Efficacy of tumor necrosis factor ╨Ю┬▒ blockade for enthesitis in spondylarthropathyComment on the article by Marzo-Ortega et al.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 46, No. 12, December 2002, pp 3390–3398 © 2002, American College of Rheumatology LETTERS Wait times for new patients to see rheumatologists are lengthy, ranging from 4 to 24 weeks in both community practices and academic medical centers. This is unacceptable, particularly in light of our new understanding of the disease progression of our core diseases, including rheumatoid arthritis. Delay in treatment of even several months may be deleterious to patients with rheumatoid arthritis (Pincus T, Gibofsky A, Weinblatt ME. Urgent care and tight control of rheumatoid arthritis as in diabetes and hypertension: better treatments but a shortage of rheumatologists. Arthritis Rheum 2002;47:851– 4). With the crisis in the number of practicing rheumatologists, we need to develop better systems to reduce the wait times for patients with systemic rheumatic disease. It is unacceptable for patients with rheumatoid arthritis to wait months for a newpatient appointment. We need to triage and manage patients better so that patients with systemic rheumatic diseases can be seen in a more timely manner. I am delighted that my address generated such lively discussion, having received many calls, letters, and e-mails, particularly regarding my comments about ethics, industry relations, and the work force situation. This crisis in work force must be addressed, because without a sufficient number of rheumatologists to care for all of our patients, rationing of visits for those with nonsystemic rheumatic illnesses (including fibromyalgia) may be required to adequately care for those with systemic rheumatic disease. DOI 10.1002/art.10569 The value of rheumatologists to patients with fibromyalgia: comment on the presidential address by Weinblatt To the Editor: Although I reviewed the American College of Rheumatology presidential address (Weinblatt ME. ACR presidential address: the best of times, the worst of times, rheumatology 2001. Arthritis Rheum 2002;46:567–73) with great interest as soon as it arrived, I regret that its Tale of Two Cities metaphor inspired not only juxtaposition, but also a conflicting emotional response quite separate from its intended message. Although the address triumphantly chronicled many accomplishments and described our new challenges, I felt belittled by the comments regarding fibromyalgia. Rheumatologists have a proud tradition of walking where others fear to tread. Our participation in investigating the enigmas of breast implants, Lyme disease, tryptophan, and myriad other puzzles only hastened the eventual understanding of these problems. Who is better qualified than rheumatologists to finally unravel the daunting mystery of fibromyalgia? I believe that Dr. Weinblatt may be inaccurate when he suggests that rheumatologists provide “little value” to patients with fibromyalgia. The comments regarding Mary Betty Stevens personified my hopes and aspirations as well. While each specialty seems to be trying to discard their most emotionally challenging disorders to primary care physicians and psychiatrists, I doubt that those inspiring pioneers ever took the easy road by “restricting followup visits.” We will overcome this daunting adversary called fibromyalgia. And, as with previous challenges, we will eventually be just as proud of that effort and determination. We are all committed to caring for patients with inflammatory diseases, but our past success should inspire us to conquer all of our challenges, not just to enjoy the fruits of our recent advances for a portion of our patients. Michael E. Weinblatt, MD Brigham and Women’s Hospital and Harvard Medical School Boston, MA DOI 10.1002/art.10562 Increased osteoprotegerin and decreased pyridinoline levels in patients with ankylosing spondylitis: comment on the article by Gratacós et al Andrew J. Holman, MD Seattle, WA To the Editor: As previously reported in Arthritis & Rheumatism, measurement of bone mass in patients with ankylosing spondylitis (AS), shows conflicting results (1). The same appears to occur in the evaluation of biochemical markers of bone metabolism in AS (2). We reasoned that some of these discrepant results observed in the various studies using urinary markers of bone resorption were attributable to the fact that the markers are expressed in relation to the amount of creatinine excreted, and that considerable variation could be expected due to the fact that various degrees of immobilization related to the ankylosis could lead to distinct levels of creatinine in the urine, altering the amount of pyridinoline present. To bypass these limitations, we assessed serum (rather than urine) pyridinoline values, using the novel serum osteoprotegerin (OPG) assay in a select population of patients with AS. DOI 10.1002/art.10572 Reply To the Editor: I thank Dr. Holman for his comments regarding my presidential address. I had hoped that my comments would generate lively discussion (“as a soon to be past president, I now welcome controversy!”). I certainly appreciate his comments regarding the issue of our specialty and fibromyalgia. In fact, many of our colleagues, including Drs. Bennett, Goldenberg, Smythe, and others, have made extraordinary contributions to this field. Our specialty and our patients are indebted to those investigators in the area of fibromyalgia. However, as I noted in my address, the issue now really is access to care. 3390 LETTERS 3391 Table 1. Clinical characteristics of 25 patients with ankylosing spondylitis* Age, mean ⫾ SD years Disease duration, mean ⫾ SD years Male/female, no. Peripheral arthritis plus spinal involvement, no. Spinal involvement only, no. BASFI score, mean ⫾ SD (0–10) BASDAI score, mean ⫾ SD (0–10) 38.5 ⫾ 9.0 13.5 ⫾ 7.6 23/2 23 2 5.5 ⫾ 1.9 4.7 ⫾ 2.1 * BASFI ⫽ Bath Ankylosing Spondylitis Function Index (see ref. 9); BASDAI ⫽ Bath Ankylosing Spondylitis Disease Activity Index (see ref. 8). OPG is a naturally occurring cytokine that is a member of the family of tumor necrosis factor receptors and as such plays a critical role in the regulation of bone resorption. It has been shown that OPG acts as an inhibitor of osteoclastogenesis and increases bone density (4,5). We studied 25 patients (23 men and 2 women) with AS, selected from among those attending the outpatient rheumatology clinic of the Hospital Central Santa Casa de São Paulo. The mean age of the patients was 37.0 years, and the mean duration of disease was 13 years (range 1–26 years). All patients fulfilled the New York revised criteria for AS (6). Twenty-three patients had both spinal and peripheral involvement (Table 1). The control group included 40 healthy ageand sex-matched individuals with a mean ⫾ SD age of 44 ⫾ 3 years. We used the CrossLaps (Osteometer, Copenhagen, Denmark) carboxy-pyridinoline serum assay, performed according to the instructions. The intraassay coefficients of variation were 6.0 and 6.2, respectively; these values were obtained internally using a large group of patients (7). Direct quantitative determination of OPG in serum was performed by a standard 96-well enzyme-linked immunosorbent assay format (Immunodiagnostic, Bensheim, Germany). Disease activity was measured according to published criteria (8,9). Data were usually reported as the mean ⫾ SEM, with correlations by Spearman’s coefficient test. P values less than 0.05 were considered statistically significant. The results observed are shown in Table 2. The serum pyridinoline values of AS patients were significantly reduced compared with those of normal controls, and serum OPG levels were significantly increased in AS patients compared Table 2. Biochemical bone markers in patients and controls* Study group Marker Serum pyridinoline, pmoles/ liter Serum osteoprotegerin, pg/ml * Values are the mean ⫾ SD. Ankylosing spondylitis Control P 1,255 ⫾ 983 2,176 ⫾ 252 ⬍0.01 138 ⫾ 25 62 ⫾ 43 ⬍0.01 with controls. There was a significant negative correlation between serum pyridinoline and OPG levels (r ⫽ 0.78). Our study shows that in patients with AS, serum pyridinoline levels are reduced at the same time that OPG levels are increased. The lower levels observed in patients with AS suggest that osteoclastic activity is reduced in AS, pointing to the possibility that we may be dealing with low bone remodeling in such patients. This is the first study of its kind to assess OPG levels in patients with AS. Two pitfalls of our investigation are the fact that OPG is synthesized by various skeletal and extraskeletal tissues and cell types and regulation of this synthesis is dependent on a variety of hormones and cytokines, and the fact that circulating OPG levels may only partially reflect the bone/bone marrow microenvironment. However, these pitfalls are present in all studies of bone biology using serum markers. Taking in consideration that OPG may soon be used for the therapy of bone diseases, our results may also have future clinical aplications. Ricardo Prado Golmia, MD Branca Dias Batista Sousa, MD Morton Aaron Scheinberg, MD, PhD, FACP Center for Clinical Immunology and LID Laboratory São Paulo, Brazil 1. Gratacós J, Collado A, Pons F, Osaba M, Sanmartı́ R, Roqué M, et al. Significant loss of bone mass in patients with early, active ankylosing spondylitis: a followup study. Arthritis Rheum 1999;42: 2319–24. 2. Bronson WD, Walker SE, Hillman LS, Keisler D, Hoyt T, Allen SH. Bone mineral density and biochemical markers of bone metabolism in ankylosing spondylitis. J Rheumatol 1998;25:929–35. 3. Beck-Jensen JE, Kollerup G, Sorensen HA, Pors Nielsen S, Sorensen OH. A single measurement of biochemical markers of bone turnover has limited utility in the individual person. Scand J Clin Lab Invest 1997;57:351–9. 4. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309–19. 5. Hofbauer LC, Khosla S, Dunstan CR, Lacey D, Boyle WJ, Riggs BI. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 2000; 15:2–12. 6. Moll JM, Wright V. New York clinical criteria for ankylosing spondylitis: a statistical evaluation. Ann Rheum Dis 1973;32: 354–63. 7. Christgau S, Rosenquist C, Alexandersen P, Bjarnason NH, Ravn P, Fledelius C, et al. Clinical evaluation of the Serum CrossLaps One Step ELISA, a new assay measuring the serum concentration of bone-derived degradation products of type I collagen C-telopeptides. Clin Chem 1998;44:2290–300. 8. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994;21:2286–91. 9. Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, Mallorie P, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 1994;21:2281–5. 3392 LETTERS DOI 10.1002/art.10571 Reply To the Editor: We read with interest the letter by Golmia et al concerning the controversial topic of the physiopathologic mechanism responsible for the loss of bone mass observed in patients with AS. In our opinion, the bone mass loss in AS patients is not controversial. In this respect, sufficient data have been published in the literature to support the loss of bone mass in early stages of the disease, with no clear relationship with vertebral stiffness and limitation (1,2). Moreover, this bone mass loss recently has been shown to be associated with inflammatory activity of AS, as demonstrated in our study (2) and later confirmed by other investigators (3). However, and in agreement with Golmia et al, the precise mechanism by which distinct factors, particularly inflammatory activity, play a role in bone remodeling remains controversial (4–8). Using novel laboratory tests (serum pyridinoline and OPG determinations), Golmia et al observed reduced osteoclastic activity, which raises the possibility of low bone remodeling in these patients. The majority of previously reported studies, however, support increased bone resorption in AS patients (4–6). Furthermore, given the association between the bone mass loss and the inflammatory activity of AS and the well-known effects on bone exerted by proinflammatory cytokines (interleukin-6, tumor necrosis factor ␣) (9–10) in this process (11–12), increased bone resorption would appear to be a more logical mechanism to account for the demineralization. Moreover, the study by Golmia et al lacks the assessment of other classic bone remodeling biochemical markers (e.g., bone-specific alkaline phosphatase, osteocalcin, urine pyridinium cross-links), and, consequently, their possible correlation with the biochemical bone markers reported by the authors. In our opinion, this is of importance, bearing in mind that the definitive validation of serum pyridinoline and OPG determinations in clinical practice is still pending. Although all these observations do not invalidate the interesting results reported by Golmia et al, they do require that these data be regarded with caution. Furthermore, they underline the enormous difficulty encountered in assessing the physiopathologic mechanism implicated in the bone mass loss in patients with AS when this mechanism is evaluated far away from the site of bone mass loss, using only a few biochemical bone markers. In this regard, the complex network of relationships between cells involved in bone remodeling and the inflammatory process driven by several local factors (cytokines, etc.) point to the need for local tissue studies to gain further insight into this topic. Jordi Gratacós, MD Raimon Sanmarti, MD University Hospital of Parc Tauli Barcelona, Spain 1. Will R, Palmer R, Bhalla AK, Calin A. Osteoporosis in early ankylosing spondylitis: a primary pathological event? Lancet 1989; 2:1483–5. 2. Gratacós J, Collado A, Pons F, Osaba M, Sanmartı́ R, Roqué M, et al. Significant loss of bone mass in patients with early, active ankylosing spondylitis: a followup study. Arthritis Rheum 1999;42: 2319–24. 3. Dos Santos FP, Constantin A, Laroche M, Destombes F, Bernard J, Mazieres B, et al. Whole body and regional bone mineral density in ankylosing spondylitis. J Rheumatol 2001;28:547–9. 4. Acebes C, de la Piedra C, Traba ML, Seibel MJ, Garcia Martin C, Armas J, et al. Biochemical markers of bone remodeling and bone sialoprotein in ankylosing spondylitis. Clin Chim Acta 1999;289: 99–110. 5. Macdonald AG, Birkinshaw G, Durham B, Bucknall RC, Fraser WD. Biochemical markers of bone turnover in seronegative spondyloarthropathy: relationship to disease activity. Br J Rheumatol 1997;36:50–3. 6. Toussirot E, Ricard-Blum S, Dumoulin G, Cedoz JP, Wendling D. Relationship between urinary pyridinium cross-links, disease activity and disease subsets of ankylosing spondylitis. Rheumatology (Oxford) 1999;38:21–7. 7. Mitra D, Elvins DM, Collins AJ. Biochemical markers of bone metabolism in mild ankylosing spondylitis and their relationship with bone mineral density and vertebral fractures. J Rheumatol 1999;26:2201–4. 8. Speden DJ, Calin AI, Ring FJ, Bhalla AK. Bone mineral density, calcaneal ultrasound, and bone turnover markers in women with ankylosing spondylitis. J Rheumatol 2002;29:516–21. 9. Macdonald BR, Gowen M. Cytokines and bone. Br J Rheumatol 1992;31:149–55. 10. Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling: emerging insights into the pathophysiology of osteoporosis. N Engl J Med 1995;332:305–11. 11. Gratacós J, Collado A, Filella X, Sanmartı́ R, Cañete J, Llena J, et al. Serum cytokines (IL-6, TNF-␣, IL-1␤ and IFN-␥) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol 1994;33:927–31. 12. Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbest H, et al. Use of inmunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995;38: 499–505. DOI 10.1002/art.10565 Increased cutaneous reactions to hydroxychloroquine (Plaquenil) possibly associated with formulation change: comment on the letter by Alarcón To the Editor: We read with interest Alarcón’s case report of retinopathy in a patient receiving hydroxychloroquine (HCQ) (1). We have not seen any patients with HCQ retinal toxicity in our large clinic cohort. However, over the last year we have noticed a marked increase in the number of cutaneous reactions occurring in patients who are taking HCQ. Antimalarials are generally well tolerated when compared with other disease-modifying drugs (2). In terms of cutaneous reactions, antimalarials can induce urticaria, pruritus, alopecia, hair bleaching, dry skin, pigment changes, rashes, flares of psoriasis and exfoliating lesions, as well as a Stevens– Johnson-like syndrome (3–10). Most patients continue HCQ therapy in the long term, but ⬃3% discontinue HCQ because of adverse cutaneous reactions. We now report a marked increase in the number of cutaneous reactions to HCQ over the last year, which apparently coincided with a change in formulation by the manufacturer. 44 60 44 36 54 56 49 49 1 2 3 4 5 6 7 8 9 10 11 Probable SLE Discoid lupus Discoid lupus SLE SLE, DLE Lupus-like syndrome SLE, cryoglobulinemia SLE SLE, APS SLE, APS SLE, DLE Diagnosis Asthma, hypertension – Hyperlipidemia Multinodular goiter, TIA – TIA, depression Breast cancer Epilepsy, peripheral neuropathy Trigeminal neuropathy Cecum cancer Endometriosis Other main diseases Yes No No Yes No Yes Yes No No No Yes Sjögren’s syndrome Morphine, fluoxetine, carbamazepine, tramadol, amitriptyline No No No No Penicillin No Co-trimoxazole Penicillin No No Drugs No No No Alcohol No No No No No No No Food Allergies No No No Metal clips, elastoplast, perfume No No Nickel, cobalt No No No No Other No No No No No No No No No No No Family history No No No No No No No No No MI, CVA CVA Other family history * The study period for patient 1 was October 1999 to October 2000; the study period for all other patients was October 2000 to October 2001. SLE ⫽ systemic lupus erythematosus; APS ⫽ antiphospholipid syndrome; TIA ⫽ transient ischemic attack; MI ⫽ myocardial infarction; CVA ⫽ cerebrovascular accident; DLE ⫽ discoid lupus erythematosus. 33 62 56 Patient Clinical characteristics of 11 female patients with cutaneous reactions to hydroxychloroquine* Age, years, at time of reaction Table 1. LETTERS 3393 3/20/01 7/14/01 3/7/01 7/13/01 3/29/01 10/15/97 10/8/00 1/98 7/31/00 3/15/01 1 2 3 4 5 6 7 8 9 10 11 8/4/01 11/15/00 10/27/00 10/00 11/28/00 4/7/01 6/8/01 3/19/01 7/14/01 3/24/01 10/18/99 9 30 19 20 20 23 23 12 1 4 – 2 6 3.8 4 4 5 5 2 5 1 – Total grams of new formulation taken No Yes No Yes Yes No No No No Yes No HCQ continued after reaction Severe irritating, widespread rash Mild rash Facial rash Rash and nausea Rash on arms Rash on arms Rash on face, trunk, arms, and legs Neck, chest, and leg rash, vomiting Blisters, irritation and swollen hands Widespread rash Hyperpigmentation Type of reaction Warfarin, HRT, naproxen, ranitidine, steroid Aspirin, rofecoxib, tamoxifen Steroid cream, enalapril, aspirin Aspirin, lisinopril, ibuprofen Steroid cream, depomedrone Rofecoxib, lanzoprazole Aspirin, praxiline Aspirin – Clomipramine, Dermovate Pravastatin Concomittant medications Pos Pos Neg Neg Pos Neg Pos Pos Pos Pos Neg ANA Neg Neg Neg Ro (⫹) Neg Neg Neg Neg Neg Neg Neg ENA 1.17 0.52 1.26 0.99 0.78 1.00 0.94 1.5 0.65 0.95 1.11 C3, gm/ liter 0.24 0.16 0.26 0.16 0.12 0.55 0.26 0.34 0.06 0.17 0.17 C4, gm/ liter Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg DNA * The study period for patient 1 was October 1999 to October 2000; the study period for all other patients was October 2000 to October 2001. Patient 1 received the orange formulation of HCQ; all other patients received the white formulation. ANA ⫽ antinuclear antibody; ENA ⫽ extractable nuclear antigen; HRT ⫽ hormone replacement therapy. 1/28/98 Patient Date of event No. of days taking new formulation until event Associations between formulation change of hydroxychloroquine (HCQ) and cutaneous reactions in 11 female patients* Date HCQ started Table 2. 3394 LETTERS LETTERS We audited our records for HCQ reactions for 1 year prior to October 2000, when the formulation of HCQ was changed, and compared these data with the incidence of adverse cutaneous reactions associated with HCQ from October 2000 until October 2001. The information sources used included our patient database as well as clinical records and pharmacy records. All patients who experienced cutaneous reactions were interviewed. The chi-square test, with Yates’ correction for small numbers, was used to assess the difference in the incidence of HCQ reactions between the 2 periods of study. P values less than 0.05 were considered significant. During the year from October 1999 to October 2000, only 1 patient had a possible HCQ-related skin reaction, out of a total of 149 new prescriptions for HCQ (0.07%). During the year from October 2000 to October 2001, we observed 10 patients with a cutaneous reaction associated with HCQ therapy, out of a total of 137 new prescriptions for HCQ (7.3%). This difference was significant (2 ⫽ 8.5, P ⬍ 0.01). The clinical characteristics of these patients are shown in Table 1. The most common diagnosis was systemic lupus erythematosus (SLE), although HCQ was also prescribed for other diseases (Sjögren’s syndrome, discoid lupus). The median age of the patients was 49.4 years (range 33–62 years), and they had been taking the old and new formulations of HCQ for a median of 255 and 15.3 days, respectively. For patient 1, the cumulative dose of the old formulation was 51 gm. For the other 10 patients, the median cumulative dose of the new formulation was 3.78 gm. Three patients had experienced previous allergic reactions to penicillin or cotrimoxazole, and 1 patient had previous allergic reactions to multiple drugs (morphine, fluoxetine, carbamazepine, tramadol, and amitryptiline) (Table 1). In all 10 patients observed between October 2000 and October 2001, HCQ hypersensitivity was manifest as an acute skin reaction. The time range between commencement of the new formulation of HCQ and the appearance of a rash was 1–30 days (most reactions occurred in the first 1–2 weeks). Generally, the rash was mild and disappeared 1–3 weeks after the drug was stopped. Concomitant medications used by the patients are shown in Table 2. The skin lesions included rashes, blisters, irritation, and burning and swelling mainly over the face, arms, hands, chest and/or legs. Two patients also experienced nausea and/or vomiting. In 8 patients, the cutaneous reaction resolved after discontinuing HCQ. Four patients (patients 2, 7, 9, and 10) cautiously restarted HCQ in spite of the skin reactions, because it had controlled their symptoms, and none experienced any further reactions. Patient 2 stopped taking HCQ after 4 days of nausea, diarrhea, and vomiting then restarted it, without further complications. All of the other patients stopped taking HCQ completely, because the adverse effects were extensive. From October 1999 until October 2000, only 1 patient had a skin reaction while receiving the previous orange-coated formulation. In this patient, the reaction consisted of hyperpigmentation of the skin 20 months after starting the old formulation of HCQ and was, therefore, not a true allergic reaction. Between October 2000 and October 2001, 10 patients apparently developed true cutaneous reactions to the new white formulation of HCQ, and this was not related to any increase in the number of new prescriptions for HCQ. We have informed the Committee on Safety of Medicines for the United Kingdom of these reactions via the yellow card system. Cutaneous reactions to HCQ are uncommon; ⬃3% of 3395 patients experience an allergic skin reaction. In the literature, there are several case reports of severe cutaneous reactions following HCQ administration. For example, a woman with seronegative polyarthritis developed an acute generalized exanthematous pustulosis, a typical skin reaction to drugs (8), and another developed a widespread rash after receiving puvatherapy and HCQ (9). In other patients, HCQ induced pustular psoriasis or a bullous rash (6,10). Our data show that there has been no increase in the rate of new prescriptions for HCQ in our connective tissue disease clinics. However, over the 2 years of study, we observed a 100-fold increase, from 0.07% to 7.3%, in the frequency of cutaneous adverse effects associated with new HCQ prescriptions. In our experience over the last 20 years, the prevalence of cutaneous reactions to HCQ has been consistent with that in the published literature (⬃3% or less). In October 2000, the formulation of HCQ was changed by the manufacturer, with the removal of a coloring agent (sunshine yellow E110). The tablets changed in color from orange to white. The marked increase in skin reactions that we have observed is thus rather unexpected, given that coloring agents are often associated with allergies. Indeed, our data have shown that the incidence of drug and other allergies is high in patients with SLE (11). The prevalence of penicillin allergy in the general population is also high. However, there did not appear to be cross-reactivity between HCQ and penicillin allergies in our patients. To date, unpublished data from the manufacturers of HCQ have not demonstrated any increase in skin reactions in other countries where this new formulation has been used. Thus, the reasons for this sudden increase remain unclear. However, rheumatologists and patients should be aware of the apparently increased risk of skin reactions associated with the new formulation of HCQ. M. Salido, MD, PhD Rayne Institute, St. Thomas’ Hospital London, UK and Hospital Clinico San Carlos Madrid, Spain B. Joven, MD, PhD Rayne Institute, St. Thomas’ Hospital London, UK and Hospital 12 de Octubre Madrid, Spain D. P. D’Cruz, MD, FRCP M. A. Khamashta, MD, PhD, MRCP G. R. V. Hughes, MD, FRCP Rayne Institute, St. Thomas’ Hospital London, UK 1. Alarcón GS. How frequently and how soon should we screen our patients for the presence of antimalarial retinopathy? [letter]. Arthritis Rheum 2002;46:561. 2. D’Cruz DP. Antimalarial therapy: a panacea for mild lupus? Lupus 2001;10:148–151. 3. Meier H, Elsner P, Wuthrich B. [Occupationally-induced contact dermatitis and bronchial asthma in an unusual delayed reaction to hydroxychloroquine]. Hautarzt 1999;50:665–9. 4. Holme SA, Holmes SC. Hydroxychloroquine-induced pruritus. Acta Derm Venereol 1999;79:333. 5. Jimenez-Alonso J, Tercedor J, Jaimez L, Garcia-Lora E. Antima- 3396 6. 7. 8. 9. 10. 11. larial drug-induced aquagenic-type pruritus in patients with lupus. Arthritis Rheum 1998;41:744–5. Vine JE, Hymes SR, Warner NB, Cohen PR. Pustular psoriasis induced by hydroxychloroquine: a case report and review of the literature. J Dermatol 1996;23:357–61. Sibilia J, Cribier B, Javier RM, Pflumio F, Kuntz JL. Recurrent psoriatic onychoperiostitis induced by hydroxychloroquine. Rev Rhum Engl Ed 1995;62:795–7. Assier-Bonnet H, Saada V, Bernier M, Clerici T, Saiag P. Acute generalized exanthematous pustulosis induced by hydroxychloroquine. Dermatology 1996;193:70–1. Bonnetblanc JM, Combeau A, Dang PM. [Hydroxychloroquinepuvatherapy photoinduced acute generalized exanthematous pustulosis]. Ann Dermatol Venereol 1995;122:604–5. Kutz DC, Bridges AJ. Bullous rash and brown urine in a systemic lupus erythematosus patient treated with hydroxychloroquine. Arthritis Rheum. 1995;38:440–3. Sequeira JF, Cesic D, Keser G, Bukelica M, Karanagnostis S, Khamashta MA, et al. Allergic disorders in systemic lupus erythematosus. Lupus 1993;2:187–91. DOI 10.1002/art.10596 Efficacy of tumor necrosis factor ␣ blockade for enthesitis in spondylarthropathy: comment on the article by Marzo-Ortega et al To the Editor: We read with great interest the article by MarzoOrtega and coworkers on the efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy (SpA) (1). Using magnetic resonance imaging (MRI), the authors demonstrated that tumor necrosis factor ␣ (TNF␣) blockade can induce marked improvement or regression of enthesitis and associated osteitis in both the axial skeleton and the peripheral skeleton. The following case presentation confirms their observations. The patient is a 34-year-old man with HLA–B27– positive juvenile-onset undifferentiated SpA lacking axial involvement. In 1996, he had a severe, disabling, nonsteroidal antiinflammatory drug (NSAID)–resistant flare of the disease in his left knee and in the insertions of the Achilles tendon and plantar fascia (both sites), which was treated with sulfasalazine at a dosage of 3 gm/day. After 6 months of therapy, the daily dosage was reduced to 2 gm/day, and after 12 months sulfasalazine was discontinued. The disease remained in remission until August 2000, when the patient experienced severe pain in his right hip that was resistant to indomethacin at a dosage of 150 mg/day. Physical examinations performed on several occasions in the following months showed severe tenderness and limitation of motion of the right hip. There was also slight tenderness in the left hip. On October 14, 2000, radiographs of the pelvis were normal, and laboratory evaluation showed a normal erythrocyte sedimentation rate and a C-reactive protein (CRP) value of 17.6 mg/liter (normal ⬍5). MRI showed an increased signal on short tau inversion recovery images in both hips, extending from the right femoral head to the intertrochanteric region, caused by bone marrow edema (Figure 1A). Because of the severity of the clinical situation and the MRI findings, we decided to treat the patient with infliximab, after obtaining his informed consent. He received the drug at LETTERS a dose of 5 mg/kg by intravenous infusion at 0, 2, and 6 weeks. He was evaluated at baseline, on days 3, 7, and 14, and then every 2 weeks. The day after the first infusion, the hip pain improved, and after 1 week the daily dose of indomethacin was reduced to 100 mg. On the day of the second infusion, CRP was normal, and hip pain was less severe. The dosage of indomethacin was reduced to 50 mg/day. On the day of the third infusion, the pain had disappeared, and indomethacin was discontinued. A repeat MRI, performed 8 weeks after the first examination and the beginning of infliximab therapy, showed a dramatic improvement of bone edema at the right hip and regression on the left side (Figure 1B). On T1weighted images, with fat saturation obtained after the administration of intravenous gadolinium, there was low enhancement in the right femoral head and no enhancement in the left. To date, the disease has remained in remission, and the patient has taken no medication. A third MRI performed at month 6 was normal. Both main biologic agents blocking TNF␣, the chimeric monoclonal IgG1 antibody infliximab and the 75-kd IgG1 fusion protein etanercept, have been proven effective in both ankylosing spondylitis (2,3) and psoriatic arthritis (3–6). Both agents can ameliorate the enthesitis-related bone edema that is visible on MRI (1,7). Unresponsiveness of undifferentiated SpA to sulfasalazine is another possible indication for TNF␣ blockade therapy (8). We decided to use infliximab to treat our patient with undifferentiated SpA, because of the severity of hip pain and the impressive MRI findings showing enthesitis and osteitis involving the femoral head and neck. The appearance of enthesitis and osteitis on MRI was similar to that of idiopathic transient osteoporosis of the hip from which our case can be differentiated, especially based on the absence of localized osteoporosis on radiographs (9). As suggested by Marzo-Ortega et al, bone edema caused by enthesitis and osteitis is the forerunner of severe destruction and new bone formation in SpA (1). The authors also suggested that by suppressing the diffuse osseous pathology, TNF␣ blockade may prevent destructive arthritis. In our case, infliximab may have prevented destructive hip arthritis. Future studies on a large number of similar cases will resolve this question. Ignazio Olivieri, MD Angela Padula, MD San Carlo Hospital of Potenza and Madonna delle Grazie Hospital Potenza and Matera, Italy Enrico Scarano, MD San Carlo Hospital of Potenza Potenza, Italy 1. Marzo-Ortega H, McGonagle D, O’Connor P, Emery P. Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: a clinical and magnetic resonance imaging study. Arthritis Rheum 2001;44:2112–7. 2. Brandt J, Haibel H, Cornely D, Golder W, Gonzalez J, Redding J, et al. Successful treatment of active ankylosing spondylitis with anti–tumor necrosis factor ␣ monoclonal antibody infliximab. Arthritis Rheum 2000;43:1346–52. 3. Van den Bosch F, Kruithof E, Baeten D, De Keyser F, Mielants H, Veys EM. Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) in spondyloarthropathy: an open pilot study. Ann Rheum Dis 2000;59:428–33. LETTERS 3397 Figure 1. Magnetic resonance imaging (MRI) of the hips. A, Short tau inversion recovery image showing increased signal extending from the right femoral head to the intertrochanteric region due to bone marrow edema. B, Repeat MRI, performed 8 weeks after the first examination and the beginning of infliximab therapy, showing dramatic improvement of bone edema at the right hip and regression at the left side. 3398 LETTERS 4. Antoni C, Dechant C, Ogilvie A, Kalden-Nemeth D, Kalden JR, Manger B. Successful treatment of psoriatic arthritis with infliximab in a MRI controlled study. J Rheumatol 2000;27 Suppl 59:24. 5. Braun J, de Keyser F, Brandt J, Mielants H, Sieper J, Veys E. New treatment options in spondyloarthropathies: increasing evidence for significant efficacy of anti-tumor necrosis factor therapy. Curr Opin Rheumatol 2001;13:245–9. 6. Mease PJ, Goffe BS, Metz J, Vanderstoep A. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000;356:385–90. 7. Stone M, Salonen D, Lax M, Payne U, Lapp V, Inman R. Clinical and imaging correlates of response to treatment with infliximab in patients with ankylosing spondylitis. J Rheumatol 2001;28:1605–14. 8. Brandt J, Haibel H, Reddig J, Sieper J, Braun J. Successful short term treatment of severe undifferentiated spondyloarthropathy with the anti-tumor necrosis factor-alpha monoclonal antibody infliximab. J Rheumatol 2002;29:118–22. 9. Major NM, Helms CA. Idiopathic transient osteoporosis of the hip. Arthritis Rheum 1997;40:1178–9. DOI 10.1002/art.10597 Reply To the Editor: We are very pleased that our original observation that TNF␣ blockade can induce marked improvement/regression of enthesitis and osteitis in SpA has been confirmed by Olivieri and colleagues. They describe a case in which a dramatic response, with rapid and sustained improvement, was achieved after 3 infusions of infliximab in a patient with undifferentiated SpA. Recent double-blind studies have confirmed the efficacy of the TNF blocking agents infliximab (1,2) and etanercept (3) in the treatment of the different subtypes of SpA. Likewise, the experience reported by Olivieri et al confirms our own (4), showing the efficacy of these drugs in the treatment of enthesitis, the characteristic pathologic manifestation of these diseases. These are, however, early days in our experience with these drugs. Importantly, Olivieri and colleagues raise the question of long-term benefit. Although ⬎300 patients with SpA have been reported in trials worldwide, general experience is still short-lived. This is clearly an issue that will determine the cost-effectiveness of this therapy. Studies are already in place to answer this question. Helena Marzo-Ortega, MD Dennis McGonagle, MD Paul Emery, MD University of Leeds Leeds, UK 1. Van den Bosch F, Kruithof E, Baeten D, Herssens A, de Keyser F, Mielants H, et al. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor ␣ (infliximab) versus placebo in active spondylarthropathy. Arthritis Rheum 2002; 46:744–65. 2. Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359:1187–93. 3. Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 2002;346:1349–56. 4. Marzo-Ortega H, McGonagle D, O’Connor P, Emery P. Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: a clinical and magnetic resonance study. Arthritis Rheum 2001;44:2112–7. Erratum In the article by Aganna et al published in the September 2002 issue of Arthritis & Rheumatism (pp 2445–2452), the name of the eighth author, Alison Bybee, PhD (Royal Free Medical School, London, UK) was inadvertently omitted. We regret the error.