoporosis in women by image analysis, Scand J Rheumatol 2003, 32: 295-299 Florea C, Vertan C, Florea L, Logarithmic model-based dynamic range enhancement of hip X-ray images, in Blanc-Talon Jet al, "LNCS vol. 4678", Springer Verlag, Berlin Heidelberg, 2007: 587-596 Sandau K, Kurz H, Measuring fractal dimension and complexity an alternative approach with an application, J Microsc 1997, 186:164-176 Bissonette JA, Wildlife and Landscape Ecology: Effects of Pattern and Scale, Springer-Verlag, New York, 1997 Vertan C, tefan I, Florea L, Detection of postmenopausal alteration of bone structure in digitized Xrays, in Kropatsch W.G., Kampel M., Hanbury A.,"LNCS, vol. 4673", Springer Verlag, Berlin Heidelberg, 2007: 278-284
13.
14.
15.
16.
17.
18. 19.
LUCRRI ORIGINALE
INFLUENA TRATAMENTULUI CU LEFLUNOMID I METOTREXAT ASUPRA UNOR PARAMETRI DE STRES OXIDATIV LA PACIENI CU POLIARTRIT REUMATOID
Carolina Negrei (1), D. Bllu (1), Andra Blnescu (2), Mihaela Ilie (1), Denisa Margin (3), Daniela Baconi (1), Denisa Predeeanu (2), Violeta Bojinc (2), F. Berghea (2), Daniela Opri (2), Ruxandra Ionescu (2) (1) Disciplina de Toxicologie, Facultatea de Farmacie, (2) Centrul de Cercetare n Patogenia i Tratamentul Bolilor Reumatice, Spitalul Clinic Sfnta Maria (3) Disciplina de Biochimie, Facultatea de Farmacie, Universitatea de Medicin i Farmacie Carol Davila, Bucureti
Rezumat
Premise: Cercetrile recente au evideniat faptul c bolile inflamatorii articulare, n special poliartrita reumatoid (PR), sunt asociate cu o producie n exces a speciilor reactive de oxigen (ROS). Scopul prezentului studiu a fost evaluarea unor parametri de stres oxidativ (activitatea glucozo-6-fosfat-dehidrogenazei eritrocitare - G6PDH, susceptibilitatea eritrocitar la peroxidare lipidic - ESP) la pacieni cu PR tratai cu leflunomid (LF) sau metotrexat (MTX), comparativ cu un grup de control (voluntari sntoi). Materiale i metode: Studiul clinic a inclus 37 de pacieni cu PR, diagnosticai conform criteriilor revizuite din 1987 ale Colegiului American de Reumatologie. Nousprezece dintre acetia se aflau sub tratament cu LF i 18 cu MTX. Niciunul nu au primit corticosteroizi sau antagoniti de TNF-?. Conform evalurii clinice bazat pe scorul DAS28, toi pacienii aveau boal activ (DAS28 > 5.1). Grupul de control a fost format din 19 voluntari sntoi. Din probele de snge venos recoltate jeun au fost separate eritrocitele, care au fost utilizate pentru determinarea activitii G6PDH i ESP, prin determinarea nivelului de malondialdehid eritrocitar. Rezultate: Activitatea G6PDH a fost semnificativ sczut la pacienii cu PR tratai cu LF comparativ cu grupul de control (38.678.99 UI vs. 25.7513.87 UI, p=0.01); ESP a fost semnificativ mai mare la pacienii cu PR comparativ cu grupul de control (495.25116.92 mM MDA/g Hb n cazul pacienilor tratai cu LF, respectiv 454.26157.84 mM MDA/g Hb pentru pacienii tratai cu MTX vs. 443.454.38 mM MDA/g Hb pentru grupul de control, p=0.01). Concluzii: Mecanismele patogenice implicate n evoluia PR presupun dereglarea mecanismelor antioxidante endogene de la nivel eritrocitar (G6PDH, susceptibilitatea membranar la peroxidare). Calculele statistice au evideniat faptul c, la pacienii diagnosticai cu PR i tratai cu LF sau MTX, activitatea G6PDH este redus iar susceptibilitatea membranei eritrocitare la peroxidare este crescut comparativ de grupul de control. Cuvinte-cheie: poliartrit reumatoid, stres oxidativ, leflunomid, metotrexat
Summary Oxidative stress in patients with rheumatoid arthritis treated with either leflunomide and methotrexate
Background: Reactive oxygen species that are produced in inflamed joints can cause the impairment of the antioxidant defense systems and increase the oxidative stress in rheumatoid arthritis (RA). The aim of the study was to evaluate some redox stress parameters (erythrocyte activity of glucose-6-dehydrogenase - G6PDH, susceptibility of erythrocytes to lipid peroxidation - ESP) in leflunomide (LF) or methotrexate (MTX) treated RA patients (pts.) compared to healthy controls. Methods: The study included 37 RA patients (pts) diagnosed according to the 1987 revised criteria of the American College of Rheumatology, 19 treated with LF and 18 with MTX. None of them received corticosteroids or TNF-? antagonists. Based on the clinical evaluation using DAS28, all pts had active disease (DAS28>5.1). The control group included 19 healthy subjects. G6PDH and ESP were assessed on red blood cells separated from venous blood samples (evaluated spectrophotometrically as G6PDH activity and malondialdehyde concentration, respectively). Results: G6PDH was significantly lower in RA pts (38.678.99UI vs. 25.7513.87UI, p=0.01. ESP was higher at RA pts compared to controls (495.25116.92 mM MDA/g Hb - LF, 454.26157.84 mM MDA/g Hb - MTX vs. 443.454.38 mM MDA/g Hb - control group, p=0.01). Conclusions: Pathogenic mechanisms involved in RA are likely to produce the impairment of the endogen antioxydative systems (decrease of the G6PDH activity, membrane antioxydative defense). RA pts treated with LF or MTX exhibit an increased redox stress. Key words: rheumatoid arthritis, oxidative stress, leflunomide, methotrexate
Abrevieri: PR=poliartrita reumatoid, NADP+ = nicotinamid fosfat, PBS = tampon fosfat salin, PBMC = celule mononucleare provenite din snge periferic, G6PDH = glucozo-6-fosfat dehidrogenaza, ESP = susceptibilitatea eritrocitelor la peroxidare, MDA = malondialdehida
208
209
INTRODUCERE
PR este o boal inflamatorie sistemic cronic, cu etiologie necunoscut i patogenie autoimun, caracterizat printr-o artropatie cu evoluie cronic, progresiv, deformant, distructiv i manifestri sistemice multiple (1). Literatura de specialitate menioneaz faptul c modificrile de tip oxidativ determinate de dezechilibrul ntre producerea speciilor reactive ale oxigenului n organismele vii si activitatea sistemelor antioxidante endogene sunt asociate cu numeroase stri patologice cum ar fi: ateroscleroza, diabetul zaharat, maladiile neurodegenerative, dar i cu bolile reumatice i cele autoimune, cum ar fi poliartrita reumatoid sau lupusul eritematos sistemic [2]. Este cunoscut faptul c numeroase dintre perturbrile celulare care stau la baza acestor stri patologice sunt determinate de formarea unor produi de peroxidare lipidic, proteic sau ai ADN. Astfel, produii de peroxidare lipidic (printre care 4-hidroxi-nonenalul i malondialdehida) sunt foarte reactivi fa de proteine, cu care formeaz o gam larg de aduci inter- i intramoleculari. Acesi aduci pot activa rspunsul imun al celulelor B si T, inducnd astfel reacii autoimune. Studiile efectuate pn n prezent au raportat existena unor perturbri oxidative n lichidul sinovial al pacienilor cu poliartrit reumatoid, perturbri determinate de creterea producerii de specii reactive de oxigen, fenomen asociat cu diminuarea activitii sistemelor antioxidante endogene. n cazul RA, producerea de specii reactive ale oxigenului depete capacitatea antioxidant celular. Acestea sunt asociate cu procese oxidative generalizate, cu apariia produilor de peroxidare lipidic n plasm, precum i cu reacii de peroxidare localizate la nivel eritrocitar. Peroxidarea lipidelor determin depleia moleculelor de acizi grai polinesaturai de la nivelul membranelor celulare i subcelulare, ducnd la pierderea integritii celulelor, la alterarea structural i funcional a membranelor i a receptorilor membranari [4,5]. Astfel, se consider n prezent c radicalii liberi de oxigen sunt mediatori importani n patogeneza RA [4,6].
MATERIALE I METODE
Am realizat un studiu clinic care a inclus 37 de pacieni cu PR, diagnosticai conform criteriilor
revizuite din 1987 ale Colegiului American de Reumatologie i tratai cu medicamente de tipul DMARD (disease modifying anti-rheumatic drugs), 19 dintre acetia cu LF i 18 cu MTX. Niciunul nu a primit corticosteroizi sau antagoniti de TNF-?. Conform evalurii clinice bazat pe scorul DAS28, toi pacienii aveau boal activ (DAS28>5.1). Grupul de control a fost format din 19 voluntari sntoi. Au fost exclui din studiu pacienii care fuseser diagnosticai cu boli renale, hepatice, hematologice, cardiovasculare severe sau cu afeciuni maligne. A fost obinut acordul subiecilor inclui n studiu, iar protocolul de lucru a fost supus aprobrii Comitetului de Etic. Reactivi folosii: citrat de sodiu, clorur de sodiu, clorur de trietanolamin, nicotinamid fosfat (NADP+), sarea disodic a glucozo-6-fosfat, tampon fosfat salin (PBS), acid tiobarbituric, azid sodic, acid tricloracetic. Aparate: spectrofotometru de absorbie UV-VIS Cary 100 BIO (Varian Inc.), echipat cu suport de cuv termostatat prin efect Peltier, adaptat pentru determinri biochimice. Pregtirea probelor: Probele de snge venos au fost recoltate jeun, folosind EDTANa2 ca anticoagulant. Eritrocitele au fost separate, splate de dou ori cu soluie de NaCl 0,9% i standardizate la 1g hemoglobin / 100mL suspensie eritrocitar, apoi au fost utilizate pentru determinarea G6PDH i ESP (prin determinarea nivelului de malondialdehid eritrocitar). Activitatea glucozo-6-fosfat dehidrogenazei eritrocitare (G6PDH) a fost evaluat pe hemolizat proaspt obinut din eritrocite. Rata formrii NADPH, a fost evaluat spectrofometric la 340 nm [7,8]. Susceptibilitatea la peroxidare lipidic a eritrocitelor (ESP) a fost evaluat prin msurarea concentraiei malondialdehidei (MDA) eliberat de suspensia eritrocitar standardizat [9,10], tratat timp de 1 or cu 10 mM H2O2 (1:1, v/v). MDA rezultat din peroxidarea lipidelor membranei eritrocitare a fost evaluat spectrofotometric la 535 nm folosind acid tiobarbituric (0.67%). Rezultatele au fost prezentate ca mediideviaii standard, semnificaia statistic a parametrilor determinai a fost evaluat cu ajutorul testului t Student.
210
REZULTATE
Prin prezentul studiu s-a urmrit determinarea activitii G6PDH i a susceptibilitii la proxidarea lipidic a eritrocitelor pentru 37 de pacieni diagnosticai cu poliartrit reumatoid i respectiv
pentru un grup de control format din 19 voluntari sntoi. Pacienii inclui n studiu au fost tratai cu MTX (n=18) i respectiv cu LF (n=19). n tabelul nr 1 sunt prezentate valorile parametrilor evaluai pentru ntreg grupul luat n studiu.
Tabel 1.Valorile parametrilor de stres oxidativ pentru grupul de pacieni inclus n studiul clinic
Prin analiza statistic a datelor s-a evideniat faptul c activitatea G6PDH este redus iar ESP este crescut la pacienii cu poliartrit reumatoid coparativ cu subiecii din grupul de control (tabelul 2). Glutation-peroxidaza este o selenoproteina care reduce hidroperoxizii si peroxidul de hidrogen, cu oxidarea concomitenta a glutationului. Reducerea glutationului oxidat se realizeaz n prezenta
NADPH, care este furnizat la nivel celular in primul rind ca urmare a activitatii G6PDH. Rezultatele au indicat faptul c activitatea G6PDH a fost semnificativ sczut la pacienii cu PR tratai cu LF (25.7513.87 UI vs. 38.678.99 UI, p=0.01) i respectiv la cei tratai cu MTX (27.3415.07 UI vs. 38.678.99 UI, p=0.045) comparativ cu grupul de control - figura 1.
Tabel 2.Valorile parametrilor evaluai la pacienii cu PR comparativ cu grupul de control
Figura 1. Activitatea G6PDH la pacienii tratai cu MTX i respectiv cu LF comparativ cu grupul de control
Rezultatele privind susceptibilitatea la peroxidare lipidic indic valori ale concentraiei MDA mai mari la pacienii cu PR comparativ cu grupul de control (495.25116.92 mM MDA/g Hb pentru pacienii tratai cu LF, 454.26157.84 mM MDA/g Hb pentru pacienii tratai cu MTX vs. 443.454.38 mM MDA/ g Hb n cazul lotului de control) - figura 2.
Figura 2. Susceptibilitatea la peroxidarea lipidic la pacienii cu PR comaparativ cu grupul de control
DISCUII
Conform literaturii de specialitate, la pacienii cu inflamaii articulare, fluidul sinovial este
caracterizat printr-o concentrare local a celulelor implicate n rspunsul inflamator, aa cum sunt neutrofilele activate, celule care produc cantiti importante de specii reactive de oxigen (anioni superoxid - O2-, peroxid de hidrogen - H2O2, radicali hidroxil - HO, etc). Neutrofilele din fluidul sinovial al pacienilor cu artrit reumatoid produc preponderent cantiti mari de anioni superoxid,
211
probabil datorit expunerii lor la aciunea citokinelor prezente, de asemenea, n lichidul sinovial. Procesele de ischemie i reperfuzie asociate micrilor articulare contribuie, de asemenea, la producerea radicalilor liberi de oxigen la nivel articular (2, 4]). Anionii superoxid se formeaz n cantiti mari la nivel articular la pacienii cu artrit reumatoid. Aceti anioni i pot amplifica aciunea agresiv prin reacia cu oxidul nitric (NO) existent n mod fiziologic organism i genereaz anioni peroxinitrit (OONO-) care sunt specii puternic prooxidante (5). Astfel, rezultatele obinute sunt n acord cu datele din literatura de specialitate, conform creia PR este
asociat cu o producie crescut a speciilor prooxidante la nivel articular, ceea ce determin instalarea stresului oxidativ la nivel sangvin i sistemic.
CONCLUZII
Rezultatele obinute indic creterea ESP la pacienii cu PR prin creterea aciunii speciilor reactive de oxigen la nivel eritrocitar i, de asemenea, scderea activitii G6PDH, cu diminuarea n consecint a produciei de NADPH i a capacitii antioxidante celulare.
Mulumiri: Experimentele au fost realizate n cadrul grantului CNCSIS TD 126/01.10.2007 i a proiectului PNCDII Parteneriate, Nr. 61-037/14.09.2007 2007.
BIBLIOGRAFIE
1. 2. Blnescu A, Poliartrita reumatoid - de la patogenie la clinic, Editura Medical Amaltea, Bucureti, 2007 Taysi S, Polat P, Gul M et al, Lipid peroxidation, some extracellular antioxidants and antioxidant enzymes in serum of patients with rheumatoid arthritis, Rheumatol Int 2002, 21: 200-204 Vanu RR, Palanivelu S, Panchanatham S, Evaluation of antioxidant effect of Semecarpus anacardium Linn. nut extract on the components of immune system in adjuvant arthritis, Vasc Pharmacology 2005, 42:179-186 Ozkan Y, Yardm-Akaydn S, Sepici A et al, Oxidative status in rheumatoid arthritis, Clin Rheumatol 2007, 26: 64-68 5. Nivsarkar M, Improvement in circulating superoxide dismutase levels: role of nonsteroidal anti-inflammatory drugs in rheumatoid arthritis, Biochem Biophys Res Com, 2000, 270:714-716 6. Jaswal S, Mehta HC, Sood AK et al Antioxidant status in rheumatoid arthritis and the role of antioxidant therapy, Clin Chim Acta 2003, 338:123-129 7. Lohr GW, Waller DH, Methods of Enzymatic Analysis, vol 2, Academic Press, New York 1974, 636-643 8. Shibib BA, Khan LA, Rahman R, Biochem J 1993, 292, 267-270 9. Yagi K Free Radical and Antioxidant Protocols 1998, 108, 101-106 10. Margin D, Grdinaru D, Mitrea N, Timi (Articol publicat n parteneriat cu Rheumatology 2008;47:985990)oara Med J, 2005, 55, 197-199
3.
4.
n actualitate Rspunsul la adalimumab n poliartrita reumatoid precoce i avansat
Acest articol prezint o subanaliz a studiului DE019 care a comparat efectul adalimumabului asupra evoluiei clinice, radiografice i funcionale a bolnavilor cu poliartrit reumatoid (PR) precoce (durat sub 3 ani) i avansat (durat peste 3 ani). Dintre 407 pacieni nrolai, 78 aveau PR precoce i au primit adalimumab (N = 41) sau placebo
(N = 37), n vreme ce n grupul de boal avansat cu 329 de cazuri aceste cifre au fost de respective 166 i 163. Cei cu boal precoce au nregistrat mai frecvent rezultate bune dup tratament dup criteriile ACR 20 (reducere de 20% ACR20), 50 i 70, n proporie de respective 61, 46,5 i 24,4% la 52 de sptmni, dect cei cu boal avansat, unde
proporiile succesului au fost de 56, 37,3 i 19,9%, dup aceleai criterii. Reducerea scorului HAQ a fost de 0,44 n primul grup i de 0,25 n cel de al doilea. Dup tratamentul cu adalimumab, reducerea scorului Sharp fa de placebo a fost de 5,32 n PR precoce fa de 2,06 n cea avansat.
Sursa: Jamal S, Patra K, Keysotone EC, Adalimumab in early versus established rheumatoid arthritis, Clin Rheumatol 2008, 17: 162-158
LUCRRI ORIGINALE
EVALUAREA STILULUI DE VIA AL PACIENILOR CU POLIARTRIT REUMATOID

tefania Marinea*, C. Cernescu**, Denisa Predeeanu***, Andra Blnescu***, Violeta Vlad*** *Centrul Medical Vademecum, **Institutul de Virusologie St. S. Nicolau, ***Clinica de Medicin Intern i Reumatologie, Spitalul Clinic Sf. Maria, Bucureti
Rezumat
Acest studiu de tip caz-control a fost realizat pentru a investiga indicele de mas corporal i consumul de toxice (fumat, consum de cafea) precum i relaia dintre fumat i indicele de activitate al bolii (DAS28), factorul reumatoid i istoricul familial de poliartrit reumatoid (PR). Au fost observai 90 de bolnavi cu PR i un grup egal de bolnavi cu artroze ca i referin. Obervaiile noastre au artat c mai mult de jumtate dintre subiecii studiai erau obezi: 52% poliartritici i 69% artrozici. Stilul de via a fost asemntor ntre cele dou grupuri, fr nici o legtur ntre fumat i serpozitivitate sau indicele DAS28 la bolnavii cu PR, dar fumatul a fost un obicei mai frecvent ntlnit la poliartriticii fr istoric familial de PR. Cuvinte-cheie: poliartrit reumatoid, artroz, indice de mas corporal, fumat.
Summary Life-style evaluation in patients with rheumatoid arthritis

The present case-control study was conducted to investigate body mass index, prevalence of the smoking and coffee consumption in rheumatoid arthritis (RA) patients as well as the relationship between smoking and DAS28, rheumatoid factor-positive rheumatoid arthritis and family history of RA. Ninety patients with RA an equal group of patients with osteoarthritis have been observed. We noticed that over half of the patients were obese (52% of those with RA and 69% of those suffering from osteoarthritis). Lifestyle factors are likewise in the two groups. There was no relationship between smoking and DAS28 and seropositive RA, but smoking was more prevalent in patients with RA without a family history of disease. Key words: rheumatoid arthritis, osteoarthritis, body mass index, smoking.
INTRODUCERE
Poliartrita reumatoid (PR) are o etiologie multifactorial, ce implic att terenul genetic, ct i factorii de mediu. Studiile pe perechi de gemeni indic faptul c factorii genetici justific 60 % din variaia susceptibilitii la boal. Asocierea cu HLA poate explica, ntr-o oarecare msur, variaia geografic a prevalenei bolii (1). PR are caracteristicile unei boli autoimune cu un rspuns imun dominant de tip Th1, dar antigenul care iniiaz i perpetueaz boala nu a fost identificat (2). O serie de elemente ale stilului de via au fost studiate ca factori de risc poteniali pentru PR. Puine evaluri au la baz studii ale incidenei bolii i informaii suficient de precise cu privire la relaia dintre timpul expunerii la un anume factor de risc i debutul bolii. O asociere a PR cu obezitatea a fost raportata la un numar de studii. In studiile caz-control privind influena dietei, consumul de ulei de msline i ulei de pete, a fost semnalat c protejeaz mpotriva
212
riscului de apariie a PR. Exista dovezi insuficiente c deficitul de cupru i deficitul de seleniu au o legtur cu PR (1). O cretere a riscului pentru PR asociat cu fumatul a fost artat att n studii transversale, ct i n studii longitudinale. Asocierea pare s fie mai ales vizibil pentru marii fumtori i pentru PR seropozitive (3). Consumul de cafea a fost i el implicat ca factor de risc pentru PR seropozitiv (4). Consumul de alcool pare s fie protectiv, dar dovezile nu sunt concludente. La acestea s-ar mai putea aduga anumite expuneri la diverse substane, specifice profesiei (1). Dintre potenialii factori de risc, asocierea dintre fumat i PR pare s fie cel mai intens studiat. Unii autori consider c fumatul poate influena incidena PR, dar i c fumatul poate avea influene negative asupra severitii PR, ntr-un mod dependent de doz (5, 6). Riscul pentru PR poate s rmn pentru mai muli ani, dup ncetarea fumatului (10-19 ani) (7). Ali autori consider c doar fumatul n cantiti apreciabile (41-50 pachete
213
pe an) i nu fumatul n sine predispune la PR, acest obicei fiind mai prevalent la persoanele cu PR far istoric familial de PR (3). Alte date sugereaz c fumatul a peste 30 de igri pe zi predispune la risc pentru PR independent de pozitivitatea FR sau istoric familial de PR (8, 9). Fumatul pentru o perioad lung de timp (cel puin 20 de ani), ntr-un anume context genetic (shared epitop) pare s stimuleze producerea de facor reumatoid (posibil i de anticorpi anti peptid ciclic citrulinat), cu apariia acestora nainte de debutul bolii (10). Unele studii au artat c IgA FR este mai strns asociat cu PR, n special cnd este gsit alturi de IgM FR (11), iar prezena IgA FR se asociaz cu un prognostic rezervat pentru PR (12). Ipoteza c fumatul contribuie parial la apariia PR prin producerea de FR este atractiv, dar mecanisme alternative pot fi implicate mai probabil. De exemplu: fumatul timp ndelungat determin leziuni vasculare sistemice; fumatul este strns asociat cu vasculita n PR activ (13). Fumul de igar conine numeroi ageni oxidani care pot inactiva inhibitorul de proteinaz ?1 (?1 PI) (14), inhibitorul natural al elastazei neutrofilice, o serinproteaz ce poate degrada cartilajul articular. Fumul de igar poate stimula i degranularea neutrofilelor, cu eliberare de elastaz, activeaz macrofagele pentru a produce metaloproteaze matriceale, crete producerea de IL-1? i IL-8, scade producerea de antagonist de receptor IL-1 i scade IL-10 (15,16). Marii fumtori pot avea o artrit inflamatorie de scurt durat, benign i care, prin mecanismele de mai sus, poate evolua spre PR (17). La fumtori exist o cretere a producerii de IL-4 (18) i o scdere a raportului CD4+/CD8+ al limfocitelor T (19), modificri ce par protective faa de PR. Sunt autori care afirm c i fumtorii pasivi pot fi predispui la PR, prin modificrile care au loc la nivelul nazofaringelui. Att pneumococul, ct i meningococul sunt transportai la nivelul nazofarigelui i bolile produse de aceste bacterii sunt semnificativ mai frecvente la fumtorii pasivi (20, 21, 22), dect n populaia general. Astfel, fumatul pasiv poate predispune potenial subiecii la PR, ca rezultat al modificrilor din nazofaringe, printr-o o stimulare antigenic. Este interesant de notat c neoplasmul nazo-faringian se asociaz cu fumatul, dar i cu virusul Epstein-Barr (EBV), unul din virusurile implicate n patogenia PR (23). Consumul de cafea poate fi i el un factor de
risc pentru PR, posibil prin mecanisme ce contribuie la producerea de FR (24). Exist numeroase date care sugereaz intervenia factorilor dietetici n producerea bolii (25-28). Acest studiu caz - control i-a propus s evalueze comparativ dou loturi de pacieni, unul cu PR, iar cellalt cu artroz, cu privire la: indicele de mas corporal, prevalena fumatului i a consumului de cafea, dar i o comparaie ntre pacienii cu PR, fumtori i nefumtori, n ceea ce privete activitatea bolii, prezena FR i relaia dintre fumat i antecedentele familiale de PR.
PACIENI I METODE
Studiul a cuprins un lot de pacieni cu PR i unul de control, format din pacieni cu artroz. Primul lot a fost format din 90 de pacieni, care au ndeplinit criteriile ACR pentru PR, revizuite n 1987. Acesti pacieni au fost internai n Clinica de reumatologie i Medicin intern a Spitalului clinic Sf. Maria, sau au fost dispensarizai la Centrul medical Vademecum, Bucureti. Lotul de control a fost format din 90 de pacieni cu artroz, cu diferite localizri (coloana vertebral, articulaii periferice), diagnostic confirmat radiologic. Aceti pacieni au fost dispensarizai la Centrul medical Vademecum. Toi pacienii au fost de acord cu participarea la studiu i prelucrarea datelor obinute. Datele personale i despre boal (sex, vrst, domiciliu, durata bolii, tratamente urmate i prezente), datele despre stilul de viaa (fumatul, consumul de cafea), antecedentele familiale (cu privire la PR, rude de gradul I i II), antecedentele personale (fiziologice i patologice) au fost obinute pe baza unui interviu. Examenul clinic a urmrit determinarea nalimii i masei corporale, necesare calculrii indecelui de mas corporal (IMC, kg/m2), numrul de articulaii dureroase si tumefiate dintre cele 28 necesare calculrii scorului de activitate a bolii DAS28. Probele biologice necesare acestui studiu au fost: viteza de sedimentare a hematiilor (VSH, mm/h), proteina C reactiv (PCR, mg/dl), factorul reumatoid (FR), determinat prin metode de aglutinare. Seropozitivitatea a fost definit pentru o valoare > 10 UI/ml. Analiza statistic a datelor a cuprins calcularea de medii, deviaii standard, comparaiile ntre loturi i n cadrul aceluiai lot fcndu-se cu ajutorul testului Student i testului x2.
214
REZULTATE
Vrsta medie a pacienilor cu PR a fost de 55.17 ani (limite 24 - 88 ani), iar numrul de femei a fost de 82 (91%). Vrsta medie pentru lotul control a fost de 53.55 ani (limite 34 - 65 ani), iar numrul de femei a fost de 75 (83%). La pacienii cu PR durata medie a bolii a fost de 8.14 ani (limite 0.2 - 35 ani) (tabelul 1)
Tabelul 1. Caracterisicile loturilor studiate.
In funcie de indicele de mas corporal, pacienii din cele dou loturi au fost mprii n trei categorii: subponderali (IMC<20), normoponderali (20? IMC <25) i supraponderali sau obezi (IMC ?25) (figura 1). In lotul de pacieni cu PR distribuia a fost urmtorea: 5 pacieni (6%) subponderali, 38 pacieni normoponderali (42%) i 47 pacieni supraponderali sau obezi (52%). Lotul de pacieni cu artroz s-a prezentat astfel: 2 pacieni subponderali (2%), 26 de pacieni normoponderali (29%) i 62 pacieni supraponderali sau obezi (69%). Investigarea stilului de via, n ceea ce privete fumatul i consumul de cafea, a fost fcut comparativ ntre cele dou loturi, pe sexe, aa cum se evalueaz i la nivelul populaiei generale, deoarece exist diferene notabile (tabelul 2).
Figura 1. Indicele de mas corporal la cele dou loturi (PR = poliartrit reumatoid, A = artroz, IMC = idice de mas corporal).
Tabelu 2. Prevalena fumatului i a consumului de cafea la cele dou loturi, pe sexe
Din punctul de vederea a activitii bolii, pacienii au fost mprii n trei categorii: boal inactiv sau slab activ (DAS28 < 3.2), boal
moderat activ (3.2 ? DAS28 <5.2) i boal intens activ (DAS28 ? 5.2), iar activitatea bolii a fost analizat comparativ la pacienii cu PR fumtori
215
versus pacienii cu PR nefumtori (tabel 3). Seropozitivitatea pentru IgM FR a fost de 70% la pacienii cu PR fumtori i de 74% la pacienii cu PR nefumtori. Niciunul dintre pacienii fumtori nu a avut rude de gradul I sau II cu PR, n comparaie cu pacienii nefumtori, la care 8 pacieni au avut astfel de antecedente familiale (tabel 3).
Tabel 3. Compararea activitii bolii, a prezenei FR i a antecedentelor familiale de PR la pacienii cu PR, fumtori i nefumtori
DISCUII
Loturile studiate comparativ, formate din pacieni cu PR, respectiv pacieni artrozici, nu prezint diferene semnificative n ceea ce privete vrsta medie (0.4 > P > 0.2) i nici n ceea ce privete distribuia pe sexe (P > 0.995). Calcularea indicelui de mas corporal a evideniat c att n lotul PR (52%), dar mai ales n lotul de pacieni artrozici (69%), peste jumtate dintre acetia sunt supraponderali sau obezi (IMC ? 25). Acest aspect poate avea un efect negativ asupra ambelor boli. In cazul PR a fost deja prezentat legtura dintre starea de nutriie i sistemul imun. Greutatea corporal, n exces, solicit mecanic anumite articulaii, iar leptina, alturi de alte citokine proinflamatorii, are efect negativ asupra cartilajului articular prin stimularea sintezei de oxid nitric la nivelul condrocitelor (29). Distribuia IMC la cele dou loturi a fost comparativ nesemnificativ (0.100 > p > 0.050). In lotul PR, statutul de fumtor a fost atribuit acelor pacieni care au fumat att la debutul bolii ct i la momentul includerii n studiu. De altfel, nu au existat pacieni care nu fumau la debutul PR i dup aceea au nceput s fumeze. Se consider c 18% din persoanele fumtoare diagnosticate cu PR renun la fumat n primii trei ani de boal si mai puin de 1% dintre pacienii nefumtori ncep s fumeze dup diagnosticul de PR n aceti ani (13).
La pacienii artrozici, calitatea de fumtor definete pacienii care erau fumtori la momentul introducerii n studiu. Valorile obinute n privina fumatului au artat c acest obicei este rspndit n ambele loturi de pacieni. Comparaia a fost fcut pe sexe. Astfel, 10% dintre femeile cu PR sunt fumtoare versus 19% dintre femeile cu artroz, iar 25% dintre brbaii cu PR sunt fumtori versus 53% dintre brbaii cu artroz. Prevalena fumatului n studiul nostru nu a fost mic. La noi n ar exist o tendin de cretere a numrului de fumtori, de ambele sexe, n condiiile n care vrsta de debut a fumatului scade. Romnia ocup locul al doilea n Europa ca numr de fumtori, prevalena fumatului n rndul populaiei generale fiind de 46,4% pentru brbai i de 24,1% pentru femei (30). In acest studiu nu au fost inclui fumtorii pasivi. Determinarea de cotinin seric i tiocianat, recomandat pentru detectarea unei expuneri indirecte la tutun, indic doar o expunere recent, ori pentru o posibil legtur cu PR trebuie demonstrat o expunere mai ndelungat (31, 32). Consumul de cafea este un obicei mai frecvent dect fumatul, n ambele loturi studiate i la ambele sexe. Nu exist diferene semnificative n ceea ce privete consumul de cafea ntre cele dou loturi. Acest lucru se explic, n parte, prin faptul c, pacienii nu consider c exist legtur ntre aportul de cafea i bolile reumatice, n general. Studierea consumului de cafea nu a inclus i consumul de alte buturi ce conin cofein (cola, ceai). Asocierea dintre consumul de cafea i PR poate fi datorat i asocierii dintre stres i PR, dei acest aspect a fost infirmat de Helivaaraa (4). Scorul de activitate a bolii DAS28 a artat o distribuie nesemnificativ a valorilor acestuia la pacienii cu PR fumtori, comparativ cu pacienii PR nefumtori (0.200 > p > 0.100). Aceti pacieni se aflau n tratament cu unul sau mai multe medicamente remisive (metotrexat, sulfasalazin, leflunomid, hidroxicloroqin), iar unii dintre ei erau i sub tratament biologic (Infliximab). Rezultatele obinute de noi sugereaz c, activitatea bolii nu este influenat semnificativ de ctre fumat la pacienii cu PR, aflai sub tratament specific. Prezena IgM FR a fost asemntoare la cele dou loturi de pacieni cu PR, fumtori respectiv nefumtori, i nu pare a fi influenat de ctre fumat. In ceea ce privete corelaia dintre fumat i antecedentele familiale de PR, se poate observa c
216
n cazul pacienilor cu PR fumtori nu exist nici un pacient cu astfel de antecedente familiale, n schimb n lotul de pacieni cu PR nefumtori, exist 8 pacieni cu antecedente familiale de PR (rude de gradul I i II). Observaia noastr se coreleaz cu datele din literatur (3) i poate sprijini ipoteza implicrii fumatului n etiologia PR, la pacienii fr antecedente familiale. Limitele studiului sunt date de numrul relativ mic de pacieni inclui. Nu s-a realizat o analiz doz-efect pentru fumat i nici pentru consumul de cafea, pentru c acest studiu nu a umrit evaluarea incidenei PR la fumtori i la consumatorii de cafea, iar datele furnizate de pacieni erau destul de subiective n ceea ce privete doza, pentru c pe de o parte se fcea apel la memorie, iar pe de alta parte n condiiile spitalizrii i n contextul unei boli cronice, datele relatate erau probabil mai mici dect cele reale.
Nu au fost investigate obiceiurile alimentare ale pacienilor pentru c, n ara noastr consumul de pete i ulei de msline este destul de redus. Un studiu comparativ ntre ri cu variaii mari ale acestor obiceiuri alimentare ar avea relevan mai mult n ce privete evoluia PR i mai puin n ceea ce privete prevalena PR, care este relativ egal n lume.
CONCLUZII
1. Peste jumtate dintre pacienii cu PR i artroz sunt supraponderali sau obezi. 2. Stilul de via (fumatul, consumul de cafea) este asemntor la cele dou loturi. 3. Fumatul nu influeneaz activitatea PR, dar poate fi implicat n etiologia PR la pacienii fr antecedente familiale de PR.
BIBLIOGRAFIE
Firestein GS Etiology and pathogenesis of rheumatoid arthritis in Kelley, Harris, Ruddy, Sledge "Textbook of Rheumatology", 6th Ed, Saunders Company, 2001:921-967 2. Reckner Olsson A, Skogh T, Wingren G Comorbidity and lifestyle, reproductive factors, and environmental exposures associated with rheumatoid arthritis, Ann Rheum Dis 2001, 60: 934-939 3. Hutchinson D, Shepstone L, Moots R et al Heavy cigarette smoking is strongly associated with rheumatoid arthritis, particularly in patients without a family history of RA, Ann Rheum Dis 2001, 60: 223-227 4. Helivaaraa M, Ahoa K, Knekta P et al Coffee consumption, rheumatoid factor, and the risk of rheumatoid arthritis, Ann Rheum Dis 2000, 59: 631-635 5. Saag KG, Cerhan JR, Kolluri S at al Cigarette smoking and rheumatoid arthritis severity, Ann Rheum Dis 1997, 56: 463-469 6. Msdttir B, Jnsson T, Manfresdttir V et al Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis, Rheumatology 2000, 39: 1202-1205 7. Stolt P, Bengtsson C, Nordmark B et al Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases, Ann Rheum Dis 2003, 62: 835-841 8. Masi AT, Aldag JC, Fecht T et al Rheumatoid factor positivity and current cigarette smoking of 30+ daily are independent, long-term predictors of RA, Abstr. Arthr Rheum 1997, 40(suppl): 312 9. Masi AT, Aldag JC, Chatterton RT et al Independent risk markers for RA onset in males include rheumatoid arthritis in a first degree relative, rheumatoid factor, combined low serum cortisol and testosterone, and heavy cigarette smoking, Abstr Arthr Rheum 2000, 43 (suppl): 70 10. Klareskog L, Alfredsson L, Rantap-Dahlqvist S et al What precedes development of rheumatoid arthritis? Ann Rheum Dis 2004, 63:1128-1131 11. Sweder W, Wallman J, Froelich CJ, Trodorescu M Routine measurement of IgM, IgG and IgA RF: high sensitivity, specificity and predictive value for rheumatoid arthritis, J Rheumatol 1997, 24:1037-1344 12. Arinbjarnarson S, Jonsson TH, Steinsson K et al IgA rheumatoid factor correlates with changes in B and T lymphocyte 1. subsets and disease manifestations in rheumatoid arthritis, J Rheumatol 1997, 24: 269-274 Voskuyl AE, Zwinderman AH, Breedveld FC, Hazes JMW Smoking and the risk of vasculitis in rheumatoid arthritis, Abstr Br J Rheumatol 1997, 36 (suppl 1):164 Evans MD, Pryor WA Cigarette smoking, emphysema, and damage to alpha 1-proteinase inhibitor, Am J Physiol 1994, 266: 593611 Hofbauer LC, Muhlberg T, Konig A et al Soluble interleukin-1 receptor antagonist serum levels in smokers and nonsmokers with Graves' ophthalmopathy undergoing orbital radiotherapy, J Clin Endocrinol Metab 1997, 82: 2244-2247 Takanashi S, Hasegawa Y, Kanehira Y et al Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers, Eur Respir J 1999, 14 309-314 Kuschner WG, D'Alessandro A, Wong H, Blanc PD Dosedependent cigarette smoking-related inflammatory responses in healthy adults, Eur Respir J 1996, 9: 1989-1994 Byron KA, Varigos GA, Wootton AM Il-4 production is increased in cigarette smokers, Clin Exp Immunol 1994, 95: 333-336 Wallace JM, Oishi JS, Barbers RG et al Lymphocytic subpopulation profiles in bronchoalveolar lavage fluid and peripheral blood from tobacco and marijuana smokers, Chest 1994, 105: 847852 Silman AJ Smoking and the risk of rheumatoid arthritis J Rheumatol 1993, 20:1815-1816 Nuorti JP, Butler JC, Farley MM et al Cigarette smoking and invasive pneumococcal disease, N Engl J Med 2000, 342: 681-689 Kriz P, Bobak M, Kriz B Parental smoking, socioeconomic factors, and risk of invasive meningococcal disease in children: a population based case-control study, Arch Dis Child 2000, 83:117-121 Wollier W Rheumatoid arthritis and Epstein-Barr virus: a case of living with the enemy? Ann Rheum Dis 2000, 59: 497-499 Halldrsdttir HD, Jnsson T, Thorsteinsson J, Valdimarsson H A prospective study on the incidence of rheumatoid arthritis among people with persistent increase of rheumatoid factor, Ann Rheum Dis 2000, 59:149-151 Palmer G, Gabay C A role for leptin in rheumatic diseases? Ann Rheum Dis 2003, 62: 913-915 Linos A, Kaklamani VG, Kaklamani E et al Dietary factors in relation to rheumatoid arthritis: a role for olive oil and cooked vegetables? Am J Clin Nutr 1999, 70: 1077-1082
13.
14.
15.
16.
17.
18. 19.
20. 21. 22.
23. 24.
25. 26.

27. Hafstrm I, Ringertz B, Spngberg A et al A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens, Rheumatology 2001, 40: 1175-1179 28. Skldstam L, Hagfors L, Johansson G An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis, Ann Rheum Dis 2003, 62: 208-214 29. Otero M, Gomez-Reino JJ, Gualillo O et al Leptin synergizes interleukin-1 in inducing nitric oxide synthase in chondrocytes, Arthr Rheum 2003, 48: 654
217
30. Mihlan F, Ciobanu M Tabagismul, consecine i tratament, Editura Medical, Bucureti, 2001 31. Perkins SL, Livesey JF, Escares EA et al High-performance liquid-chromatographic method compared with a modified radioimmunoassay of cotinine in plasma, Clin Chem 1991, 37: 1989-1993 32. Butts WC, Kuehneman M, Widdowson GM Automated method for determining serum thiocyanate, to distinguish smokers from nonsmokers, Clin Chem 1974, 20: 1344-1348
n actualitate Artrita psoriazic juvenil (APJ): manifestri clinice i evoluia la 119 pacieni Au fost revizuite nregistrrile medicale a 122 pacieni care au ndeplinit criteriile Vancouver sau ILAR de APJ. Pacienii au fost mprii n patru grupe n funcie de manifestrile lor clinice: a) oligoarticular, b) poliarticular cu FR negativ, c) poliarticular cu FR pozitiv i d) entezite. n lotul de 119 pacieni, 59(49,6%) au avut afectare poliarticular, dintre acetia 54 (47,8%) au fost cu FR negativ i 4 (3,3%) cu FR pozitiv. La diagnostic, pacienii cu entezite au fost mai n vrst comparativ cu cei cu afecatare oligo- i poliarticular (11,6 2,2 ani versus 7,7 4,3 ani i 7,1 4,5 ani) (p<0,001). Pacienii cu manifestri poliarticulare au avut mai des afectare MCF, IFP i de umr comparativ cu cei cu afectare oligoarticulare i entezite (p<0,001). Cei cu entezite au suferit de o afectare semnificativ mai frecvent a oldului i a articulaiilor sacroiliace comparativ cu celelalte grupuri (p<0,001). Modificri ale unghiilor au fost observate la 66 pacieni (57%) i au fost asociate la prezentare cu afectarea articulaiilor IFD (p=0,0034) Durata de timp pn la obinerea remisiei a fost semnificativ mai lung la pacienii cu afectare poliarticular comparativ cu cei cu afectare oligoarticular i entezite.
Butbul Z, Tyrrell PN, Feldman BM et al, Juvenile psoriatic arthritis clinical features and outcome of 119 patients, Pediatric Rheumatology Congress, London, 2008
Vizitai site-ul
SOCIETII ROMNE DE REUMATOLOGIE www.srreumatologie.ro
LUCRRI ORIGINALE
CONSIDERAII ASUPRA TERAPIEI CU ETANERCEPT LA COPII CU ARTRIT IDIOPATIC JUVENIL

Mariana tefan Clinica de Pediatrie a Spitalului " MS Curie ", Bucureti
Rezumat
Obiective: Evaluarea eficacitii tratamentului cu etanercept la pacienii diagnosticai cu AIJ, prin monitorizarea evoluiei procesului inflamator, evaluarea complianei la tratament i prezena eventualelor reaciilor adverse la tratament. Material i metod: Au fost supui unei analize retrospectiv-observaionale un lot de 12 copii, diagnosticai cu AIJ n Clinica de Pediatrie a Spitalului MS Curie, n perioada 2004-2008, carora le-a fost iniiat terapia cu Etanercept (0.4 mg/kgc*2/spt). Pacienii au fost evaluai prin examen clinic obiectiv, monitorizarea markerilor inflamaiei (VSH, CRP) i utilizarea scorului Children Health Assessment Questionnaire. Rezultate: S-a constatat reducerea marcat a prezenei simptomelor AIJ la pacienii aflai sub terapie. S-au nregistrat 2 cazuri de ntrerupere a tratamentului, datorit ineficienei, respectiv non-complianei la tratament. Nu s-au nregistrat reacii adverse. Cuvinte-cheie: artrit idiopatic juvenil, anti-TNF alfa, etanercept
Summary Etanercept in children with juvenile idiopathic arthritis

Objective: Evaluation the effectiveness of treatment with etanercept in patients with juvenile idiopathic arthritis (JIA), by monitoring of the inflammatory process, evaluation of treatment compliance and monitoring of possible adverse reactions to the therapy Material and methods: The subject of a retrospective-observational analysis is a group of 12 children diagnosed with JIA in the "MS Curie" Clinic Hospital of Pediatrics, during a 5 years period, which have been treated by etanercept (0.4 mg / kg twice weekly). Patients were evaluated by clinical examination, monitoring of inflammation markers (ESR, CRP) and the CHAQ score. Results: There was an important reduction of JIA symptoms inmost of the treated patients, without major adverse events. In two cases treatment was interrupted because lack of efficacy and noncompliance respectively Key words: juvenile idiopathic arthritis, anti-TNF alpha, etanercept
INTRODUCERE
Artrita idiopatic juvenil (AIJ) reprezint un grup heterogen de afeciuni caracterizate prin prezena artritei n una sau mai multe articulaii, nsoit de febr i semne generale. Aceste manifestri debuteaz sub vrsta de 16 ani i sunt persistente n timp (cel puin 6 sptmni). Pentru diagnosticarea i clasificarea AIJ exist mai multe criterii. Acestea au fost elaborate separat de American College of Rheumatology (ACR) i de European League Against Rheumatism (EULAR). Clasificarea AIJ cuprinde trei tipuri de boal : tipul oligo/pauciarticular, cu prezena artritei n 1pn la 4 articulaii, tipul poliarticular, definit ca artrit n 5 sau mai multe articulaii (fiecare articulaie fiind numrat separat, cu excepiile reprezentate de coloana cervical, cap i tors, considerate a fi o singur articulaie).
218
forma sistemic, caracterizat prin prezena zilnic a febrei, cu croete de 39-40 C, cu o durat de cel puin 2 sptmni, la care se asociaz artrita n una sau mai multe articulaii nsoit i de alte semne sistemice. Abordarea terapeutic a AIJ se face n funcie de forma clinic de boal i de participarea altor organe. Terapia biologic n este indicat dup esecului tratamentului cu medicamente modificatoare de boal, medicamente de linia a doua, n special metotrexat. La aceti copii, pe lng metotrexat, s-a ncercat administrarea i altor medicamente modificatoare de boal (sulfasalazin, leflunomide). n caz de eec, exist oportunitatea de a ncerca administrarea de etanercept, singurul medicament biologic cu indicaie n tratarea AIJ. Acesta este o protein de fuziune format prin cuplarea receptorului uman p75 al factorului de necroz tumoral cu un fragment Fc obinut prin tehnici de recombinare ADN n cadrul unui sistem
219
de exprimare pe celulele de hamster chinezesc (OHC). n aceast analiza retrospectiv-observational obiectivele au fost reprezentate de monitorizarea evoluiei procesului inflamator, aprecierea complianei la terapia cu etanercept i prezena eventualelor reacii adverse aprute la terapia cu acest agent biologic.
11 ani. Vrsta medie a debutului este de 12,6 +/3,1 ani, ceea ce corespunde vrstei citate n literatura de specialitate.
Tabel 2. Debutul bolii la cazurile studiate
MATERIAL SI METODA
Au fost luai n observaie 12 pacieni care s-au internat n vederea stabilirii diagnosticului i instituirii tratamentului, n perioada 2004-2008 i care, datorit lipsei de rspuns la tratamentul cu medicaia de linia a doua, persistenei semnelor inflamatorii i activitii intense a bolii, au fost propui pentru nceperea tratamentului cu etanercept. Diagnosticul de AIJ a fost pus pe baza examenului clinic obiectiv, cu aprecierea numrului de articulaii dureroase i tumefiate i a investigaiilor paraclinice i de laborator (monitorizarea markerilor inflamaiei,VSH i CRP). Toi copiii diagnosticai cu AIJ care a fost propui pentru terapia cu etanercept au fost n prealabil vaccinai impotriva hepatitei virale cu virus A i mpotriva varicelei, conform protocolului de iniiere a terapiei biologice n AIJ. De asemenea, aceti pacieni au primit metotrexat n doz de10 mg/m 2 suprafaa corporal o dat pe sptmn, naintea anterior instituirii tratamentului biologic i i l-au continuat pe toat durata administrrii etanerceptului.
Durata medie medie a bolii a fost de 5,5 +/- 1,4 ani, valorile extreme fiind reprezentate de 3 ani (perioada minim de evoluie a bolii), respectiv 8 ani (perioada maxim de evoluie a bolii) (tabelul 3).
Tabel 3. Durata bolii la cazurile observate
REZULTATE I DISCUII
Din totalul celor 12 copii diagnosticai cu AIJ, un numr de 5 cazuri a fost biei, iar 7 fete. n procente, sexul femeiesc reprezint 58.3% vs 41.7% sexul brbtesc (tabelul 1).
Tabel 1. Demografie
Urmrirea evoluiei procesului inflamator a presupus monitorizarea articulaiilor cu artrita activ i a VSH, la iniierea terapiei i la evaluarile periodice ulterioare. La momentul iniierii terapiei cu etanercept, numrul de articulaii dureroase a nregistrat o valoare medie de 18,83+/-8,59. La 3 luni dup iniierea terapiei cu etanercept se constat o scdere cu >50% a numrului de articulaii dureroase, respectiv la o valoare medie de 8,3 +/-3,4. Pe msur ce durata tratamentului a crescut, numrul de artculaii dureroase a sczut, atingnd valori ce tind spre 0 la >24 luni de observaie.
Tabel 4. Evoluia numrului de articulaii dureroase
Repartiia lotului de pacieni funcie de vrst debutului AIJ a evideniat o inciden minim a bolii la vrst de 7-8 ani. Incidena crete dup vrsta de
220
Aceeai evoluie se remarc i n ceea ce privete numrul de articulaii tumefiate, unde, de asemenea, se observ o scdere cu >55% a numrului acestora la 3 luni de tratament, de la valoarea medie de 6.9 +/-3.8 la iniierea terapiei la cea de 16.8+/-9.6 la 3 luni dup aceea (tabelul 5).
Tabel 5. Evoluia articulaiilor tumefiate
Un element important n aprecierea evoluiei bolii a fost scorul CHAQ. Acesta a prezentat o evoluie descresctoare pe parcursul monitorizrii pacienilor. La 3 luni de la iniierea terapiei, valoarea medie a scorului CHAQ era de 6.90 vs 9.67 la momentul iniierii terapiei, ceea ce presupune o scdere cu >25%. Din punct de vedere clinic, acest lucru s-a concretizat n mod obiectiv prin reducerea impotenei funcionale articulare i indirect, prin creterea calitii vieii pacienilor, dnd posibilitatea copilului s duc o via aproape/chiar normal.
Tabel 7. Evoluia CHAQ
Monitorizarea paraclinica i de laborator a procesului inflamator confirm evoluia ce fusese remarcat din punct de vedere clinic. Astfel, dac la iniierea terapiei, valoarea medie a VSH era de 66 +/- 19.7 mm/h (valoare minim, 35 mm/h, valoare maxim 98 mm/h) iar dup 3 luni de la nceperea tratamentului, valoarea medie nregistrat pentru VSH a fost de 49.7 +/- 25.0 mm/h. La 12 luni de la iniierea tratamentului cu etanercept, valoarea medie a VSH a ajuns la 19.440+/-13.049, ceea ce reprezint o scdere cu >66% raportat la valoarea la de nceput
Tabel 6. Evoluia VSH la cazurile tratate
Din cei 12 pacieni diagnosticai cu AIJ i aflai n tratament cu etanercept, n dou cazuri s-a ntrerupt terapia biologic datorit ineficienei, respectiv noncomplianei la tartament. Pe parcursul observaiei nu s-au nregistrat reacii adverse legate de administrarea etanerceptului n dozele practicate.
CONCLUZII
1. Pacienii diagnosticai cu AIJ supui terapiei cu etanercept au avut o evoluie favorabil, att din punct de vedere clinic ct i biologic. 2. Compliana la terapia cu etanercept a fost bun, nregistrndu-se un singur caz de ntrerupere a terapiei din acest motiv. 3. Nu s-au nregistrat reacii adverse majore legate de administrarea etanerceptului.
BIBLIOGRAFIE :
1. 2. Bojinca M, Suteanu St, Bleanu M Asocieri ale tratamentului de fond n poliartrita reumatoid, Rev Reumatol 1997, 5 : 1-10 Cassidy J, Petty R Textbook of Pediatric Rheumatology, 5th Ed, 2005 3. 4. Prieur AM Rhumatologie Pediatrique, Flammarion, Paris, 2005 Femke HM. Prince MT, Cate R et al Long-term follow-up on effectiveness and safety on etanercept on JIA, BMJ Publishing Group
CAZUISTIC INSTRUCTIV
PROBLEME TERAPEUTICE LA UN PACIENT CU SPONDILIT ANCHILOZANT I STATUS POST-HEMORAGIE CEREBRAL

Adriana Sarah Nica1, Ana-Magdalena Meila1, L. Macovei2, Consuela Brailescu1 1 Institutul Naional de Recuperare i Medicin Fizic, 2 Spitalul Clinic Dr. I. Cantacuzino, Bucureti
PREZENTAREA CAZULUI
Prezentm cazul pacientului MI, n vrst de 53 de ani, pensionar, din mediul rural, care s-a internat n Clinica de Recuperare Medical III Bucureti, pentru deficit motor de tip paretic hemicorp stng post accident vascular cerebral (AVC) hemoragic n urm cu 4 luni. Concomitent a prezentat la internare artralgii de tip inflamator la nivelul umrului stg, gleznelor bilateral, precum i talalgii bilaterale. Din anamnez aflm c pacientul este un fost mare fumtor (40 tigarete/zi) i consumator cronic de buturi alcoolice, abstinena instalndu-se n urm cu 4 luni. Bolnavul a fost diagnosticat cu spondilit anchilozant (SA) form central la vrsta de 20 de ani i a urmat un tratament intermitent cu AINS i kinetoterapie n reeaua teritorial, evoluia, cu pusee repetate, ducnd la o afectare marcat a coloanei vertebrale cervico-dorso-lombare cu ankiloz i afectarea articulaiilor coxo-femurale. n urm cu 5 ani, pentru coxartroz sever se decide realizarea unei intervenii chirurgicale, cu artroplastia total a articulaiei coxo-femurale stngi. De asemenea prezena valori mari ale TA (Tamax = 220/110 mmHg ) de 5-6 ani, pentru care a fcut intermitent tratament specific hipotensor, cu dieta hiposodat neglijat. Cu 4 luni anterior internrii, pacientul sufer un AVC hemoragic, confirmat prin CT cerebral, localizat la nivel putaminal drept (sediul predilect al hemoragiilor intracraniene din hipertensiunea arterial), cu hemiplegie stng cu debut brutal, pe fondul unei TA = 250/140 mmHg. Intervenia
terapeutic prompt n Clinica de Neurologie Prof. Dr. V. Voiculescu Bucureti este urmat de o evoluia favorabil post-acut, dei n timpul spitalizrii prezint i un episod de bronhopneumonie remis sub antibioterapie. Examenul clinic general la internare arat stare general relativ bun, tegumente i mucoase palide, cu cicatrice postoperatorie supl pe coaps i oldul stng faa lateral, facies asimetric, murmur vezicular diminuat bilateral, zgomote cardiace ritmice, AV = 80b/min, TA la internare = 220/110 mmHg, ulterior, sub tratament cardiologic, echilibrat hemodinamic TA=140/80 mmHg, polakiurie, manifestri anxioase, insomnii, agresivitate verbal. Examenul neuro-mio-artro-kinetic arat parez facial stng de tip central, hemianopsie homonim lateral stng, atitudinea membrului superior stng n poziie vicioas, parial reductibil, cu braul stng n uoar abducie, antebratul stng flectat pe bra, cu mna n pronaie, degetele II-V acoperind policele. Membrul inferior stng n extensie, cu planta n rotaie intern i degetele II-V flectate, mers cosit, posibil fr sprijin, pai inegali, distana i viteza de deplasare diminuate. Probele de parez au fost pozitive la nivelul hemicorpului stng (mai accentuate la nivelul membrului superior), spasticitate medie, predominnd pe flexori la membrului superior i pe extensori la membrului inferior, (mai accentuat brahial), de gradul II pe scala Ashworth. Reflexele osteotendinoase au fost exagerate la nivelul hemicorpului stng, reflexele cutanate abdominale absene pe partea stng, reflex
221
222
cutanat plantar pozitiv n stnga, hiperestezie cutanat, n special la nivelul membrului superior stng, tulburri de sensibilitate termic moderate, predominant la nivelul membrului inferior stng, uoar disfonie, sfinctere continente. Examenul coloanei vertebrale: accentuarea marcat a cifozei dorsale cu tergerea lordozei lombare, limitarea micrilor coloanei cervicale, cu capul flectat (testele occiput-perete, menton-stern irealizabile), anchiloza dorso-lombar, durere la percuia articulaiilor sacro-iliace bilateral. Indicele cirtometric = 2,5 cm. Articulaia coxo-femurala dreapta cu durere i limitarea rotaiei interne i a flexiei coapsei pe bazin; articulaia coxo-femural stng cu cicatrice postoperatorie supl, mobilitate articular dificil de interpretat deoarece artroplastia este pe aceeai parte cu hemipareza. Bolnavul prezint hipotonie de cvadriceps, fesier mare i mijlociu stng, genunchii cu mobilitate pstrat i cracmente, glezne tumefiate, dureroase spontan i la mobilizare, durere calcanean bilateral, umr stng czut, dureros spontan i la mobilizare, afectarea mobiliii fiind determinat prin asocierea SA i hemiparezei. La examenul funcional pacientul realizeaz singur transferurile pat-ezut-ortostatism, mersul este posibil, cosit, cu sprijin unilateral n carja canadian, cu centrul de greutate translatat spre anterior prin flexia importana cervico-dorsal Nu poate urc scrile fr ajutor dar se poate hrni i realizeaza igiena personal zilnic cu ajutor minim. Conform scalei FIM ( Functional Independence Measure) scorul funcional este 5: supraveghere, pacientul nu poate fi lsat singur, dar nu necesit contact fizic pentru a putea merge, disfuncie locomotorie i de autongrijire moderate. Investigaiile paraclinice au artat sindrom inflamator biologic moderat: VSH = 43mm/h, CRP = 8 mg/dl, fibrinogenemie = 560 mg/dl. Ag HLA B27 pozitiv, precum i acid uric = 9,5 mg/dl. Radioscopia pulmonar a artat hili pulmonari mrii, fibroza interstiial peribronhovascular, mai accentuat hiliobazal. Pe ECG apare ischemie subendocardic lateral stng. Ecografia cardiac - arat hipertrofie ventricular stng, calcificare de inel mitral posterior i regurgitaie aortic de gradul I. La spirometrie se evideniaz deficit ventilator de tip restrictiv. Radiografiile au indicat urmtoarele anomalii: a) coloana dorso-lombar (figura1): tergerea lordozei lombare, calcificri discale, sindesmofite, vertebre ptrate i imagine
Figuea 1
de coloan de bambus, b) bazin (figura 2): proteza total coxofemural stng, coxartroz dreapt, c) articulaiile sacroiliace: sacro-iliita gradul IV, semne de entezit tuberoziti ischiadice bilateral.
Figuea 2
n baza examenelor clinice i a investigaiilor paraclinice s-au stabilit urmtoarele diagnostice: Sechele posthemoragie cerebral putaminal dreapt. Hemiparez stng predominant brahial cu spasticitate medie (grad II Ashworth). Pareza facial stng de tip central, n remisiune. Spondilit
223
anchilozant forma axial gradul IV cu disfuncie respiratorie de tip restrictiv, forma medie. Sechele algo-funcionale post-artroplastie total old stng. Hipertensiune arterial stadiul II (JNC 7). Cardiopatie hipertensiv cu hipertrofie ventricular stng. Boala cardiac ischemic, forma silenioas Insuficien aortica gr I. Diateza uric. Sindrom anxios. Diagnosticul diferenial al spondilitei anchilozante, n fazele anterioare internrii prezente, s-a fcut cu discopatia lombar, spondiloza hiperosteozant, artroza articulaiilor sacro-iliace, prezent marker-ului HLA B27 stabilind etiologia (1) La internare pacientul prezent stabilit diagnosticul de hemoragie cerebral (confirmare prin CT cerebral), iar patologia cardio-vascular a fost evaluat clinic i terapeutic n urma consultului cardiologic de specialitate. Tratamentul cazului a vizat urmtoarele obiective: meninerea n limite de sigurana terapeutic a parametrilor biologici i cardiovasculari, controlul durerii i al procesului inflamator articular i periarticular, corectarea i meninerea, pe ct posibil, a mobilitii articulare, ameliorarea funciei respiratorii, creterea gradului de independen funcional (ADL) i ameliorarea calitii vieii i reinseria social (3,4). n cadrul terapiei educaional i a regimul igieno-dietetic, pacientul a fost informat corect asupra diagnosticului, evoluiei i prognosticului bolii, s-a insistat asupra continuitii terapiei, mai ales c pacientul se dovedise a fi puin compliant la internare, dieta normocaloric, hiposodat, evitnd alimentele bogate n uri, interzicerea consumului de alcool i a fumatului, evitarea suprasolicitrilor fizice i psihice, a contrastele termice, tratarea infeciilor intercurente (vaccinare antigripal anual), efectuarea zilnic a programului de kinetoterapie nsuit n clinic (pentru AVC i spondilit anchilozant) (4). Tratamentul medicamentos instituit a urmrit echilibrarea cardiovascular cu antihipertensive (blocante ale canalelor de calciu, inhibitori ai enzimei de conversie, diuretice) i antianginoase, combaterea contracturii musculare prin miorelaxante, terapia antialgic cu poten ridicat
(tramadol) i terapia anxiolitic. Pentru combaterea procesului inflamator, innd cont de asocierea celor dou patologii, s-a inpus consultul interdisciplinar ntre neurolog, reumatolog i recuperator. Decizia a fost de a nu administra AINS. Existau, de asemenea, contraindicaii pentru terapia imunosupresiva (methotrexat, leflunomid) i terapia biologica (infliximab) datorit hemoragiei cerebrale, iar corticoterapia nu i-a dovedit eficiena n spondilita ankilozant. Ca mijloace de recuperare medical s-au folosit electroterapia, cu pruden, avnd n vedere c exist un puseu inflamator i pentru ca tensiunea arterial a fost stabilizat doar dup 4-5 zile de terapie. Au fost aplicate a) unde scurte n doza IIoligoterma pentru umrul stng, 6 minute zilnic, timp de 8 zile, cu efect antiinflamator i analgetic) (2), b) crioterapia ca modalitate de terapie antiinflamatorie, prin masajul cu gheta timp de 10 min, de 2-3 ori/zi, la nivelul gleznelor, urmrind reacia vascular, cu mai mare atenie la glezna stng unde s-au identificat tulburri de sensibilitate termic (5) c) masajul terapeutic de tip sedativ i trofic la nivelul hemicorpului drept i d) manevre de netezire i vibratie pe hemicorpul stng, innd cont de prezena spasticitii (4). Kinetoterapia a avut ca obiective terapeutice principale: ntreinera posturii i aliniamentului n contextul afectrii coloanei vertebrale, a centurii pelvine i a ncrcrii plantare, ntreinerea mobilitii articulare la un nivel de maxim independena prin promovarea micrii, reeducarea transferurilor, ameliorarea mersului prin reeducarea mersului cu sprijin unilateral n crj canadian, ameliorarea disfunciei ventilatorii prin gimnastic respiratorie adaptat. Exerciiile s-au realizat la pat i la sala de kinetoterapie (7). Evoluia clinico-funcional a unui astfel de caz depinde de compliana pacientului, aderen lui la terapia medicamentoas (n special antihipertensiv), respectarea programului de recuperare medical la domiciliu, modificarea stilului de via (evitarea consumului de alcool, fumatului, suprasolicitrilor fizice i psihice) i existena unei motivaii sociale. Prognosticul quo ad vitam, ad functionem i ad laborem le-am apreciat ca fiind rezervate (8,9).
224
DISCUIA CAZULUI
Dificultatea cazului a constat n faptul c un pacient cu o patologie cardio-vascular complicat cu hemiparez stng post AVC hemoragic relativ recent (de 4 luni), asociaz un puseu inflamator n contextul unei SA, tratamentul pentru cele dou afeciuni excluzndu-se reciproc: tratamentul medicamentos specific al SA este contraindicat n statusul post-hemoragie cerebral, iar programul funcional locomotor i cardiovascular pentru
hemiparez este limitat de puseul inflamator din SA i de nivelul funcional cardio-vascular (8,10). n acest context s-a procedat la terapie de fond cardio-vascular, terapie medicamentoas simptomatic i asocierea procedurilor fizicale cu efect antialgic, miorelaxant-decontracturant, vasculotrop, pregtind esuturile articular i periarticular pentru programul activ, adaptat de kinetoterapie, aplicat progresiv (la pat i la sal), pacientul necesitnd continuarea programul la domiciliu (5).
BIBLIOGRAFIE:
1. 2. 3. 4. 5. Klippel A, Kelly J Rheumatology, 13 th Ed, 1998 Rdulescu A Electroterapie, Editura Medical, Bucureti, 2004 Braddom RL Physical Medicine and Rehabilitation, 3rd Ed, 2007 DeLisa C Physical Medicine & Rehabilitation. Principles and Practice, 4th Ed, Lippiucott, Williams & Wilkins, 2005 Sarah Nica A Recuperarea Medicala, Editura Universitar Carol Davila, Bucureti 2004. 6. 7. 8. 9. Cinteza D Termoterapia, Editura Libra Vox, Bucureti 2003 Sbenghe T Kinesiologie. tiina micrii, Editura Medical, Bucureti, 2005 Cinteza D Recuperarea medical a bolnavilor cardiaci sechelari dup accident vascular, Editura Libra Vox, Bucureti, 2003 Popescu E, Ionescu R Compendiu de Reumatologie, Editura Tehnic, Bucureti, 2003
n actualitate Efectul calcitoninei asupra nivelului -endorfinei la pacientele cu osteoporoz postmenopauz i dorsalgie Mecanismele efectului antialgic al calcitoninei n osteoporoz sau n boala Paget sunt ipotetice: creterea nivelului -endorfinei plasmatice, un mecanism periferic implicnd prostaglandinele i tromboxanii i o aciune central. Un studiu publicat recent a evaluat efectul calcitoninei asupra nivelului -endorfinei la pacientele cu cu osteoporoz postmenopauz i dorsalgie. Studiul a fost efectuat pe 30 paciente cu vrsta medie de 58 ani care au primit zilnic 1000 UI calcitonin subcutan i 1000 mg calciu elementar i un grup similar, tratat cu calciu i injecii de placebo. Obiectivul secundar a fost evaluarea durerii i calitii vieii la aceste paciente. Nivelul plasmatic al -endorfinei a fost msurat iniial i la 2 sptmni. Durerea i calitatea vieii, precum i evaluarea pacientei asupra activitii bolii au fost apreciate printr-o serie de chestionare aplicate iniial, la o sptmn i la 2 sptmni. Nivelul endorfinei la grupul tratat a fost semnificativ mai mare dect la grupul placebo, la sfritul studiului (p<0.001). Dei scorurile durerii i calitii vieii s-au ameliorat la ambele grupuri dup dou sptmni (p<0.05), ameliorarea a fost mai important la grupul tratat (p<0.05). n concluzie, efectul analgetic al calcitoninei n osteoporoza postmenopauz se exercit cel puin prin creterea nivelului plasmatic al -endorfinei, cu ameliorarea secundar a calitii vieii.
Ofluoglu D, Akyuz G et al: The effect of calcitonin on -endorfin levels in postmenopausal osteoporotic patients with back pain. Clin Rheumatol 2007; 26:44-49.
CAZUISTIC INSTRUCTIV
REACTIVARE TUBERCULOAS LA UN PACIENT CU SPONDILIT ANCHILOZANT N TRATAMENT BIOLOGIC O ANSA SPULBERAT

Cristina Pamfil, Maria-Magdalena Tamas, Ana Petcu, Bianca Gusho, Ileana Nicoara, Siao-pin Simon, Simona Rednic Clinica Reumatologic U.M.F. Iuliu Haieganu, Cluj-Napoca
PREZENTAREA CAZULUI
Prezentm cazul pacientului F.G., n vrst de 58 de ani, pensionar, provenind din mediul urban, care s-a prezentat n ambulatorul clinicii pentru dureri cu caracter inflamator la nivelul ntregului ax vertebral, gleznelor, genunchilor, carpului, umerilor bilateral, limitarea mobilitii coatelor, genunchilor i soldurilor bilateral, rigiditatea important a axului vertebral, impotena funcional marcat, cu mers n sprijin. Boala actual a debutat n 1979 prin sindrom Reiter (uretrit, conjunctivit, keratodermie blenoragic, artrit, lombalgie joas) interpretat iniial ca reumatism articular acut (RAA) i tratat cu penicilin ntr-o alt unitate. A urmat un interval de 18 ani minim simptomatic din punct de vedere articular (cu excepia unei lombalgii joase intermitente), dar cu acuze n sfera urogenital, pacientul fiind diagnosticat cu prostatita cronic. n 1999 pacientul s-a adresat pentru prima dat unui serviciu de reumatologie acuzand cervicalgie i lombalgie joas cu caracter inflamator, nsoite de artrite ale genunchilor bilateral. S-a stabilit diagnosticul de spondilartropatie artrita reactiv persistent i s-a iniiat tratament cu sulfasalazin (SSZ) 2g/zi i antiinflamatoare nonsteroidiene (AINS) cu ameliorarea simptomatologiei. n evoluie pacientul a dezvoltat modificri ale tranzitului intestinal i entezite la diferite sedii, ridicndu-se suspiciunea afectrii enterale n cadrul bolii de baz, fr a fi ns dovedit. In 2002 s-a diagnosticat spondilita anchilozant (SA) sacroiliita bilateral stadiul IV i osteoporoza secundar. Clinic, sub terapie cu metotrexat (MTX) 15 mg/sptmna, SSZ 2,5g/zi, AINS i bisfosfonai (alendronat) boal a
rmas active, att axial ct i periferic, cu evoluie spre anchiloze, aa nct n 2004 s-a iniiat terapie cu infliximab (obinut prin sponsorizare) asociat cu MTX 15 mg/sptmn. Terapia biologic a fost urmat timp de 10 luni de evoluie discret favorabil, cu o reducere a scorului de activitate a bolii BASDAI de la 7,5 la 6, ns a fost sistat din motive obiective i datorit necesitii artroplastiei totale de old. Boal a rmas n evoluie activ n pofida asocierilor de MTX i leflunomid, astfel nct n 2007 s-a iniiat a doua terapie biologic cu adalimumab, de aceast dat cu rspuns terapeutic spectaculos (scor de activitate a bolii la 12 luni de la terapie BASDAI = 2,35, scor funcional BASFI = 3,7). La un an de tratament biologic, pacientul a dezvoltat tuberculoz pulmonar i peritoneal, iar terapia cu adalimumab a fost, n consecin, sistat. S-a introdus cvadrupla terapie tuberculostatic sub care pacientul a dezvoltat hepatit acut medicamentoas, remis prin modularea tuberculostaticelor. Boala a redevenit intens activ la multiple sedii att axial ct i periferic, s-a complicat cu uveita acut, iar opiunile terapeutice limitate au fost puin sau deloc eficiene. Ultima schem a pacientului a cuprins SSZ 1g/zi, Prednison 10 mg/zi i leflunomid 20mg/zi. La examenul obiectiv din prezent se constat paloare tegumentar, artrite radiocarpiene, ale gleznelor, genunchilor, umerilor bilateral, semianchiloze ale coatelor, genunchilor i oldurilor bilateral, sensibilitate la percuia apofizelor spinoase ale ntregului ax vertebral rigiditatea important a axului vertebral, disabilitate marcat. Biologic se constat sindrom inflamator intens (VSH = mm/h, CRP = 11 mg/dl), sindrom
225
226
anemic uor (Hb = 11 g/dl, Ht = 34%), restul analizelor fiind n limite normale. Diagnosticele de SA i osteoporoza secundar se menin, ridicndu-se problema strategiilor terapeutice posibile.
DISCUIA CAZULUI
Prima problem care s-a ridicat n acest caz a fost ntrzierea diagnosticului pozitiv de spondilartropatie (artrita reactiv interpretat ca RAA), distana de la primele simptome ale bolii i momentul diagnosticului fiind de 20 ani. Datele din literatur arat c media ntrzierii diagnosticului este de 6 +/- 5 ani (1), diagnosticul precoce fiind extrem de important pentru un prognostic mai bun. Mai mult dect att, este cunoscut faptul ca evoluia artritei reactive poate fi spre cronicizare n 2-18 % din cazuri, spre sacroiliit n 14-50% din cazuri sau spre spondilit anchilozant n 12-25% din cazuri, uretrit fiind un factor suplimentar de risc pentru evoluia ctre SA (2). Interpretarea diagnostic iniial de RAA a avut ca i consecin terapeutic administrarea de penicilin, care nu acoper ns spectrul microorganismelor inductoare de artrit reactiv, iar lipsa urmririi n timp a evoluiei bolii s-a soldat cu o evoluie natural spre anchiloz. A doua problem care se impune a fi discutat este reactivarea tuberculozei sub tratament biologic cu blocani de factor de necroz tumoral (TNF ) alfa. Terapiile biologice sunt considerate soluii de necontestat n managementul SA, fiind asociate cu risc important de activare a infeciei tuberculoase (3). n cazul pacientului prezentat complicaia s-a validat la nivel peritoneal, prin ascit, clinic cu subfebrilitai i dureri abdominale difuze, iar biologic cu sindrom de colestaz. Ecografic s-au obiectivat multiple formaiuni hipoecogene splenice, dilatarea venei splenice, vegetaii peritoneale, colecie peritoneal. S-au exclus limfomul splenic sau alte diagnostice difereniale. S-a practicat laparoscopie diagnostic cu biopsie peritoneal, care a artat aspect morfopatologic de peritonita granulomatoas, cultur i citologia din lichidul de ascit neaducnd informaii suplimentare. Diagnosticul stabilit n aceast etap a fost unul presupus, i anume peritonit bacilar. Nici radiografia pulmonar, i nici examenul microscopic sau culturile din sput nu au pledat pentru etiologia tuberculoas la acel moment.
S-a iniiat tratament tuberculostatic, n cvadrupla asociere. La scurt timp pacientul a dezvoltat hepatit toxic medicamentoas, cu creteri ale trasaminazelor de 40 de ori fa de valorile normale, fiind necesar modularea terapiei pentru meninerea eficienei. Diagnosticul de tuberculoz miliar s-a stabilit la o lun de la nceperea chimioterapiei, dup repetarea investigaiilor n sfera pulmonar (culturile din sputa pozitive pentru bacilul Koch (BK)). Reiese din acest demers dificultatea stabilirii diagnosticului de tuberculoz, acesta fiind dependent pe de o parte de fidelitatea testelor utilizate i, pe de alt parte, de dificultatea izolrii BK. Totodat subliniem importana ridicrii suspiciunii diagnostice la pacienii tratai cu ageni biologici, n special cu antagoniti TNFalfa. Unele studii arat o frecven mai mare a reactivrii tuberculoase n cazul anticorpilor monoclonali (infliximab i adalimumab) fa de receptorii solubili de TNFalfa (etanercept) (4). Un alt aspect const n iniierea precoce a chimioterapiei la aceti pacieni imunosupresai cu risc crescut de mortalitate, ct i conducerea corect a terapiei (5). Ghidurile actuale de tratament ce recomand screening -ul tuberculos anterior iniierii terapiei biologice au cobort barier de iniiere a chimioprofilaxiei de la o valoare a IDR la PPD de 10 mm la 5 mm (6). Pacientul a avut IDR = 5 mm nainte de nceperea tratamentului biologic, situndu-se la grania atitudinii chimioprofilactice. Studii retrospective recunosc procente mari de reactivare tuberculoas chiar i la valori ale IDR < 5 mm (7). O ultim problem ce se impune a fi discutat este abordarea terapeutic. Pacientul prezint n urma sistrii terapiei biolgice o reactivare a bolii articulare, fiind n prezent neresponsiv la medicaia de fond i puin responsiv la AINS zilnice. Soluile de abordare sunt restrnse. Corticosteroizii (CS) cu administrare intraarticular sunt o rezolvare tranzitorie i neaplicabil numrului mare de articulaii periferice implicate. Rmne n discuie administrarea CS in pulse-terapie, avnd n vedere activitatea clinic i biologic a bolii. n ceea ce privete reluarea tratamentului cu ageni anti TNFalfa dup infecia tuberculoas exist puine date n literatur. Unii autori au demonstrat pe loturi mici de pacieni eficiena n condiii de siguran (8). Rmn dou ntrebri deschise privind sigurana i momentul optim de rentroducere a terapiei.
227
Alte terapii biologice nu i-au dovedit eficiena n SA. Au fost raportate efectele pozitive ale bisfosfonailor pe metabolismul osos, inflamaie i imunomodulare: perfuziile lunare cu pamidronat diminu activitatea bolii i mbuntesc indicii de funcionalitate i mobilitate spinal (9,10).
CONCLUZII
Un diagnostic rapid i corect al bolii influeneaz n sens pozitiv evoluia natural. Instituirea precoce
a terapiei cu AINS i anti- TNF alfa singurele capabile s reduc proliferarea osoas i deci singurele care influeneaza prognosticul este principiul de baza n managementul SA. Terapia cu anti- TNF alfa aduce un risc important al reactivrii tuberculoase, ce implic un potenial de mortalitate i atrage dup sine retragerea terapiei biologice la o categorie de pacieni cu arsenal terapeutic redus. Soluiile terapeutice n acest caz rmn extrem de limitate.
BIBLIOGRAFIE
1. Dincer U, Cakar E, Kiralp MZ, Dursun H Diagnosis delay in patients with ankylosing spondylitis: possible reasons and proposals for new diagnostic criteria, Clin Rheumatol 2008, 27: 457-462 Hannu T, Inman R, Granfors K, Leirisalo-Repo M Reactive arthritis or postinfectious arthritis? Best Pract Res Clin Rheumatol 2006, 20: 419-433 Carmona L, Gmez-Reino JJ, Rodrguez-Valverde V et al Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists, Arthr Rheum 2005, 52:1766-1772 Wallis RS, Broder MS, Wong JY et al Granulomatous infectious diseases associated with tumor necrosis factor antagonists, Clin Infect Dis 2004, 38: 12611265 Keane J, Bresnihan B Tuberculosis reactivation during immunosuppressive therapy in rheumatic diseases: diagnostic and therapeutic strategies, Curr Opin Rheumatol 2008, 20: 443-449 Fonseca JE, Lucas H, Canho H et al Guidelines for the diagnosis and treatment of latent tuberculosis infection and active
2.
3.
4.
5.
6.
tuberculosis in patients with inflammatory joint diseases proposed for treatment with tumour necrosis factor alpha antagonist drugs, Rev Port Pneumol 2006, 12: 603-613 7. Fonseca JE, Canho H, Silva C, Miguel C et al Tuberculosis in rheumatic patients treated with tumour necrosis factor alpha antagonists: the Portuguese experience, Acta Reumatol Port 2006, 31: 247-253 8. Aslanidis S, Pyrpasopoulou A, Douma S, Petidis K Is it safe to readminister tumor necrosis factor alpha antagonists following tuberculosis flare? 2008, 58: 327-328 9. Malaviya AN, Kapoor S, Garg S, Ahmad I, Raja RR A new strategy of drug treatment in NSAID-unresponsive ankylosing spondylitis: combination of pamidronate and methylprednisolone monthly intravenous infusions on the background of a combination of disease modifying drugs sulfasalazine and methotrexate, Abstr J Assoc Phys India 2007, 55: 380 10. Toussirot E, Wendling D Antiinflammatory treatment with bisphosphonates in ankylosing spondylitis, Curr Opin Rheumatol 2007, 19: 340-345
n actualitate Compararea nivelului seric al IL1-, sIL-2R, IL-6 i TNF- cu parametrii de activitate a bolii n spondilita anchilozant Etiologia spondilitei anchilozante (SA) rmne nc incomplet cunoscut. Citokinele, proteine solubile cu roluri specifice n rspunsul inflamator, intervin n interaciunile dintre celulele sistemului imun. Activitatea SA este frecvent cuantificat utiliznd parametrii inflamaiei, ca proteina C reactiv (CRP) i viteza de sedimentare a hematiilor (VSH). Studiul i-a prop-us evaluarea relaiilor dintre nivelul unor citokine i parametrii clinici i de laborator ai pacienilor cu SA, fa de subiecii sntoi. Nivelurile serice ale receptorului solubil al interleukinei-2 (sIL-2R), interleukinei-6 (IL-6), i cel al factorului de necroz tumoral a (TNF-) au fost semnificativ mai mari la pacienii cu SA fa de grupul de control, n schimb nu s-au observat diferene privind nivelul interleukinei-1. Titrul CRP a fost corelat cu cel al IL-6, iar nivelul VSH cu cel al sIL-2R, IL-6 i TNF-. Dintre parametrii clinici ai bolii, indicele metrologic Bath i indicele funcional Bath s-au corelat doar cu nivelul sIL-2R. Autorii sugereaz c sIL-2R, IL-6 i TNF- ar putea avea un rol n patogeneza SA i c aceste citokine ar putea fi utile ca markeri de diagnostic i de activitate a bolii.
Bal A, Unlu E et al: Comparison of IL1-, sIL-2R, IL-6 and TNF- levels with disease activity parameters in ankylosing spondylitis. Clin Rheumatol 2007; 26:211-215.
Instruciuni pentru autori

Structura revistei
Revista Romn de Reumatologie public urmtoarele tipuri de materiale: editoriale, articole de orientare, lucrri originale, cazuri clinice, subiecte pentru rezideniat, vignete terapeutice sau imagistice, chestionare de autoevaluare, quiz-uri, actualiti i articole de sociomedicin i educaie medical, coresponden (ntrebri, comentarii, puncte de vedere etc.), recenzii. Principalele seciuni cu format impus sunt: Articole de orientare Coninut: informaie general de actualitate axat pe probleme teoretice i/sau practice (revista literaturii). Dimensiuni: maximum 12 pagini (la nevoie, articolul poate fi mprit pentru a fi publicat n numere consecutive). Format: text compact (nu schematizat), fr sau cu puine subcapitole. Bibliografie: recent (75% titluri din ultimii 5 ani), cu prioritate pentru articole publicate in extenso, citnd puine rezumate, capitole de manual sau cri n ntregime, introdus n text. Lucrri originale Coninut: cercetri fundamentale sau clinice (diagnostic sau tratament). Dimensiuni: 6-8 pagini, cu 4-5 materiale ilustrative (texte, grafice sau figuri). Format: introducere (starea actual a problemei, premisele i scopul cercetrii), material i metode, rezultate, discuii, concluzii (numerotate, redactate sintetic i strict referitoare la constatrile personale). Bibliografia introdus n text (vezi mai jos). Cazuri clinice Coninut: observaii clinice de excepie sau care pun/clarific o problem, din categoria celor care se ncheie cu o confirmare (morfologic, terapeutic, evolutiv etc.). Dimensiuni: 3-5 pagini, cu 1-2 ilustraii originale (clinice, imagistice, morfologice etc.). Format: prezentarea cazului, comentarii. Bibliografie n text (la comentarii). Instruciuni pentru redactare Autorii sunt rugai s respecte cu strictee toate recomandrile care urmeaz, pentru a facilita munca de (tehno)redactare. Materialele trimise pentru publicare vor fi culese n programul Word cu caractere Arial de 12, la un rnd i jumtate, n trei exemplare, tiprite pe o singur parte a filei i salvate pe dischet (pstrai i dvs un exemplar!). Pentru a evita ntrzierile i corespondena inutil, v rugm s avei n vedere urmtoarele: Titlul cu font 14 bold. Numele autorilor precedat de iniiala prenumelui pentru brbai i de prenumele n ntregime pentru femei. Denumirea complet a instituiei/instituiilor crora le aparin autorii indicnd prin cifre apartenena (dac este cazul) i localitatea, culese cu corp italic (cursive). Adresa complet a primului autor sau a celui din colectivul de autori, care este abilitat s poarte corespunden n numele acestuia (cu redacia, pentru cerere de extrase etc.), cu numerele de telefon/ fax i, dac exist, adresa de e-mail. Rezumat n limbile romn i englez, redactat sintetic, de preferin structurat pe scop, material i metode, rezultate, discuii i concluzii (pentru lucrrile originale). Rezumatul trebuie ntocmit i pentru articolele de orientare. Nu utilizai prescurtri. Folosii acronime, sub form de caractere capitale, numai dac un termen revine de mai multe ori n text i avei grij s le explicai la prima utilizare. Evitai termenii mprumutai din alte limbi prefernd traducerea romnesc acceptat n literatur. Dac acest lucru nu este posibil, culegei-i cu italice.
Bibliografia va fi alctuit n sistemul Oxford (adaptat ca mai jos). Indicai n text numrul titlului bibliografic de pe lista citrilor, acolo unde ideea a fost preluat, ntre paranteze. Lista bibliografic va fi ntocmit n ordinea citrilor n text, nu dup alfabet. Componentele surselor, care trebuie redactate strict ca n exemplele de mai jos, pot fi: Cri n ntregime: Autori/editori, cu numele i iniiala prenumelui Titlul ntre ghilimele i cu majuscule iniiale Ediia (dac este cazul) Editura Locul publicrii Anul apariiei Exemplu: Iagru N., Reumatologie Pediatric, Editura Medical Amaltea, Bucureti, 2003 Capitole din cri sau tratate, semnate de autori distinci: Autorul capitolului, cu numele i iniiala prenumelui Titlul capitolului Autorii sau editorii volumului, cu nume i iniiala prenumelui, urmai de Titlul volumului, ntre ghilimele i cu majuscule iniiale, introdui prin particula n: Ediia (dac este cazul) Editura Locul publicrii Anul apariiei urmat de dou puncte Paginile ntre care este cuprins capitolul Exemplu: Boloiu H.D., Man L., Rednic S., The effect of methylprednisolone pulse therapy in polymyositis/ dermatomyositis, in: Mallia C., Uitto J. Current Issues in Rheumatology and Dermatology, Kulver Academic and Plenum Press, New York, 1999: 349-358 Articole: Autori, cu numele i iniiala prenumelui (numai primii trei, urmai de etc, n cazul n care sunt mai muli de patru) Titlul articolului Titlul revistei n prescurtare internaional, n italice Anul, urmat de virgul Volumul, urmat de dou puncte Paginile ntre care este cuprins articolul Not: Dac articolul citat este publicat n rezumat (ex. revist, volum cu rezumatele unor manifestri tiinifice), sursa va fi indicat precedat de Rez. n: sau Abstr. in: Exemplu: Lems W.F., Ader H.J., Lodder M.C. etc, Reproductibility of bone mineral density measurements in daily practice, Ann Rheum Dis 2004, 63: 285-289 Exemplu: Blnescu A., Nat R., Predeeanu D. etc, Influena tratamentului imunosupresor asupra imunofenotipului celulelor dentritice din sinoviala reumatoid, Rez. n: Rev Reumatol 2003, 11 (Supliment): 56 Coresponden Orice coresponden adresat revistei va fi expediat la urmtoarea adres: Dr. Laura Damian, Secretar de redacie, Revista Romn de Reumatologie, Clinica Reumatologic, Str. Clinicilor nr. 4, 400006 ClujNapoca, tel 0264 598443 sau 0264 591942 int 464, fax 0264 431040, e-mail: meddoi@cluj.astral.ro Abonamente Membrii Societii Romne de Reumatologie sunt abonai de drept la Revista Romn de Reumatologie, prin efectul plii cotizaiei. Persoanele din afar se pot abona adresndu-se secretariatului redaciei, la adresa de mai sus. Reclame Angajarea activitilor de reclam i plata pentru aceste servicii se face prin negociere cu editorul (Editura Medical AMALTEA, Bucureti, Str. Sptarului nr. 31, tel. 021/210.45.55; Persoan de contact: Dr. M.C. Popescu). Societatea Romn de Reumatologie i rezerv dreptul de a aviza includerea oricrui material promoional n revista sa i percepe o cot parte din beneficii, n condiiile contractului cu acesta.

Revista Romana de Reumatologie 2008 NR 4

Încărcat de

Informații document

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Revista Romana de Reumatologie 2008 NR 4

Încărcat de

Drepturi de autor:

Formate disponibile

Revista Romn de

SERENDIPITATE I TRATAMENTUL REUMATOLOGIC

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

MOST FREQUENTLY OCCURRING SIDE EFFECTS

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

(Articol publicat n parteneriat cu Rheumatology 2007;46:10491051)

n actualitate Amiloidoza n poliartrita reumatoid

SOCIETII ROMNE DE REUMATOLOGIE www.srreumatologie.ro

BISPHOSPHONATES AND OSTEONECROSIS OF THE JAW

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

11. 12. 13.

VERY EARLY RHEUMATOID ARTHRITIS COHORTS: LIMITED BY SELECTION

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

USE OF RA CLASSIFICATION CRITERIA IN EA COHORTS

THE EFFECT OF PATIENT RECRUITMENT AND LOST-TO FOLLOW-UPS IN EA COHORT STUDIES

ANTI-CCP TEST IN GUIDING THE MANAGEMENT OF ERA

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

RADIOLOGICAL OUTCOME OF PATIENTS WITH EA

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

Figura 2. ROI 0 binarizat

Figura 3. Spectru multifractal

Figura 1. Dispunerea celor 3 ROI.

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

Figura 4. Reprezentarea tridimensional a unei ROI 0.

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

Tabel 2.Valorile parametrilor evaluai la pacienii cu PR comparativ cu grupul de control

Figura 2. Susceptibilitatea la peroxidarea lipidic la pacienii cu PR comaparativ cu grupul de control

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

n actualitate Rspunsul la adalimumab n poliartrita reumatoid precoce i avansat

EVALUAREA STILULUI DE VIA AL PACIENILOR CU POLIARTRIT REUMATOID

Summary Life-style evaluation in patients with rheumatoid arthritis

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

Tabelu 2. Prevalena fumatului i a consumului de cafea la cele dou loturi, pe sexe

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

20. 21. 22.

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

SOCIETII ROMNE DE REUMATOLOGIE www.srreumatologie.ro

CONSIDERAII ASUPRA TERAPIEI CU ETANERCEPT LA COPII CU ARTRIT IDIOPATIC JUVENIL

Summary Etanercept in children with juvenile idiopathic arthritis

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

PROBLEME TERAPEUTICE LA UN PACIENT CU SPONDILIT ANCHILOZANT I STATUS POST-HEMORAGIE CEREBRAL

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REACTIVARE TUBERCULOAS LA UN PACIENT CU SPONDILIT ANCHILOZANT N TRATAMENT BIOLOGIC O ANSA SPULBERAT

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 4 - 2008

Instruciuni pentru autori

S-ar putea să vă placă și