Question by dottie: Is anti-tnf effective for ankylosing spondylitis?
Has anyone any any pro or con stories/info about it

Best answer:

Answer by nephthys_tombguardian
Effect of anti-TNF therapy in spondyloarthritides

In the open pilot study performed in Berlin, infliximab ameliorated the disease activity in patients with severe AS with a mean disease duration of 5 years [95], as measured by the BASDAI [96]. Eleven patients received three infusions of infliximab (5 mg/kg body weight at weeks 0, 2 and 6). Significant efficacy was already noted on the first day of therapy. Spinal pain, fatigue and morning stiffness in particular were ameliorated, and so was peripheral arthritis.

Nine of ten patients showed an improvement of >50% on the BASDAI; the median improvement of the BASDAI after 4 weeks was 70%. Importantly, quality of life, as measured by the ‘short form’ 36-item instrument (including only 12 questions instead of 36), significantly improved after 4 weeks. In comparison with an age- and sex-matched normal, healthy German population, the AS patients studied had clearly impaired initial assessments; in particular, their level of physical functioning was very low. This level was significantly increased by anti-TNF-? therapy within 4 weeks. One patient has remained in remission for at least 18 months after only the initial three infusions of infliximab. As major side effects, three patients developed allergic reactions and could not receive further treatment.

The patients in this study were followed up for another 9 months. The next infusion of infliximab was not given until after a relapse, which was defined as at least 80% of the initial activity [97]. The first symptoms came back after a mean of 6 weeks and a relapse occurred after a mean of 12 weeks. These patients were treated three more times. Although all responded again, they did less well than at the start of the study, probably because there was no initial saturation phase in the repeat treatments.

In the meantime, there have now been several open-label studies on infliximab in AS [98-102]. In a Belgian study, 21 SpA patients, including 11 with AS, were treated with infliximab with a dose regimen similar to that in the study just discussed, but the patients had a longer disease duration (15 years) and the intervals between the infusions were longer (14 weeks). The spinal and peripheral symptoms of all these patients with SpA improved significantly [98]. There have been other studies – two in Canada, one with 24 [99] and one with 21 AS patients [100]; one in France, with 50 AS patients [101]; and one in Spain, with 42 SpA patients [102] – in which treatment with infliximab was successful, all with a similarly good response in about 80% of the patients. In one Canadian study [99] and the Spanish study [102], patients with disease of long duration and with advanced radiographic disease/ankylosis apparently benefited less from the therapy. In the other Canadian study [100], a relatively small dose, 3 mg/kg every 8 weeks, was sufficient to cause significant improvement.

In a French study, the bone mineral density of 31 patients (26 men and 5 women, mean age 40 years, mean disease duration 18 years) increased by 3.3 ± 5.5% at the lumbar spine (P < 0.002), and 1.9 ± 3.1% at the femoral neck (P < 0.008) after 6 months of infliximab therapy [103]. A recent randomized, double-blind, controlled trial in Germany has provided class-B evidence (according to 'evidence based medicine' criteria) that infliximab is effective against AS [104]. This placebo-controlled, multicenter study conducted over 12 weeks included 70 AS patients with a BASDAI >4 and spinal pain on a visual analogue scale >4. A highly significant effect of infliximab treatment (5 mg/kg body weight given at weeks 0, 2 and 6), with the primary outcome parameter of a 50% improvement of disease activity (BASDAI), was achieved in the treated group in comparison with the placebo group. Again, other parameters such as BASFI, BASMI and the short-form 36-item instrument showed a similar clear-cut improvement. There is some evidence that patients with elevated concentrations of C-reactive protein benefited more than those with low or normal levels [104]. Preliminary results from imaging follow-ups with spinal MRI assessing both acute and chronic spinal changes suggest a significant effect of infliximab on disease progression assessed on this basis. Taken together, these data strongly suggest a major breakthrough in the short-term therapy of severe AS.

After the placebo phase of the study, these 70 patients are now being treated with infliximab at 5 mg/kg body weight every 6 weeks for 2 years. After 48 weeks (when this article was written), about 75% of the patients are still being treated. So far, there is no indication of loss of efficacy. When complete, the study should provide more information about the long-term efficacy and safety of infliximab treatment in AS.

Another controlled study, from Belgium, has been recently published [105]. Both primary end points of this study, improvement in the patient’s and the physician’s global assessment of disease activity on a visual analogue scale, improved significantly in the infliximab group in comparison with baseline values, while there was no improvement in the placebo group. Significant efficacy was noted as early as week 2 and was sustained up to week 12, until the end of this study.

Regarding the optimal dosage of infliximab in SpA, only limited data are available. In a small study, we and our colleagues found that a dose of 5 mg/kg body weight was better than 3 mg/kg in patients with undifferentiated SpA [106]. However, the lower dosage of infliximab seemed to work also. Some patients may not need doses of infliximab higher than 3 mg/kg.

Treatment of AS with the soluble TNF-?-receptor etanercept has not been studied as extensively in SpA, but preliminary data from single cases [107], an open study [108] and now a double-blind study [109] also indicate a clearly favorable effect. This is in accord with our own preliminary experience with this therapy in 30 patients. In a study by Davis and coworkers in California [109], 40 patients were given either etanercept (25 mg given subcutaneously twice daily) or a placebo. A major difference from our own studies was that patients taking DMARDs (40%) or steroids (25%) were allowed to continue taking them during the study. Furthermore, different outcome parameters were used. After 6 months, main outcome parameters such as morning stiffness and nocturnal spinal pain had improved significantly in patients given etanercept but not in those given the placebo. The disease activity combination score used in that study had also improved significantly by 6 months but not by 6 weeks. Further studies with this drug are in progress or being planned.

There are various targets of SpA therapy (Table 1). In AS, the main targets are spondylitis, spondylodiscitis and peripheral arthritis. Other targets that are sometimes difficult to treat are enthesitis [76] and uveitis [110]. As has already been mentioned, there are targets in the skin (psoriasis) and the gut (colitis associated with inflammatory bowel disease), which have been shown to respond well to anti-TNF therapy.

There is evidence from the Berlin randomized, controlled trial and from case reports that anti-TNF therapy is beneficial in patients who are refractory to standard local and systemic treatment of enthesitis with NSAIDs, DMARDs and steroids, even in longstanding cases [104,111,112].

Concerning anterior uveitis associated with SpA, there is some recent evidence from controlled trials that sulfasalazine does prevent attacks [23,27], while the data for methotrexate are less clear. In a recent retrospective study [113], 160 patients with chronic uveitis of noninfectious origin were treated with methotrexate. Control of inflammation was achieved in 76% of patients and steroids were spared in 56%. Visual acuity was maintained or improved in 90% of patients.

The response of patients with all kinds of inflammatory eye disease to anti-TNF has been recently looked at in a limited number of patients [114]. The picture is not clear: both improvement and worsening of inflammatory eye disease upon treatment with infliximab have been found. In one study [115], 16 patients (4 males and 12 females, aged 7 to 78 years) who received etanercept (n = 14) or infliximab (n = 2) for either inflammatory eye disease or associated joint disease were studied retrospectively. Uveitis (n = 9) and scleritis (n = 7) occurred in patients with RA (n = 11), AS (n = 1), and psoriatic SpA (n = 1), and 3 patients had uveitis without systemic signs of disease. Although all 12 patients with active articular inflammation experienced improvement in joint disease, only 6 of 16 with ocular inflammation (38%) experienced improvement in their eye disease. Five patients even developed inflammatory eye disease for the first time while taking a TNF inhibitor.

In a prospective study [116] with 10 children suffering chronic active uveitis, 7 had uveitis associated with pauciarticular juvenile RA and 5 were positive for antinuclear antibodies (ANAs). All patients for whom previous therapy with topical steroids and methotrexate and/or cyclosporine had failed were treated with etanercept at 0.4 mg/kg body weight twice weekly for the first 3 months, and then, if their eyes did not improve, with 25 mg twice weekly (mean 1.1 mg/kg body weight) for at least 3 additional months. Within 3 months, 10 of 16 affected eyes (63%) showed a rapid decrease in cell density in the anterior chamber (P = 0.017), including remission in 4 eyes. Uveitis exacerbated during etanercept therapy in only 1 child (7%). After a dosage increase to an average of 1.1 mg/kg after 3 months in seven children, no further improvement was noted. It is well known that the natural course of uveitis in HLA B27+ versus ANA+ patients is rather different. The authors concluded that treatment of uveitis with etanercept in systemic and/or topical form (which has not been studied so far) needs further study.

In a recent report from Austria, El-Shabrawi and Hermann [117] reported a beneficial effect of infliximab with HLA-B27-associated uveitis in three patients. The same authors have recently published in abstract form their experience with this treatment over one year [118]. Seven consecutive patients with an acute onset of an HLA-B27-associated acute anterior uveitis were treated with a single dose of infliximab (10 mg/kg given intravenously). One patient received a second infusion 3 weeks after the first dosage, because of a relapse. The median duration (± SD) of uveitis was 8 ± 12 days. All the patients responded to infliximab with a rapid improvement of clinical symptoms and a decrease of cells in the anterior chamber of the eye. Only one patient did not develop total resolution of the uveitis. On follow-up, three of the seven patients were found to have experienced a relapse after a median of 120 days. These authors concluded that infliximab was very effective for treating acute anterior uveitis.

Most recently, treatment with infliximab has also been reported beneficial in patients with uveitis associated with Crohn’s disease [119]. Thus, the results from these uncontrolled observations are basically positive. In addition, our own experience with infliximab in a randomized trial with AS patients [104] is also suggestive of a beneficial effect, since three patients out of 35 in the placebo group, versus one out of 35 in the infliximab group, developed uveitis over 3 months.

However, the natural course of anterior uveitis in SpA is rather benign in the vast majority of patients. Thus, anti-TNF therapy should only be considered in severe, refractory cases. Controlled studies in homogeneous patient populations and a systematic comparison with local and systemic steroid therapy is clearly needed.

Outline Side effects of anti-TNF therapy

Although new, very effective therapies are arising, the greatest concern is of course about undesired and potentially severe side effects. There clearly are side effects to be considered in patients treated with anti-TNF agents. Information about side effects can come from various sources: directly from the clinical studies performed, from publication of the cases reported to the US Food and Drug Administration (FDA) or other agencies, from the data released by the drug companies, from case or group reports of cases and from personal experience. Every source has advantages but also shortcomings: clinical studies are controlled and randomized but special ‘ideal’ patients are selected for a limited amount of time; reports to the FDA are relevant because they reflect how the product is used in clinical practice but they are uncontrolled and they may lead to both underestimation and overestimation of the real risk due to the Weber effect and reporting bias; data from the drug companies should be most complete but the reports are also difficult to control and the reports are potentially influenced by the financial interest of the companies; case reports and single experiences may not be truly indicative, but they may, nevertheless, induce strong feelings because of personal experience. Thus, we have to select an optimal mixture from these different sources to arrive at valid statements; this is difficult. At the moment, final statements are still difficult because of the paucity of data available.

After the first years of anti-TNF therapy, the following seven types of adverse events seem to be of special concern for patients so treated:

1. infections, including sepsis and tuberculosis

2. malignancies, such as lymphoma

3. other hematologic disorders, such as anemia and pancytopenia

4. demyelinating disorders/neuropathy

5. worsening of congestive heart failure

6. occurrence of autoantibodies and autoimmunity

7. infusion/injection and hypersensitivity reactions.

From the postmarketing data collected by the FDA on the basis of spontaneous reporting – which are, according to agency officials, known to be of limited reliability – about 18,400 adverse events are known for etanercept and 2300 for infliximab, including 290 and 201 deaths, respectively. These figures do not indicate that the mortality is increased and there is also no reason to think that there is a difference in mortality between the two compounds. These data are taken from the FDA website http://www.fda.gov, where they are regularly updated. The estimated overall frequency of treatments worldwide is about 200,000 for infliximab and 150,000 for etanercept. The main reason for the different numbers of adverse events reported is that there was a telephone system installed for etanercept, which facilitates reporting, including by the patients themselves. Therefore, it is likely that the total number of adverse events for etanercept is an overestimate.

Although, on the basis of their different pharmacologic profiles (see above), it is generally conceivable that infliximab and etanercept have a distinct potential to cause adverse events, most statements made in this article rather relate to a class effect of these biologic agents, because this best reflects current knowledge. There may be a few exceptions, one of which may be with regard to tuberculosis (see below).

Infections

The outstanding and most frequent problem with both biologic agents are infections, accounting for 28% of all reports regarding etanercept and 39% for infliximab. The numbers of infections and deaths on treatment with the two agents were 5143 and 291, respectively, with etanercept and 901 and 228 with infliximab (double reporting possible; see above).

As recently reported, infection with mycobacteria seems to be associated with anti-TNF therapy, as it now stands, and mainly for infliximab [120]. By the end of November 2001, 117 cases had been reported to the agency [121]. The risk of developing tuberculosis in the first year of infliximab therapy has been estimated at 0.03% in the USA and 0.2% outside the USA. However, there have also been 18 cases of tuberculosis, including 5 deaths (up to 30 June 2001) associated with etanercept therapy, and one case of osteoarticular tuberculosis in a child has been published [122]. It is not clear at present whether the patients treated with etanercept are demographically comparable with those who received infliximab. Demographic factors could explain differences – especially if it becomes clear that patients treated with etanercept have lived in a safer environment. In the Berlin [104] and the Belgian randomized AS/SpA trials [105] with infliximab, disseminated tuberculosis occurred in one case at each site.

What is the reason for this increased frequency of tuberculosis? Since most of the infections of patients treated with inflixmab occurred during months 2–5 after the initiation of therapy, reactivation of latent tuberculosis seems to be the most likely explanation. However, both activation of latent tuberculosis and also new infections in the case of challenge with virulent microbes may occur [121]. Reactivation of tuberculosis has also been described in vaccinated patients [123].

TNF-deficient mice had similar survival rates in a conventional environment but were clearly more susceptible to a challenge with mycobacteria than normal controls [124]. Indeed, TNF seems to affect several aspects of the immune response to mycobacteria, including IFN-?-independent but TNF-dependent nonspecific mycobactericidal effects of macrophages [121]. However, the immunologic mechanisms that explain the link between TNF blockade and the failure of granuloma to contain bacilli are poorly understood. The T cells in TNF-deficient mice infected with tuberculosis seem to function normally [125]. All things considered, TNF-? has important, clinically relevant immune functions that need to be effective for clearance of certain microbes including mycobacteria. Whether a reactivated infection is due more to a heavy bacterial load or to a genetically determined functional variant or to alteration of the immune system needs to be determined. For example, there are at least partially genetically determined differences in the capacity to secrete cytokines such as TNF-? between individuals and between patients and controls [[126]; see below].

Other types of infection have been reported in patients treated with both anti-TNF agents. These include rare but fatal cases of severe pneumonia [127,128], meningitis [129], sepsis [130], histoplasmosis [121,131] and aspergillosis [132]. Furthermore, infections with listeria, Pneumocystis carinii, coccidioides, and candida [131] were listed in the FDA database.

In the ATTRACT trial (Anti-TNF Trial in Rheumatoid Arthritis with Comcomitant Therapy), there were seven deaths of patients treated with infliximab, versus four of control RA patients treated with methotrexate only [75]. The deaths were mostly related to the cardiovascular system or were due to advanced age. However, several patients died from severe infections, including sepsis and tuberculosis (see below).

According to the Centocor (manufacturer of infliximab) database containing data from all studies performed (n = 1372), there were 22% serious adverse events (SAE) on infliximab, versus 16% on placebo. In the totality of studies with infliximab, 63% of the patients had at least one infection, versus 51% of controls (n = 192). Treated infections were identified in 36% of the patients, versus 26% of the controls. Serious infections, however, occurred in 6.3% of infliximab-treated patients, versus 6.8% of patients on the placebo. The most frequent localization was the respiratory tract. Serious pneumonia was reported in 1% of the infliximab-treated patients, versus 0.5% among controls.

In recent, open-label, multicenter trials with infliximab, 8.5% of 553 RA patients in the USA had serious adverse events [133], and in a German trial, 25 of 263 RA patients (9.5%) withdrew because of side effects and 6 had a serious infection [134].

In a recent retrospective review of the medical records of 180 patients [135], most with RA (n = 144) started on etanercept, 81% of these patients remained on therapy for >6 months and 43% for >12 months. Corticosteroid dose reduction was possible in 56%, and tapering of the methotraxate dose was possible in 51%. Forty-three patients (23.9%) discontinued etanercept. Serious adverse events occurred in 5 patients (2.9%), mostly infections including psoas abscess secondary to infection with Mycobacterium avium intracellulare, septic wrist, bacteremia, and septic total hip replacement. There were two deaths associated with infection.

The FDA database also contained many reports of infections without an identified organism, with 28 deaths during or after etanercept administration and 11 with infliximab.

Fatal infections may occur with both agents. Tuberculosis has been more frequently reported with infliximab. However, as things stand now, the overall quality and quantity of the data are not good enough to make consistent risk/benefit calculations. Before treatment, patients should be informed about their immunocompromised status, especially in the first months of therapy, and educated to take signs of infection seriously and present to the responsible physician as soon as possible. Thus, all patients who are treated with anti-TNF therapy should be carefully screened for infections and treated with antibiotics if there is a suspicion of bacterial infection. Caution is needed before starting anti-TNF therapy, since latent infections such as subclinical pulmonary tuberculosis, or of abdominal tuberculosis in patients with Crohn’s disease, may be overlooked [136]. If there is a suspicion or a high risk of exposure, patients should not be treated with anti-TNF agents. Pre-emptive treatment with isoniaziol for the first 6–9 months of therapy should be given in patients who need and have agreed to start infliximab treatment and who are at risk of latent tuberculosis, being positive for purified protein derivative or who have x-ray evidence of exposure to mycobacteria or a recent history of confirmed tuberculosis contact.

Malignancy/hematologic disorders

The FDA database showed 26 cases of lymphoma reported with etanercept and 10 with infliximab. In a long-term follow-up of patients treated with etanercept, no increased incidence of malignancies was observed [137]. A similar finding has been reported for infliximab [138]. Rapid development of squamous cell carcinoma has been reported in a few patients treated with etanercept [139].

Looking at all studies with infliximab, 17 (1.2%) of the patients who had received at least one dose of infliximab had a reported malignancy (including lymphomas), whereas in the control group only 1 case was noted (0.5%). Since both patients with RA and with Crohn’s disease have an increased risk of malignancy, particularly lymphoma, no final conclusions can be drawn but, also due to the limited time frame of follow-up so far, the issue has not been completely clarified yet.

There have been seven cases of aplastic anemia in patients taking etanercept, five of whom died. Two cases of pancytopenia during treatment with infliximab have been reported.

A very small increase in the incidence of malignancies in patients treated with anti-TNF agents cannot be definitely excluded at present, but no increased frequencies have been observed to date. Etanercept may be associated with the onset of aplastic anemia, which, however, is a rare event.

Blood counts should be taken regularly in patients who are receiving anti-TNF therapy.

Neurologic disorders

The FDA database contained 16 reports of demyelinating disease in patients receiving TNF antagonists, in 15 cases associated with etanercept. This has been recently reported [140]. Earlier, two patients with multiple sclerosis were reported to have developed multiple sclerosis lesions while being treated with infliximab [141]. The basis for the discrepancy between the earlier and the more recent report is unclear [142]. Furthermore, two cases of optic neuritis and one of Guillain-Barré syndrome in a patient with RA have been reported. At present, it is unclear whether there is an increased risk of such disorders associated with anti-TNF therapy.

Etanercept may be associated with the onset of demyelinating disease, which, however, is a rare event. Patients should be regularly asked for neurologic symptoms.

Heart failure

Patients with congestive heart failure (a score >II on the New York Heart Association scale) should not be treated with either etanercept or infliximab, because, after early encouraging results, clinical studies with both agents indicated that more patients died or were hospitalized on anti-TNF therapy than on a placebo; this difference appeared to be pronounced in patients who received a high dose of infliximab (10 mg/kg). Not all these studies have been published yet.

Patients with heart failure, especially severe heart failure, may be at risk of worsening of their disease upon anti-TNF therapy. This needs to be carefully considered when therapeutic decisions are made.

Miscellaneous disorders

Development of diabetes mellitus has been reported in a young patient on etanercept [143]. Single cases of vasculitis have been described in patients treated with either agent [144,145].

Autoantibodies

Anti-TNF therapy is associated with the formation of certain autoantibodies. Looking at all those patients treated with infliximab from whom samples from before and after therapy were available (n = 1058), 55% became ANA+ at some time point, while 19% became positive on placebo. Of the patients positive for ANA at baseline, 36% became ANA-negative during the study. Autoimmune diseases such as drug-induced systemic lupus erythematosus or lupus-like syndrome (a term that is not very sharply defined) occurred very rarely – in 0.4% of all patients studied. Development of ANA or DNA antibodies was not predictive of the development of such symptoms. In an overview of data from all studies concluded with infliximab up to June 2001, 4.3% out of 1897 patients and 2% out of 192 controls discontinued treatment; 30 (16%) developed anti-dsDNA and 4 (0.2%) out of the patient group developed clinical signs of lupus-like syndrome (Centocor, data on file).

Treatment with etanercept was associated with the development of drug-induced lupus in one patient [146]. The induction of autoantibodies in patients treated with etanercept has been described: ANA developed in 11% (versus 5% on placebo) and anti-DNA antibodies occurred in 15% (versus 4% on placebo). Furthermore, the development of non-neutralizing antibodies to etanercept has been described in 5% of patients.

Patients have been tested for the development of antibodies to infliximab (anti-chimeric antibodies = HACA). In the ATTRACT trial, the overall incidence of these antibodies was 8.5%. Although there is a small trend towards a higher incidence of infusion reactions in patients who are positive for these antibodies, there is no indication to add methotrexate to infliximab to prevent infusion reactions.

Infusion/injection site reactions

The most frequent adverse event with etanercept is a local reaction at the injection site; such reactions are generally not a serious problem.

Infusion reactions due to infliximab were defined as any reaction during or 1 hour after the end of the infusion. During the studies with infliximab, infusion reactions occurred in 20% of all patients treated and in about 5% of all infusions given. The most common symptoms were headache (3.8%), dizziness (2.8%) and nausea (3.1%). Serious infusion reactions were rare (0.9%). Discontinuation of treatment due to infusion reactions occurred in 2.6% of the patients (Centocor, data on file).

Delayed adverse reactions 3–12 days after the infusion were reported in one study of patients with Crohn’s disease. On the whole, delayed hypersensitivity reactions were infrequent.

It is not clear whether immunosuppressants such as methotrexate or azathioprine should or can be succesfully added to infliximab to prevent antibody formation and allergic side effects.

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