New therapies for ankylosing spondylitis: etanercept, thalidomide, and pamidronate

Rheum Dis Clin N Am 29 (2003) 481 – 494

New therapies for ankylosing spondylitis: etanercept, thalidomide, and pamidronate John C. Davis, Jr, MD, MPH, FACP, FACRa,*, Feng Huang, MDb, Walter Maksymowych, MD, FACP, FRCP(C), FRCP(UK)c a

Division of Rheumatology, Department of Medicine, University of California—San Francisco, 533 Parnassus Avenue, Box 0633, San Francisco, CA 94143, USA b Department of Rheumatology, Chinese People’s Liberation Army General Hospital, 28 Fuxing Road, Beijing 100853, China c Division of Rheumatology, Department of Medicine, University of Alberta, 562 Heritage Medical Research Center, Edmonton, Alberta T6G 2S2, Canada

Ankylosing spondylitis is the most common of a group of diseases called the seronegative spondyloarthropathies. This group of diseases shares common demographic, clinical, and genetic features. This article reviews the rationale, clinical efficacy, and safety reports of etanercept, thalidomide, and pamidronate in the treatment of patients who have ankylosing spondylitis.

Etanercept Etanercept (Enbrel, Immunex Corp., Seattle, WA) is a fully humanized dimeric fusion protein consisting of the extracellular portion of the p75 tumor necrosis factor (TNF)-a receptor linked to the Fc portion of IgG subtype 1. It binds with high affinity to soluble TNF, rendering TNF biologically inactive. Etanercept is currently approved for the treatment of rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, and psoriatic arthritis. It is self-administered at a dose of 25 mg subcutaneously (SC) twice weekly. Etanercept can be given as monotherapy or in combination with other disease-modifying antirheumatic drugs.

This work was supported by NIH/NIAMS K23 and the Rosalind Russell Medical Center for Arthritis Research, University of California—San Francisco. Dr. Davis has received research support from Immunex Corporation, Seattle, Washington. This work was supported in part by the National Natural Science Foundation of China, grant no. 30025041. * Corresponding author. E-mail address: [email protected] (J.C. Davis). 0889-857X/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0889-857X(03)00028-0

482

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

Rationale for the use of etanercept in ankylosing spondylitis The rationale for the use of etanercept in the treatment of ankylosing spondylitis (AS) and other spondyloarthropathies (SpA) derives from its ability to inhibit TNF-a, a key proinflammatory cytokine implicated in the pathogenesis of a number of inflammatory conditions. Supporting evidence for the use of etanercept in AS includes: (1) the role of TNF-a in animal models of inflammation, (2) the presence of elevated levels of TNF-a in the serum and tissue of patients who have AS, (3) the efficacy of etanercept in treating other rheumatic disorders such as rheumatoid arthritis, and (4) radiographic evidence of reduced inflammation in patients who have SpA treated with etanercept. Animal models Observations from animal models highlight the role of TNF-a in rheumatic diseases. Transgenic mice expressing modified human TNF-a develop a condition resembling human rheumatoid arthritis [1]. In addition, inflammatory arthritis resembling human AS with axial involvement and vertebral end plate fusion was developed in a transgenic mouse engineered to overexpress murine TNF-a [2]. The murine TNF shares 80% homology with its human counterpart. Elevated tumor necrosis factor-a in ankylosing spondylitis patients Results from human studies also support the involvement of TNF-a in AS and other seronegative spondyloarthropathies. Serum TNF-a levels have been reported to be significantly higher in patients who have AS than in patients who have noninflammatory back pain [3]. A trend toward higher serum TNF-a in AS patients than in healthy patients has also been noted [4]. High levels of TNF-a mRNA have been found in the peripheral and axial joint synovia of patients who have rheumatoid arthritis, spondyloarthritis, and AS [5,6]. Improvement in other rheumatic disorders In several multicenter, double-blind, placebo-controlled studies, etanercept has been shown to improve the signs and symptoms of rheumatoid arthritis and to be effective in treating the joint and skin manifestations of psoriatic arthritis [7– 10]. Preliminary reports from open-label and placebo-controlled studies suggest that TNF blockers might be effective in other seronegative SpAs such as reactive and undifferentiated arthritis [11]. Radiographic evidence Ten etanercept-treated patients who have resistant spondyloarthropathy demonstrated significant clinical improvement and a reduction of or resolution in 86% of identified inflammatory lesions in the spine and periphery by MRI [12].

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

483

Clinical data in ankylosing spondylitis Based on the rationale described above, TNF-a has been viewed as a therapeutic target in AS and other spondyloarthropathies. Controlled and uncontrolled studies of etanercept in patients who have AS are summarized in the following sections and in Table 1. Controlled studies A randomized, double-blind, placebo-controlled trial was conducted over a 4-month period in 40 patients who had AS [13]. The primary efficacy endpoint was treatment response, defined as 20% improvement in at least three of five of the following measures: morning stiffness, spinal pain, function, patient global assessment of disease, and swollen joint score. To qualify as a responder, one of the improved measures had to be morning stiffness or spinal pain, and none of the measures could worsen. Treatment with etanercept resulted in significant and sustained improvement. At 4 months, 75% of the etanercept group had a treatment response versus 30% of the placebo group (P = 0.004). Statistically significant differences favored etanercept over placebo for morning stiffness, spinal pain, functioning, quality of life, enthesitis, chest expansion, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Etanercept was well tolerated with no significant differences in adverse events between the two groups. The study also Table 1 Studies of etanercept in spondylitis Study

Etanercept regimen control

N

Results

Gorman et al [13]

Etanercept 25 mg sc Twice a week Placebo controlled

40 AS pts

Brandt et al [14]

Etanercept 25 mg sc Twice a week Placebo controlled

30 AS pts

Marzo-Ortega et al [12]

Etanercept 25 mg sc Twice a week Uncontrolled Etanercept 0.2 – 0.8 mg/kg sc Twice a week Uncontrolled

10 AS pts

75% treatment response for etanercept versus 25% for placebo; improvements in morning stiffness, spinal pain, functioning, quality of life, enthesitis, chest expansion, ESR, and CRP levels 50% regression of BASDAI in 57% of etanercept patients versus 6% for placebo; improvement in functioning and CRP levels Improvement in spinal pain, functioning, quality of life, and MRI-detected enthesitis Improvement in morning stiffness, active joint count, hemoglobin level, and ESR

Reiff & Henrickson [15]

8 JAS pts

Abbreviations: AS, ankylosing spondylitis; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; JAS, juvenile ankylosing spondylitis; SC, subcutaneous.

484

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

included an open-label, 6-month extension study. In this portion of the trial, patients who received placebo in the blinded phase experience rapid and significant response within 28 days. Patients who received etanercept in the blinded portion maintained significant improvement over the 10-month study period. There were no serious adverse events and only upper respiratory tract infections were experienced more often in patients receiving 10 months versus 6 months of therapy. In a study conducted in Germany, 30 AS patients were randomized to receive either etanercept or placebo for 6 weeks [14]. After week 6, both groups were treated with an additional 12 weeks of etanercept therapy. Treatment with etanercept resulted in a greater than 50% regression in disease activity (measured with the Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]) in 57% of the etanercept patients versus only 6% of placebo patients at week 6 (P = 0.004). Function (measured with the Bath Ankylosing Spondylitis Functional Index [BASFI]) and mean CRP levels improved in patients taking etanercept but not in patients taking the placebo. Decreases in the number of swollen joints and enthesitic sites were also observed for etanercept and not for placebo, but the difference between treatments was not statistically significant. Six weeks after the original placebo group had switched to etanercept, a greater than 50% improvement in disease activity was achieved in 56% of those patients. Disease relapses occurred in a mean of 3 weeks after cessation of etanercept therapy. No severe adverse events or major infections were observed until week 30. Uncontrolled studies Gadolinium-enhanced and fat-suppressed MRI images were used to correlate clinical response to etanercept therapy and radiologic improvement in 10 patients who had spinal inflammation and sacroiliitis [12]. At 6 months, significant (P < 0.01) improvement was observed in spinal pain (day and night) and in BASFI, BASDAI, and Quality of Life scores. Nine patients had a total of 44 MRIdetectable entheseal lesions; there was a technical failure of the scan in one patient. Overall, 86% of MRI-detected lesions regressed completely or improved, and no new lesions developed. No adverse side effects were seen in any patients. A study was conducted to determine whether or not etanercept could sustain long-term efficacy in a group of eight children with juvenile AS and a history of disease modifying anti-rheumatic drug (DMARD) therapy failure [15]. Before beginning etanercept therapy, all eight children had persistent synovitis and an elevated ESR, six had anemia, and five had radiographic changes. Etanercept was administered at a dose of 0.2 to 0.8 mg/kg subcutaneously twice weekly. Four of eight children received concomitant methotrexate during the study. After 12 months of etanercept therapy, ESR, active joint count, hemoglobin, and morning stiffness improved. All patients tolerated etanercept without any side effects. In conclusion, TNF-a appears to be an important inflammatory mediator in the pathogenesis of spondylitis, and its inhibition by agents such as etanercept provides rapid clinical improvement. Furthermore, etanercept might play a role in potential disease modification as suggested by preliminary radiographic data.

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

485

Long-term safety and efficacy profiles of etanercept require further investigation. At present, there are no published guidelines for the initiation, monitoring, or discontinuation of anti-TNF therapy in AS. It is expected that not all patients will require therapy with biologic agents; such patients could include (1) patients who have axial disease that has been refractory or intolerant to one or more nonsteroidal anti-inflammatory agents (NSAIDs), (2) patients who have peripheral involvement that has been refractory or intolerant to sulfasalazine or methotrexate, or (3) patients who have severe enthesitis refractory to local treatment or agents mentioned for peripheral symptoms. Patients should be screened for history of demyelinating disease and tuberculosis exposure. Clinical monitoring should include vigilance for infection, injection site reactions, and neurologic symptoms. Most patients appear to experience maximum benefit by 3 to 4 months of treatment, although individuals might experience benefit within 1 week. If patients do not respond after several months, therapy should be discontinued.

Thalidomide Thalidomide is a synthetic derivative of glutamic acid, which was originally developed as a sedative in 1956. Thalidomide is metabolized mainly through nonenzymatic hydrolytic cleavage, generating a multitude of active intermediates with largely unknown functions [16]. The drug has a rapid onset of action, lack of hangover, and absence of respiratory or skeletal muscle coordination impairment. In 1960, two types of major side effects were reported: peripheral neuropathies in patients who had long-term exposure to the drug, and congenital abnormalities of the limbs (phocomelia), which led to the drug’s withdrawal from the market [17]. Since that time, thalidomide has been used under restricted conditions because of its reported efficacy in erythema nodosum leprosum, chronic cutaneous lupus, Behcet’s disease, and chronic graft versus host disease [17]. Mechanism of action Several experimental studies have provided potential explanations for the efficacy of thalidomide in inflammatory diseases [17]. Thalidomide is a relatively weak inhibitor of TNF synthesis in vitro and in vivo. In vitro, thalidomide reduces TNF production by approximately 40%. In tissue culture, this TNF inhibitory capacity is dose-dependent and selective, with no significant effect on other cytokines such as interleukin (IL)-l and IL-6. The inhibition of TNF production occurs at the transcriptional level through reduction in the half-life of TNF mRNA by nearly 50%. This effect is variable, however, and depends on the nature of the experimental system or clinical trial. Recently, blocking of NF-kB activation through a mechanism involving the inhibition of IkB kinase has been shown with thalidomide and was proposed as an upstream event that was responsible for different actions of the drug [18]. Various anti-inflammatory, immunomodulatory, and antiangiogenic activities have also been attributed to

486

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

Box 1. Immunomodulatory and anti-inflammatory properties of thalidomide Inhibits leukocyte chemotaxis into site of inflammation Alters density of TNF-B– induced adhesion molecules on leukocytes Reduces phagocytosis by polymorphonuclear leukocytes Enhances mononuclear cell production of IL-4 and IL-5; inhibits IFN-D production Inhibits production of IL-12 Inhibits production of TNF-B by monocytes and macrophages by reducing half-life of mRNA thalidomide (Box 1) [17]. Experiments have demonstrated thalidomide’s capacity to inhibit TNF-a – induced adhesion molecule expression on the leukocyte surface, a critical step in the chemotactic response. Thalidomide also reduces phagocytosis by polymorphonuclear leukocytes. In addition to proinflammatory cytokine inhibition, thalidomide exerts an effect on other in vitro immunomodulating activities such as T-cell costimulation, thereby enhancing T-cell response. This costimulatory effect appears to be greater on CD8+ T cells than on CD4+ T cells [19]. There is no evidence that thalidomide possesses immunosuppressive properties and the drug has not been associated with opportunistic infections. Antiangiogenic properties of thalidomide have also been found [20]. Clinical efficacy of thalidomide in ankylosing spondylitis Given its immunologic properties, thalidomide has been used as a putative anti – TNF-a therapy for spondylitis for several years. Results from these studies are summarized in Table 2. Table 2 Clinical studies involving thalidomide in spondylitis Study Breban et al [21] Lee et al [23] Huang et al [24] Wei et ala

Diagnosis (N)

HLA-B27+

Dosage (mg/d)

Duration (mo)

Premature discontinuation (%)

Improvement (%)

AS (9), uSpA (2), PsA (1) uSpA (1)

10/12

100 – 300

6

5 (42)

7/12 (58)

1/1

100

6

0 (0)

1/1 (100)

AS (30)

30/30

200

12

4 (13)

21/30 (70)

AS(9), PsA(1), JAS(3)

13/13

200

6

2(15)

8/10(80)

Abbreviations: AS, ankylosing spondylitis; JAS, juvenile ankylosing spondylitis; PsA, psoriatic arthritis; uSpA, undifferentiated spondyloarthropathy. a Unpublished observations, 2002.

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

487

The first description of thalidomide use was by Breban et al [21], who reported that two patients received doses of 100 to 300 mg/d [21]. In both patients, benefit was reported in axial and peripheral clinical manifestations and biological markers of inflammation (ESR and CRP) [21]. Because of this initial description, 10 additional SpA patients have been treated by the same group in a small open-label study [22]. The duration of treatment was 6 months followed by an observation period of 4 months. Of the 12 patients enrolled in this small openlabel study, five discontinued thalidomide because of side effects. Evidence of clinical efficacy was found in seven of 12 patients, of whom two achieved a reduction of BASDAI greater than 50%. The most consistent measure of efficacy was on biological parameters of inflammation (ESR or CRP). Lee at al [23] also reported efficacy of thalidomide in one woman who was affected with severe refractory spondyloarthropathy. A 12-month open-label study of 30 male patients was reported recently [24]. The severity of the disease, gender, HLA-B27 positivity, age of onset, and extra-articular phenomena were similar to those reported in most studies [25]. A composite score of 20% improvement in four of seven indices was defined as the primary outcome measure. Using this definition of response, 80% of patients who completed the 12-month study demonstrated a positive response. Nearly 50% of patients showed a 50% or more improvement in four of seven indices. Complete remission (defined as improvement  75% in seven of seven indices) was not reached in any patient. This positive response was also seen in multiple secondary outcome measures. Most notable were significant decreases in ESR and CRP, which were elevated in all patients before therapy. ESR and CRP normalized in four and 14 patients after 6 and 12 months of thalidomide, respectively. The rate of response of AS patients to thalidomide in this study was not as dramatic as patients taking anti –TNF-a therapy, in whom subjective improvement has been reported as early as 1 day after the first infusion. As an example of this, four patients withdrew from the study at the third month secondary to lack of efficacy. The patients who completed 1 year of therapy demonstrated a maximum response between 6 and 12 months. A decline in Sharp score was observed after 3 to 6 months of therapy. The response to thalidomide was highly satisfactory to the patients. Nine patients reported absence of pain. Similar to infusion therapy with anti – TNF-a antibody, maintenance of response requires continued use of the drug. It is noteworthy that there was a significant clinical relapse 3 months after discontinuing thalidomide. In most thalidomide studies, relapse seemed to occur after discontinuation of the drug, suggesting that long-term treatment would presumably be necessary to maintain efficacy. Wei et al performed a 6-month open-label study of thalidomide in 13 patients who had severe refractory AS (Wei et al, 2002). Three patients withdrew because of skin rash and two were lost to follow-up because of lack of efficacy. According to ASsessments In Ankylosing Spondylitis Working Group (ASAS) criteria, which were used to evaluate the efficacy of treatment at baseline and every

488

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

4 weeks, 8 of the 10 completers (80%) were responders (four and four patients achieved 50% and 20% improvement levels, respectively). Statistically significant improvement was achieved for BASDAI, BASFI, Bath Ankylosing Spondylitis Global Index (BASGI) and ESR (Wei et al, submitted for publication, 2002). Safety Tolerability of thalidomide has varied among studies. In the Huang et al study [24] there were no dropouts because of side effects, whereas 50% of patients dropped out because of side effects in the Breban et al [26] study. Most side effects included drowsiness (58.3%), constipation (25%), dizziness (25%), headache (16.7%), nausea/vomiting (16.7%), and paresthesias (8.3%). A similar lack of limiting side effects was observed among spondylitis patients treated by Wei et al (Wei et al, personal communication, 2002). To ensure that this unexpected lack of serious side effects was not a study bias, 22 papers published between 1981 and 2001 that involved the use of thalidomide in various conditions were reviewed. When used in the dose range of 75 to 400 mg/d for up to 2 years, 47.5% (138/581) of patients had 181 episodes of mild adverse effects such as drowsiness, constipation, dizziness, and dry mouth. Eight patients (1.38%) had suspected peripheral neuropathies, all of whom were taking a high dose of 300 to 400 mg/d. All neurological symptoms disappeared after discontinuation of thalidomide. Among these patients, 56.7% were women and none experienced phocomelia. In the Huang et al study, thalidomide was started at 50 mg/d and doubled every ten days to a steady dose of 200 mg/d, which was well tolerated (none of the 30 patients dropped out because of side-effects). Only one patient opted for a higher dose of 300 mg/d. Major side effects included slight drowsiness in 8 (30.8%), dry mouth in 6 (23.1%), and increased dandruff in 3 (11.5%). Less than 12% of patients had transient increases in liver enzymes. The increases were less than 2 fold above maximum normal values. Microscopic hematuria was observed on one or two occasions. In the Wei et al study, the initial dose of thalidomide was 100 mg/d for 1 week followed by 200 mg/d for 23 weeks (Wei et al, unpublished observations, 2002). Three patients dropped out after 2 weeks because of skin eruptions. Other minor side effects including dry mouth (7/8), constipation (7/8), dizziness (6/8), and drowsiness (3/8) were tolerated well without any modification of medication. This dosing strategy was quite different from the Breban et al [26] study, in which a loading dose of 300 mg/d was used with tapering thereafter. Side effects were frequent and included drowsiness, constipation, and dizziness. Although no major side effects of thalidomide such as birth defects or neuropathy have been reported, careful monitoring is needed, including repeated electromyogram and rigorous contraception. In summary, the use of thalidomide shows promise in treating AS, although controlled studies are needed to assess the benefits and risks of short- and longterm use. With increased use over time, commensurate energy must be expended

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

489

to control against adverse effects and monitor compliance with all facets of thalidomide’s use. Several structural analogs have been demonstrated to have several hundred times the potency of thalidomide at inhibiting TNF production and enhanced solubility and stability. The goal is to develop a drug with more potent immunomodulatory properties but without the adverse effects, particularly the teratogenicity. Preliminary investigations have been favorable regarding the teratogenic and mutagenic potential of these agents. It is hoped that these investigations might lead to a small molecule that functions as a nontoxic, selective inhibitor of TNF. It is expected that some of these agents with their increased safety profiles in comparison to thalidomide will represent useful therapies for spondylitis in the future [27].

Pamidronate Bisphosphonates are synthetic analogs of pyrophosphate and have found widespread use in disorders of bone metabolism. Their potential value as antiinflammatory agents was first recognized several decades ago when they were shown to be of benefit in limited numbers of patients who had rheumatoid arthritis [28]. Several observations in vitro have suggested that bisphosphonates can exert beneficial anti-inflammatory properties. Such properties include inhibition of antigen presentation by monocytes associated with impairment of IL-1b generation and inhibition of macrophage growth, migration, differentiation, and viability [29 – 31]. Their effects on cytokine generation are complex and dependent on the molecular class of bisphosphonate examined, the concentration employed, the cell type examined, evaluation of cultured cells versus whole blood assays, and single versus chronic dosing. Exposure of cultured macrophage cell lines to pamidronate suppresses generation of proinflammatory cytokines [32]. This suppression appears to be a dose-dependent phenomenon (observed at concentrations > 5  10 5M) and is unlikely to be evident with serum levels achieved by conventional dosing in vivo (peak level attained following a single IV infusion of 60 mg pamidronate equals 10 5 M) [33]; however, it has been estimated that drug levels in the vicinity of resorbing bone might be as high as 10 3M [34]. Bisphosphonates also appear to be efficacious in adjuvant-induced arthritis but have been less effective in collagen-induced arthritis [35 –37]. One study has shown that pamidronate retards structural damage in a TNF-a transgenic mouse model of arthritis and that this is synergistic with the osteoclast regulator osteoprotegerin [38]. Bisphosphonate therapy in ankylosing spondylitis Pamidronate is the most potent bisphosphonate available as an IV preparation and its tolerability and adverse event profile has been particularly well studied in the long-term management of Paget’s disease. It has also been given long-term to

490

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

breast carcinoma patients who had bone metastases at a dose of 90 mg IV every 3 to 4 weeks for up to 2 years and shown to alleviate pain and prevent fractures [39]. One study has shown that IV pamidronate induces prompt resolution of bone marrow edema in the idiopathic regional osteoporosis of the hip syndrome as documented on MRI [40]. Open studies evaluating pamidronate in ankylosing spondylitis Two regimens of IV pamidronate in patients who had NSAID refractory AS have been evaluated. In the first study, 16 patients who had mean disease duration of 12.3 years were examined: one group of eight patients received six monthly infusions, 30 mg for the first 3 months and 60 mg for the next 3 months, while a second group of eight patients received 60 mg monthly for 3 months [41]. The 30 to 60 mg dosage range was chosen because this falls within the range used in the management of Paget’s disease and osteoporosis. Adverse events were therefore predictable. Significant improvement was noted primarily in indices of disease activity (BASDAI), metrology (Bath AS Metrology Index [BASMI]), and ESR, primarily in patients who received six rather than three monthly infusions. Treatment was well tolerated with only one withdrawal because of adverse events over the 6-month period. The largest changes in clinical parameters and ESR were observed between the 3- and 6-month assessment time points, indicating that further evaluation of monthly pamidronate should incorporate at least a 6-month observation period. In a second open analysis, dynamic MRI with gadolinium augmentation was used [42], which allows quantification of the severity of inflammation because accumulation of gadolinium depends on blood flow and vascular permeability. Nine patients who had SpA according to European Spondyloarthropathy Study Group (ESSG) criteria and short disease duration (mean of 5.5 years) were studied. Sixty milligrams of pamidronate was given intravenously on days 1, 2, 14, 28, and 56. Treatment was well tolerated with no withdrawals. The mean BASDAI decreased by 44.2% and the BASFI decreased by 47.3%. The maximal rate and magnitude of gadolinium-enhanced MR signal in the bone marrow decreased after pamidronate. Clinical benefit was often delayed beyond 3 months. A further open-label study, described in preliminary form, evaluated 12 hospitalized patients who had active spondylitis (11 men, 1 woman) and a mean disease duration of 20 years with active AS who were treated with pamidronate 60 mg IV at days 1, 2, 14, 28, and 56. DMARDs or prednisone were withdrawn 1 month before treatment. In contrast with the previous report from Edmonton evaluating this regimen, a 30% BASDAI improvement was noted in only two of 11 patients after 3 months [42]; however, the mean disease duration in this cohort was 20 years, which contrasts with the Edmonton cohort (which had a mean disease duration of 5.5 years). A preliminary report from Cordoba describes eight patients who had AS with a mean disease duration of 14 years who were given 60 mg pamidronate monthly for 6 months [43]. A significant reduction was reported in mean BASDAI (50%)

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

491

but not in the BASFI or acute phase reactants; however, the mean baseline BASFI in these patients was only 3.7, indicating a relatively low degree of functional impairment initially.

Controlled evaluation of pamidronate in ankylosing spondylitis The observation that the most impressive changes in clinical parameters in the first open study from Edmonton were observed between the 3- and 6-month assessment time points and the high incidence of postinfusion arthralgias and myalgias on first exposure to pamidronate led to the design of a double-blinded dose – response comparison of 60 mg versus 10 mg given IV monthly for 6 months. The 10 mg dose is the lowest dose of IV pamidronate shown to induce postinfusion arthralgia and myalgia [44]. Eighty-four patients who had NSAID refractory AS from university- and community-based practice were randomized to treatment and 72 completed 6 months of therapy [45]. Treatment was well tolerated and only one patient withdrew from the 60 mg group because of adverse events. Significant efficacy was not observed at 3 months, but significant reductions in disease activity (BASDAI), improvement in function (BASFI), patient global (BASGI), and metrology (BASMI) was evident by 6 months. Sixty percent of patients had at least a 25% reduction in the BASDAI. A recent preliminary report indicates that the minimal clinically detectable change in the BASDAI is 23%, suggesting that the majority of patients who received 60 mg of pamidronate experienced clinically meaningful improvement [46] compared with only 30.2% of patients who received the 10 mg dose. Thirty nine percent of patients experienced a 50% or greater reduction in BASDAI, although further analysis did not reveal any predictive demographic or clinical variables. There were no significant differences between the 60 mg and 10 mg groups with respect to changes in acute phase reactants or in peripheral joint pain, although the number of patients who had initial peripheral synovitis was small (N = 16). In view of the short serum half-life of pamidronate of only 1 hour, this agent is likely to exert anti-inflammatory effects primarily when it is concentrated at sites of active bone turnover such as subchondral bone rather than in inflamed synovium [33]. In summary, additional studies should clarify potential demographic and clinical variables predictive of response. In this regard, bone edema observed on MRI might be an appropriate starting point. IV administration is clearly not optimal for long-term administration in routine clinical practice and future studies should examine the efficacy of orally bioavailable bisphosphonates such as alendronate with the understanding that their relative antiresorptive potencies might not necessarily reflect their anti-inflammatory properties. In view of their safety and the rapid onset of osteoporosis in some AS patients, further studies should also target patients earlier in the disease course. There is also emerging evidence that these therapies might be chondroprotective by decreasing expres-

492

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

sion of degradative metalloproteinases, decreasing breakdown of type II collagen, and preventing chondrocyte apoptosis [45,47,48].

References [1] Keffer J, et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 1991;10(13):4025 – 31. [2] Crew MD, et al. Transgenic mice expressing a truncated Peromyscus leucopus TNF-alpha gene manifest an arthritis resembling ankylosing spondylitis. J Interferon Cytokine Res 1998;18(4): 219 – 25. [3] Gratacos J, et al. Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol 1994;33(10):927 – 31. [4] Toussirot E, et al. Serum levels of interleukin 1-beta, tumor necrosis factor-alpha, soluble interleukin 2 receptor and soluble CD8 in seronegative spondylarthropathies. Rheumatol Int 1994; 13(5):175 – 80. [5] Braun J, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995;38(4):499 – 505. [6] Canete JD, et al. Comparative cytokine gene expression in synovial tissue of early rheumatoid arthritis and seronegative spondyloarthropathies. Br J Rheumatol 1997;36(1):38 – 42. [7] Mease PJ, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000;356(9227):385 – 90. [8] Weinblatt ME, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340(4): 253 – 9. [9] Moreland LW, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997;337(3):141 – 7. [10] Moreland LW, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999;130(6):478 – 86. [11] Meador R, et al. TNF involvement and anti-tnf therapy of reactive and unclassified arthritis. Clin Exp Rheumatol 2002;20(6 Suppl 28):S130 – 4. [12] Marzo-Ortega H, et al. Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: a clinical and magnetic resonance imaging study. Arthritis Rheum 2001;44(9):2112 – 7. [13] Gorman JD, Sack KE, Davis Jr. JC. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 2002;346(18):1349 – 56. [14] Brandt JKA, Listing J, et al. Six months results of a German double-blind placebo controlled, Phase III clinical trial of etanercept in active ankylosing spondylitis. Arthritis and Rheumatism 2002;46:S429. [15] Reiff AHM. Prolonged efficacy of etanercept in refractory juvenile ankylosing spondylitis. Arthritis and Rheumatism 2001;44(S292). [16] Chen TL, et al. Plasma pharmacokinetics and urinary excretion of thalidomide after oral dosing in healthy male volunteers. Drug Metab Dispos 1989;17(4):402 – 5. [17] Calabrese L, Fleischer AB. Thalidomide: current and potential clinical applications. Am J Med 2000;108(6):487 – 95. [18] Keifer JA, et al. Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity. J Biol Chem 2001;276(25):22382 – 7. [19] Marriott JB, Muller G, Dalgleish AG. Thalidomide as an emerging immunotherapeutic agent. Immunol Today 1999;20(12):538 – 40. [20] D’Amato RJ, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994; 91(9):4082 – 5.

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

493

[21] Breban M, et al. Efficacy of thalidomide in the treatment of refractory ankylosing spondylitis. Arthritis Rheum 1999;42(3):580 – 1. [22] El Hassani SDM, Gombert B, et al. Treatment of severe refractory spondyloarthropathy with thalidomide: results of an open study. Arthritis and Rheumatism 1999;42(S373). [23] Lee L, Lawford R, McNeil HP. The efficacy of thalidomide in severe refractory seronegative spondylarthropathy: comment on the letter by Breban et al. Arthritis Rheum 2001;44(10): 2456 – 8. [24] Huang F, et al. One-year open-label trial of thalidomide in ankylosing spondylitis. Arthritis Rheum 2002;47(3):249 – 54. [25] Feltkamp TE, et al. Spondyloarthropathies in eastern Asia. Curr Opin Rheumatol 2001;13(4): 285 – 90. [26] Breban M, et al. Efficacy of infliximab in refractory ankylosing spondylitis: results of a six-month open-label study. Rheumatology (Oxford) 2002;41(11):1280 – 5. [27] Corral LG, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 1999;163(1): 380 – 6. [28] Bijvoet OL, et al. APD in Paget’s disease of bone. Role of the mononuclear phagocyte system? Arthritis Rheum 1980;23(10):1193 – 204. [29] Cecchini MG, et al. Effect of bisphosphonates on proliferation and viability of mouse bone marrow-derived macrophages. J Bone Miner Res 1987;2(2):135 – 42. [30] Stevenson PH, Stevenson JR. Cytotoxic and migration inhibitory effects of bisphosphonates on macrophages. Calcif Tissue Int 1986;38(4):227 – 33. [31] Sansoni P, et al. Inhibition of antigen-presenting cell function by alendronate in vitro. J Bone Miner Res 1995;10(11):1719 – 25. [32] Pennanen N, et al. Effect of liposomal and free bisphosphonates on the IL-1 beta, IL-6 and TNF alpha secretion from RAW 264 cells in vitro. Pharm Res 1995;12(6):916 – 22. [33] Leyvraz S, et al. Pharmacokinetics of pamidronate in patients with bone metastases. J Natl Cancer Inst 1992;84(10):788 – 92. [34] Sato M, Grasser W. Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. J Bone Miner Res 1990;5(1):31 – 40. [35] Barbier A, et al. Studies on the chronic phase of adjuvant arthritis: effect of SR 41319, a new diphosphonate. Ann Rheum Dis 1986;45(1):67 – 74. [36] Francis MD, Hovancik K, Boyce RW. NE-58095: a diphosphonate which prevents bone erosion and preserves joint architecture in experimental arthritis. Int J Tissue React 1989;11(5): 239 – 52. [37] Markusse HM, Lafeber GJ, Breedveld FC. Bisphosphonates in collagen arthritis. Rheumatol Int 1990;9(6):281 – 3. [38] Redlich K, et al. Tumor necrosis factor alpha-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin. Arthritis Rheum 2002;46(3):785 – 92. [39] Lipton A, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000;88(5):1082 – 90. [40] Varenna M, et al. Intravenous pamidronate in the treatment of transient osteoporosis of the hip. Bone 2002;31(1):96 – 101. [41] Maksymowych WP, et al. An open study of pamidronate in the treatment of refractory ankylosing spondylitis. J Rheumatol 1998;25(4):714 – 7. [42] Maksymowych WP, et al. Clinical and radiological amelioration of refractory peripheral spondyloarthritis by pulse intravenous pamidronate therapy. J Rheumatol 2001;28(1): 144 – 55. [43] Collantes-Estevez E, Munoz-Villanueva MC. Clinical improvement of refractory ankylosing spondylitis by pulse intravenous pamidronate therapy. Ann Rheum Dis, in press. [44] Adami S, et al. The acute-phase response after bisphosphonate administration. Calcif Tissue Int 1987;41(6):326 – 31.

494

J.C. Davis, Jr et al / Rheum Dis Clin N Am 29 (2003) 481–494

[45] Maksymowych WP, et al. A six-month randomized, controlled, double-blind, dose-response comparison of intravenous pamidronate (60 mg versus 10 mg) in the treatment of nonsteroidal antiinflammatory drug-refractory ankylosing spondylitis. Arthritis Rheum 2002;46(3): 766 – 73. [46] Pavy S, Marks S, Calin A. Approaching the concept of minimum clinically important difference with the bath ankylosing spondylitis indies. Arthritis and Rheumatism 2001;44(Suppl):s295. [47] Lehman TJ, Striegel KH, Onel KB. Thalidomide therapy for recalcitrant systemic onset juvenile rheumatoid arthritis. J Pediatr 2002;140(1):125 – 7. [48] Van Offel JF, et al. Effect of bisphosphonates on viability, proliferation, and dexamethasoneinduced apoptosis of articular chondrocytes. Ann Rheum Dis 2002;61(10):925 – 8.