Abstract
To date, over 2 million patients worldwide have been treated with anti-tumor necrosis factor (TNF) therapies, dramatically improving the treatment outcomes of immune-mediated inflammatory diseases (IMID). Observations from clinicians have identified some curious disconnects between clinical and radiographic outcomes, and the paradoxical occurrence of anti-TNF therapy-induced IMID such as psoriasis or reactivation of uveitis and Crohn’s disease. These observations point to the need for a better understanding of the mechanisms underlying the ability of anti-TNF therapies to reduce inflammation and how this is linked to the pathogenesis of IMID.
Many patients benefit from the use of anti-tumor necrosis factor (TNF) therapies to treat immune-mediated inflammatory diseases (IMID). What is surprising is the exacerbation of existing cases, or the occurrence of new cases, of psoriasis and uveitis when anti-TNF therapies are indicated for the treatment of these diseases. In some instances, the condition resolves when the patient is switched to another TNF inhibitor, and in most cases the condition resolves upon discontinuation of treatment. These observations point to a need for more treatment options for patients who develop these paradoxical adverse events.
Of additional interest is the disconnect between clinical and radiographic outcomes in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients treated with TNF inhibitors. While TNF inhibitors reduce TNF-associated inflammation, there is not always a concomitant reduction in structural progression in AS patients, suggesting that TNF is not involved in AS-associated spinal structural changes. The opposite is observed in RA patients; i.e., reduction of radiographic progression, sometimes to levels below 0, even when there is residual inflammation. These observations point to a need for better understanding of the links between TNF inhibitors and inflammation and radiographic outcomes.
THE DISCONNECT BETWEEN THE SKIN AND JOINTS: PSORIASIS TRIGGERED BY TNF INHIBITORS
Recent paradoxical observations that TNF-α inhibitors are capable of inducing psoriasis while also being effective therapy for the very same condition puzzled many clinicians and opened a new area for TNF-related scientific research and discussions. Further, in a recent online survey of rheumatologists, 63% of responders indicated that they have encountered psoriasis or other skin reactions in patients taking anti-TNF-α therapies1. It is also important to note that this adverse reaction appears to be a class effect and it is reported mainly in patients treated with TNF antagonist for RA, AS, and Crohn’s disease (CD).
Psoriasis Induced by Anti-TNF Therapies: Review of Published Case Studies
A recent review of a series of 127 cases of TNF-inhibitor induced psoriasis observed between 1990 and 2007 showed a prevalence ranging from 0.6% to 5.3% and onset from after a few days to up to 4 years2. While psoriasis classically presents as thick, erythematous plaques with an adherent silvery scale on the extensor surfaces of extremities (with over 80% of psoriasis patients having plaque-type), psoriasis occurring during TNF blockade has been mostly reported as the pustular type occurring on the palms and soles (pustular, palmo/plantar type in > 40% of cases vs plaque-type psoriasis in just 33% of the cases).
Similar data were reported by Grinblat and Scheinberg3. Of 50 cases of TNF inhibitor-induced psoriasis and psoriasiform skin lesions reported in the literature through to 2007, psoriasis developed following the administration of more than one TNF inhibitor in 7 patients. Fifty-six percent of patients were under treatment for RA, 22% for AS, and 14% for inflammatory bowel disease (IBD). However, according to this report the most common skin eruption reported was plaque psoriasis in 29 patients, followed by pustular psoriasis in 26 patients, and guttate psoriasis in 4 patients. Four patients also reported nail involvement. In all patients the lesions resolved when therapy was discontinued, and conversely, persisted with continuation of therapy.
Harrison, et al4 identified 25 cases of new-onset psoriasis among 9826 anti-TNF-treated patients with severe RA from the British Society for Rheumatology Biologics Register (BSRBR), while none of the 2880 patients with severe RA in a comparison cohort who received only traditional disease-modifying antirheumatic drugs (DMARD) in this database developed psoriasis. The median age of patients with incident psoriasis was 60 (interquartile range 55 to 63) and the female-to-male ratio was 5.3:1. Thirteen of the 25 patients developed psoriasis within the first 6 months of anti-TNF therapy, exhibiting extensive psoriasis of multiple sites or palmoplantar pustulosis. Only one patient reported a positive family history of psoriasis. The crude incidence rate of psoriasis was higher in those treated with TNF-α inhibitor therapy (1.04 per 1000 person-years) than in the comparison cohort based on 0 cases (one-sided 97.5% confidence interval 0.71 per 1000 person-years) in 5207 person-years of followup, or a rate calculated using a hypothetical case of psoriasis (0.19 per 1000 person-years). The unadjusted incidence rate ratio for new-onset psoriasis in patients treated with TNF inhibitors compared to a hypothetical case in the comparison cohort would be 5.4 (95% CI 0.7 to 40.3).
Table 1 provides an overview of common observations that emerged from case studies reporting psoriasis induced by anti-TNF therapies5.
Etiology and Pathogenesis
A number of possible explanations for the paradoxical occurrence of psoriasis as an adverse event of anti-TNF treatment have been explored (Table 2). One theory is that patients were misdiagnosed as having RA or AS but had either psoriatic arthritis (PsA) or psoriasis associated with AS. For example, PsA may precede psoriasis in about 15% of cases4. Alternatively, patients with psoriasis as an adverse event may have a genetic predisposition to psoriasis, which is not uncommon (prevalence 2.5%) in addition to their arthritis6. It is unlikely, however, that this accounts for the majority of patients. The RA patients had typical clinical and radiographic features of rheumatoid joint disease and almost all of them were rheumatoid factor (RF)-positive5. The patients with AS also met the New York diagnostic criteria for this disorder7, and only 25% of them had a history of psoriasis. Further, palmopustular psoriasis has not been described in patients with PsA receiving TNF antagonists.
A second explanation is the triggering of the cutaneous manifestations by infections5,8. Bacterial infections have been described in the genesis of both vulgaris and palmopustular psoriasis. It has been suggested that the palmopustular lesions are actually a form of keratoderma blenorrhagicum triggered by persistent Yersinia or Chlamydia trachomatis9, which may be similar to the palmopustular form of psoriasis. However, the absence of other features of reactive arthritis (e.g., eye disease, mucous membrane involvement, and joint inflammation), coupled with no documented preceding infection in the urogenital or gastrointestinal tract, argues against keratoderma blenorrhagicum in most, if not all, of the cases reported to date.
Immunological Considerations
One plausible explanation for the onset of psoriasis is that the reduction of TNF-α levels may cause a cytokine imbalance between TNF-α and interferon-α (IFN-α), which can promote an autoimmune response. Plasmacytoid dendritic cells (PDC), which are natural IFN-α producing cells, have recently been shown to infiltrate the skin of patients with psoriasis10. It has also been demonstrated that TNF-α regulates IFN-α production11 by inhibiting the maturation of PDC from hematopoietic progenitors and by inhibiting IFN-α release by PDC activated by viral infection.
In support of this theory is the fact that other cutaneous eruptions associated with TNF-inhibitor therapy include lupus- and dermatomyositis-like eruptions and cutaneous vasculitis12. Both cutaneous lupus erythematosus13 and dermatomyositis14 have been associated with dysregulation of IFN-α. Patients using IFN-α for chronic liver disease or certain malignancies are also known to be prone to the development of new-onset psoriasis15.
In addition, changes in T cell function could potentially trigger a psoriasiform response in patients after TNF inhibition. T cells are believed to play an important role in the initiation and persistence of psoriasis16. Changes in T cell function through the subtype that expresses CD4+ CD25+ may play a role, since it suppresses autoinflammatory responses in mice and possibly in humans17. Keratinocytes and T-regulatory cells also express a glucocorticoid-induced TNF receptor (GITR) that is involved in apoptotic mechanisms. A decline in TNF levels may be involved in anti-apoptotic activity through the GITR receptor18. Finally, decreased TNF expression was recently reported in the palmopustular subtype, suggesting that suppression of TNF can facilitate the development of this subtype19.
Management of Anti-TNF Therapy-induced Psoriasis
According to published case studies2, topical corticosteroids were used over 55% of the time but led to resolution in only 25% of cases when used without any other intervention. Switching to a different TNF inhibitor led to resolution in just 15% of cases, compared to discontinuing anti-TNF therapy, which led to improvement in 50% of patients. The most effective treatment option was discontinuation of TNF-inhibitor treatment paired with initiation of systemic therapy, leading to resolution in over 64% of cases.
According to the above evidence, the most logical approach for patients receiving anti-TNF agents who develop psoriatic lesions would be to discontinue anti-TNF therapy. However, as this may result in a significant flare of the underlying disease, careful benefit/risk assessment may be necessary. The diagnosis of psoriasis should be confirmed clinically and histologically. The simultaneous use of topical treatments and occlusive dressings may be beneficial. An alternative to discontinuation is to switch to a different anti-TNF agent. Phototherapy and systemic agents such as cyclosporine may also be useful.
In summary, further work and collaboration between dermatologists, rheumatologists, and gastroenterologists are needed to identify risk factors for TNF antagonist-induced psoriasis, to advance knowledge of the pathophysiological mechanism of this phenomenon, and to determine the best therapeutic strategy.
THE DISCONNECT BETWEEN CLINICAL AND RADIOGRAPHIC OUTCOMES: SUPPRESSION OF THE OSTEOCLAST
Inflammation of rheumatoid joints causes cartilage degradation, bone resorption, and joint destruction that, if left untreated, lead to permanent disability. Progression of erosions and joint-space narrowing has been shown to be most rapid during the early stages of RA, tapering slightly in later years20. In a prospective followup study of 147 patients with recent-onset RA21, 70% of patients developed radiographic damage within 3 years of onset. Thus, a key to successful outcomes is an early and aggressive therapy. The goals of treatment for patients with RA are to reduce inflammation and to prevent radiographic progression. To that end, a variety of useful and practical tools are available to rheumatologists to assess patient prognosis and evaluate response to treatment in clinical practice. The most accepted clinical assessment tools are the response criteria of the American College of Rheumatology (ACR)22 and the European League Against Rheumatism23, as well as the Disease Activity Score (DAS)24 and its simplifications such as the Simplified Disease Activity Index (SDAI)25 and the Clinical Disease Activity Index26. Radiographic progression, on the other hand, is generally assessed by quantifying changes in joint-space narrowing and erosions visible on serial plain radiographs. Evidence from daily clinical practice, however, clearly indicates that clinical remission does not necessarily reflect radiographic remission, and vice versa.
Radiographic Progression in Patients with Clinical Response
Radiographic progression may occur in patients who have met the criteria for clinical remission, suggesting ongoing disease activity. One reason for this disparity is that current definitions of clinical remission, such as the DAS and the ACR criteria, allow for some residual disease activity. Patients may have up to 8 or 13 swollen joints while still meeting the criteria for DAS or ACR remission, respectively27.
Clinical Disease Activity in Patients with Radiographic Remission
Just as radiographic progression is observed in patients with clinical remission, patients with clinical disease activity may have little or no evidence of radiographic progression. Data from the pivotal trials with infliximab (Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy, ATTRACT), etanercept (Trial of Etanercept and Methotrexate With Radiographic and Patient Outcomes, TEMPO), and adalimumab (PREMIER) show the remarkable ability of TNF inhibitors to reduce the mean level of joint destruction28–30, even in patients with suboptimal clinical response [i.e., those not reaching 20% improvement by ACR criteria (ACR20) or with high DAS].
The ATTRACT trial assessed the relationship between inflammation and joint destruction in RA patients treated with infliximab and methotrexate (MTX) who were previously unresponsive to MTX alone29. Patients were followed to Week 54 and assessed for changes in clinical variables. Radiographic progression was compared between patients who received infliximab + MTX and those who received placebo + MTX. Patients receiving infliximab + MTX who did not reach ACR20 response did exhibit mild but statistically significant improvement in clinical variables, including the 28-joint DAS, tender and swollen joint counts, and C-reactive protein (CRP) level. Whereas the clinical and CRP changes among these ACR20 nonresponders were small and much lower compared to ACR20 responders, there was a significant inhibition of radiographic progression among ACR20 nonresponders to infliximab + MTX compared with ACR20 nonresponders to placebo + MTX (Figure 1). Further, patients receiving infliximab + MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received placebo + MTX whether they were ACR20 nonresponders through Week 54, DAS nonresponders at Weeks 30 and 54, or without any improvement in individual clinical variables29.
The PREMIER trial30,31 further demonstrates the clinical/radiographic dissociation with anti-TNF agents (Figure 2). The trial compared a combination of adalimumab and MTX with each of the 2 drugs as monotherapy. Although higher ACR responses were seen with the combination therapy than with either drug as monotherapy, there was no significant difference between the 2 monotherapies in terms of ACR response. However, patients treated with MTX monotherapy showed greater radiographic progression than patients treated with adalimumab. Cumulative probability plots revealed that, overall, the majority of patients had a change in total Sharp scores (TSS) of ≥ 0, and that the combination of MTX and adalimumab decreased both the number of patients with radiographic progression and the extent of progression in those patients32. Taken together, these studies indicate that the mechanisms that cause inflammation are not the same as those that cause joint damage. Further, radiographic remission appears to be substantially easier to achieve than clinical remission.
Smolen, et al33 propose that high TNF levels in the synovial joints play a crucial role in joint destruction in RA and that inhibiting TNF might, therefore, retard radiographic progression when clinical manifestations are not lessened in a meaningful way. This hypothesis is based on reports that RA-affected joints have much higher levels of TNF than joints affected with other inflammatory arthritides34–36, which may play a critical role in initiating osteoclastogenesis37. Based on these data, it is postulated that excessive TNF levels are unique in causing joint destruction in RA and that the advent of anti-TNF therapies has revealed an important relationship between TNF and bone erosion that is independent of inflammation.
In summary, a better understanding of the mechanisms responsible for the disconnect between inflammation and radiographic outcomes would provide justification for continuation of anti-TNF therapy in patients who exhibit little or no improvement in clinical symptoms.
THE DISCONNECT BETWEEN RADIOGRAPHIC AND CLINICAL OUTCOMES: SPONDYLOARTHROPATHIES
AS is a chronic rheumatic disease associated with spinal inflammation that subsequently leads to progression of structural damage and loss of function. A hallmark of the disease is new bone formation in the spine, which typically leads to ankylosis across disc spaces and is thought to follow the onset of inflammation38. Unlike other inflammatory rheumatic diseases such as RA and PsA, structural progression in AS appears to be independent of TNF, despite the fact that TNF is a key cytokine involved in the inflammation-related signs and symptoms of the disease. Anti-TNF therapies have been shown to increase spinal mobility, decrease the erythrocyte sedimentation rate and CRP levels, and decrease markers of cartilage degradation in patients with AS39. Restoration of Th1 cytokine production, decrease in synovial vascularity and infiltration with inflammatory cells, and improvement in magnetic resonance imaging (MRI)-defined lesions with TNF-inhibitor treatment have also been reported40. However, prevention of structural damage by TNF inhibitors has yet to be demonstrated.
The effect of anti-TNF therapies on radiographic progression in patients with AS was evaluated by comparing patients treated with an anti-TNF agent to AS patients enrolled in the Outcome Assessments in Ankylosing Spondylitis International Study [OASIS]41. OASIS patients were treated according to common practice guidelines including the use of nonsteroidal antiinflammatory drugs (NSAID), analgesics, and regular exercise therapy, but not with anti-TNF agents. Radiographic progression was measured using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS)42. There was no significant difference in the change in mSASSS from baseline to 2 years among patients who received etanercept as compared to patients from the OASIS group (Figure 3A)43, or infliximab (Figure 3B)41, or adalimumab (Figure 3C)44.
The fact that NSAID are shown to reduce radiographic progression further supports the hypothesis that TNF does not play a role in AS-associated structural damage45. NSAID are still regarded as the cornerstone of pharmacological intervention for AS, with a good antiinflammatory capacity and the ability to rapidly reduce pain and stiffness46,47. Wanders, et al45 demonstrated that longterm, continuous treatment with NSAID significantly slowed radiographic progression in AS patients compared to patients receiving on-demand NSAID therapy. Patients began treatment with celecoxib [a cyclooxygenase-2 (COX-2) inhibitor] at a starting dosage of 100 mg twice daily, and were permitted to increase this dosage to 200 mg twice daily or switch to another NSAID. COX-2, an inducible inflammatory cytokine, plays an important role in regulating osteoblastogenesis in bone formation48. Therefore, the mechanism by which COX-2 inhibitors slow radiographic progression is postulated to be through its role in blocking COX-2 and inhibiting new bone formation. In COX-2 knockout mice, the reduced bone formation phenotype can be rescued with the addition of prostaglandin E2 (PGE2), the product of the COX-2 enzyme48.
Interactions Between Inflammation and New Bone Formation
An important observation in AS patients is the development of new syndesmophytes following the resolution of inflammation by anti-TNF therapies. Maksymowych, et al49 observed that an active corner inflammatory lesion (CIL) in AS patients was more likely to evolve into a new syndesmophyte than a vertebral corner demonstrating no active inflammation. New syndesmophytes also developed more frequently in vertebral corners where inflammation had resolved than in those where inflammation persisted despite anti-TNF treatment. The findings support a relationship between inflammation and ankylosis and indicate that a syndesmophyte is more likely to develop from a prior inflammatory lesion.
The interaction between the mechanisms of new bone formation and inflammation is crucial in the pathogenesis of AS. Diarra, et al50 demonstrated that Dickkopf-1 (DKK1) plays a major role in the stimulation of osteoclasts and in the inhibition of the Wnt/ß-catenin pathway, which activates new bone formation. TNF is a key inducer of DKK1, therefore blocking TNF with anti-TNF therapy results in downregulation of DKK1, which in turn results in new bone formation. These results suggest that TNF inhibitors are unable to block new bone formation, but rather are able to induce new bone formation. Thus, it could be hypothesized that anti-TNF therapies can only prevent new bone formation if this is coupled to inflammation and if this inflammation is treated early. Studies on bone biomarkers in AS patients support the view that suppression of inflammation induces new bone formation51–53. Once inflammatory lesions are established, inflammation and osteoblastogenesis are driven by non-TNF signaling pathways and therefore anti-TNF therapies no longer have an effect on radiographic progression.
Recent evidence suggests a link between the Wnt/ß-catenin pathway and the prostaglandin pathway involving downregulation of DKK1 and sclerostin and upregulation of the Wnt pathway by PGE254. Therefore, new bone formation (Wnt pathway) may be inhibited by prostaglandin inhibitors such as NSAID, which might explain the inhibitory effect of NSAID on new syndesmophyte formation in AS45.
ORPHAN DISEASES — UVEITIS
The term “uveitis” is used to describe many forms of inflammation of the middle layer of the eye involving the uveal tract (iris, ciliary body, and choroid) and adjacent ocular structures (retina, vitreous, and optic nerve)55. Ocular inflammation can lead to permanent loss of vision56. A major subset of uveitis is associated with the immune-mediated diseases such as AS57, Behçet’s disease (BD)58, IBD59, juvenile idiopathic arthritis (JIA)60, PsA61, psoriasis62, relapsing polychondritis63, and sarcoidosis64. Sugita, et al65 analyzed ocular fluid from patients with active and inactive uveitis, as well as from control subjects without uveitis. Significantly higher levels of TNF and both soluble TNF receptors (sTNFR1 and sTNFR2) were measured in the ocular fluids of patients with active uveitis compared to patients with inactive uveitis and control patients. Further, it was demonstrated that sTNFR had the ability to enhance TNF production by intraocular T cells, suggesting that intraocular sTNFR plays a regulatory role in the ocular inflammation observed in uveitis.
TNF Inhibitors for the Management of Uveitis
It is therefore not surprising that TNF inhibitors, which are effective for many of the systemic diseases associated with uveitis, are also effective in the management of uveitis itself. Infliximab has been reported to be especially successful in the treatment of uveitis in patients with BD, producing a fast-onset therapeutic effect in patients with sight-threatening inflammation, including patients with retinal vasculitis66,67. Repetitive infliximab infusions were also reported effective in preventing ocular relapses, maintaining visual acuity, and tapering immunosuppressive therapy in the majority of patients who were intolerant of or who demonstrated an inadequate response to conventional therapy66. Infliximab shows efficacy in patients with refractory posterior uveitis and scleritis as demonstrated in a 7-year followup case series study using patients refractory to conventional therapies, i.e., steroids and at least one immunosuppressive agent68. Infliximab is effective in reducing acute episodes of uveitis in BD69 and appears to induce long-lasting remission of BD even after the end of therapy70. Infliximab has also demonstrated efficacy in the treatment of ocular inflammation associated with RA, JIA, SpA, CD, sarcoidosis, and Graves’ disease ophthalmopathy71. However, as infliximab requires intravenous administration some patients are turning to adalimumab with its subcutaneous administration as a therapy for uveitis. Further, in a study conducted by Suhler, et al72 infliximab therapy for uveitis was associated with marked toxicities. One speculation is that this toxicity results from the effect of very high serum drug levels in patients who have localized inflammation and normal baseline serum TNF.
Adalimumab has a substantial preventive effect on the frequency of uveitis flares in patients with AS (Figure 4)73 and has been reported to show efficacy in the treatment of BD-associated uveitis resistant to infliximab therapy74 (Figure 4). In their study of the efficacy of adalimumab on chronic anterior uveitis in children, Biester, et al75 found adalimumab to be effective in cases previously unresponsive to combined therapies (including infliximab), with minimal side effects (absence of anaphylactic reaction or infection). Response to adalimumab in JIA uveitis is fast and occurs within the first 2–6 weeks of therapy76. Adalimumab also appears to be a safe and effective therapy for the management of refractory uveitis77.
In summary, in patients with spondyloarthropathy, both adalimumab and infliximab are effective in reducing uveitis flares whereas etanercept has not consistently been found to prevent attacks78. Further, several small, randomized, controlled trials comparing etanercept with placebo in the treatment of chronic noninfectious uveitis79, uveitis associated with JIA80, and uveitis associated with sarcoidosis81 concluded that etanercept failed to show a treatment effect.
Uveitis During Treatment with an Anti-TNF Agent
Several studies have revealed new-onset uveitis82,83 or a worsening of pre-existing uveitis84 among patients taking anti-TNF treatment. Lim, et al85 analyzed cases of uveitis associated with etanercept, infliximab, and adalimumab therapy that were reported to the World Health Organization adverse drug events database (WHO Uppsala Monitoring Centre, Uppsala, Sweden) or the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland, OR, USA) from January 1, 1998, to January 1, 2006. There were 43 cases of uveitis associated with etanercept, 14 with infliximab, and 2 with adalimumab. After normalizing for the estimated number of patients treated with each TNF inhibitor, etanercept showed a significantly greater association with uveitis compared to both infliximab and adalimumab; no significant difference was found between adalimumab and infliximab. A priori criteria were used to exclude patients with an underlying disease associated with uveitis (e.g., AS, CD, PsA), resulting in the identification of 20 cases associated with etanercept, 4 with infliximab, and 2 with adalimumab. Repeat analysis revealed a greater number of uveitis cases associated with etanercept compared to infliximab. These results are consistent with previous studies, and suggest that this is specific to etanercept and not related to TNF inhibitors as a group; however, these observations do not support the use of infliximab over etanercept; rather, if uveitis develops while on etanercept a switch to infliximab may be warranted.
SUMMARY
The development of anti-TNF therapies has revolutionized the treatment of IMID, providing clinicians with a wider choice of effective treatments for their patients. The use of these agents in daily clinical practice, however, has revealed some counterintuitive findings. These include triggering autoimmune diseases such as psoriasis and uveitis, as well as a disconnect between clinical and radiographic outcomes in RA and AS. These observations demonstrate that gaps remain in our understanding of the role of TNF in IMID. Uncovering the underlying mechanisms and connections between inflammation and structural damage will further help clinicians to optimize the use of anti-TNF therapies.
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