Spondyloarthritides: evolving therapies
© BioMed Central Ltd 2010
Published: 17 December 2010
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© BioMed Central Ltd 2010
Published: 17 December 2010
TNF blockade therapy has substantially advanced the treatment of peripheral spondyloarthritides but revolutionised the treatment of severe ankylosing spondylitis. The capacity of biologic treatment to improve dramatically symptoms and quality of life in patients with spinal disease is undoubted, although important questions remain. Notable amongst these are concerns about skeletal disease modification and the true balance between costs and effectiveness. Guidelines for the biologic treatment of ankylosing spondylitis and psoriatic arthritis have been introduced in North America and Europe with considerable consensus. However, the absence of clear criteria for the diagnosis of early disease leaves the issue of biologic treatment of ankylosing spondylitis at the pre-radiographic stage unresolved. Newer biologic agents are entering the field, although superiority over TNF blockers will be difficult to demonstrate.
The introduction of TNF-blocking biologic drugs has constituted the greatest advance in the treatment of spondyloarthritis (SpA) over the past 50 years. At last, SpA - so long the Cinderella compared with rheumatoid arthritis - has entered the limelight with many patients previously untreated or unrecognised seeking the new magic bullet. The availability of effective anti-TNF treatment has exposed the personal and societal economics of treating and failing to treat these disorders as well as their impact on individual lives.
New treatments have complemented advances in under-standing of pathological changes in SpA, especially the key role played by enthesitis in peripheral and spinal lesions. New imaging techniques have made it clear that ankylosing spondylitis (AS), although identified historically by classic radiographic change, is a continuum from a pre-radiographic phase to a radiographic phase - the whole continuum being appropriately referred to as Axial SpA . During the radiographic phase, skeletal lesions are probably irreversible and may progress independently of ongoing inflammation; conversely, the opportunities for prevention or reduction of skeletal damage may be found during the pre-radiographic phase, although recognition of disease at this time is problematic. At this early stage, acute inflammatory lesions may be widespread and fluctuating throughout the spine [2, 3]; the transformation of these acute lesions to more chronic fatty bone and entheseal lesions may be what promotes the formation of new bone and hence ankylosis. It is therefore likely that treatment of spinal inflammation and symptoms may come to be divorced from therapeutic prevention of skeletal damage.
The crucial importance of new and emerging therapies in the field of SpA is best seen in the context of the shortcomings of current conventional treatment approaches. Undoubtedly nonsteroidal anti-inflammatory drugs reduce symptoms of AS and their continuous use may reduce the rate of ankylosis , but the mechanism of such an effect is not clear. Conventional diseasemodifying anti-rheumatoid drugs (DMARDs), however, exert neither symptomatic nor disease-modifying effects on the spine - and although used for treatment of peripheral joint disease, evidence of efficacy is limited. The evidence for efficacy of various medications on SpA has been summarised  and Assessment of Spondyloarthritis International Society (ASAS)/European League Against Rheumatism (EULAR) treatment recommendations have been made .
In spite of evidence linking infection with the pathogenesis of both axial and peripheral SpA, notably reactive arthritis, the potential efficacy of antimicrobial therapy on the course of SpA remains uncertain. The evidence of efficacy of antimicrobial treatment of reactive arthritis has been reviewed elsewhere . In both peripheral and axial SpA, therefore, there is a strong desire for more effective symptom-controlling agents and a need for drugs that truly modify disease outcome.
Key outcome measures in common use for assessment of axial disease in ankylosing spondylitis
Self-administered VAS questionnaire: fatigue, axial pain, peripheral joint pain, tenderness, stiffness
ASAS 20, 40, 70
Percentage improvement in three out of four domains: patient global, pain, function and inflammation
> 20% improvement in all four ASAS domains + one of CRP or metrology
< 20% activity in all four ASAS domains
Self-administered VAS questionnaire: 10 questions about day-to-day tasks
Self-administered VAS questionnaire: 20 questions about day-to-day tasks
Self-administered questionnaire scoring difficulty of 25 day-to-day tasks
Five clinical measurements: cervical rotation, tragus to wall distance, lateral lumbar flexion, modified Schober's, intermalleolar distance
Four clinical measurements: cervical rotation, lateral lumbar flexion, chest expansion, and internal rotation of the hip
Spine X-ray score
Disease of anterior vertebral corners on a lateral cervical and lumbar radiograph
Spine MRI score
Vertebral junction disease by quantifying bone marrow oedema
Vertebral junction disease by quantifying bone marrow oedema and erosions
Vertebral junction disease by quantifying bone marrow oedema
A simple 20-item questionnaire to measure work instability in AS
Quantitative measure of reduced productivity, both at work and during nonwork activities
Health-related quality of life
Addresses symptoms, function and disease-related concern
Physical and mental health assessment
The key therapeutic development in SpA is the introduction of TNF blockade therapy. Other agents, including orally administered drugs, may enter the field in the near future but the present review focuses on the biologic agents studied and used thus far in the treatment of SpA. Separate consideration of treatment of axial and peripheral disease is appropriate.
Biological agents in ankylosing spondylitis
Published randomised control trial data
Chimeric TNF inhibitor
8 to 9 days
Every 6 to 8 weeks
5 years 
Fusion protein TNF inhibitor
Twice a week or weekly
5 years 
Fully human TNF inhibitor
3 years 
Fully human TNF inhibitor
Every 4 weeks
24 weeks 
Anti-CD20 (anti-β cell)
24 weeks 
Fully human IL-12 and IL-23 inhibitor
Every 4 weeks in psoriatic arthritis
4 to 6 hours
24 weeks 
The TNF blockers have become well established in the management of SpA and key aspects of their use and efficacy are summarised below. Comparability between studies is hampered by use of a range of different measures and by variations in study design, although there are clear anti-TNF class effects with relatively small differences in efficacy between agents.
Intention to treat data for infliximab, etanercept and adalimumab
ASAS Partial Remission
Preliminary data are available for several other biological agents. Efficacy of golimumab, a fully humanised TNF inhibitor, is comparable with other TNF inhibitors over the short term  but longer-term experience is awaited. Rituximab, in a 24-week phase II trial (see Table 2), was as effective as TNF inhibitors in anti-TNF-naïve patients with active AS but appeared ineffective in patients who had failed such treatment . Limited data on use of anakinra have suggested less significant benefits in the treatment of AS [16, 17], and reports of the use of other biologic agents are anecdotal.
Magnetic resonance imaging (MRI), using the Ankylosing Spondylitis Spine MRI score, has established that the acute changes of spinal inflammation respond well to anti-TNFα therapy. A reduction in MRI signs of spinal inflammation of the order of 40 to 50% was seen after 3 months of treatment with infliximab, and this reduction persisted after 2 years. At this point, however, there was some residual spinal inflammation in approximately 80% of patients . Significant improvement in the Ankylosing Spondylitis Spine MRI score with etanercept treatment has been seen as early as 12 weeks, and this benefit was maintained at 6 months . Similar improvement in spinal and sacroiliac inflammation was seen in adalimumab-treated patients using the Spondyloarthritis Research Consortium of Canada scoring method. This benefit was maintained at week 52 of therapy .
Both infliximab  and adalimumab  have been shown to be effective at controlling symptoms and ameliorating MRI spinal changes in early disease (axial SpA), although any long-term disease-modifying effect has yet to be observed. The likelihood of clinical response to anti-TNF has been found to be greater in patients with shorter disease duration .
Improvement in function, as measured by the Bath Ankylosing Spondylitis Functional Index, is seen as early as 2 to 12 weeks after initiation of TNF blockade therapy [10, 24, 25] and is maintained for at least 3 to 5 years [11, 12].
This functional improvement is rapidly reversed on early discontinuation of treatment. Greater functional improvement is more likely to occur in those patients with early disease; these data should be seen in the context of the natural progression of untreated or conventionally treated disease, in which one estimate indicates natural progression of functional deterioration at 0.05 Bath Ankylosing Spondylitis Functional Index units per year .
Although separately measured, a close associate of function is the capacity for work and productivity. AS is associated with substantial work disability and loss of work productivity . Work capacity also correlates with quality-of-life measures such as the Ankylosing Spondylitis Quality of Life . Self-reported improvement in work capacity has been noted as early as 24 weeks after anti-TNF therapy , and return to work of some patients has been reported after a mean of 18 months of therapy . This clearly has important implications for individual income, self-esteem and family welfare in addition to assessment of the cost-effectiveness of these agents.
Treatment with each of the available anti-TNF agents has been associated with significant improvement in the physical component of the Short-form 36 ( SF-36) score. Improvement occurs between 6 and 12 weeks [10, 24] and is maintained in long-term trials . Nonsignificant improvements in the mental component scores also occur. Improvement in well-being is also reflected by significant improvement in Ankylosing Spondylitis Quality of Life, which is maintained in long-term trials .
Fatigue and sleep disturbance are important features of active AS. All anti-TNF agents are associated with improvement in fatigue, as reflected by reduction in the BASDAI fatigue scale, and improvement of sleep, using the Jenkins sleep scale, has been reported with golimumab treatment .
Improvement in metrology has been modest in most studies of TNF blockade therapy, reflecting both the extent of irreversible disease and insensitivity of this measure. Some improvement in the Bath Ankylosing Spondylitis Metrology Index (BASMI) score may be seen as early as 2 to 12 weeks [10, 24, 25], and this is sustained in most patients. It is clear, however, that maintenance of improvement in spinal mobility requires sustained regular mobilisation exercises.
Assessing disease progression in axial SpA is an imperfect art. Methods for scoring disease progression are problematic . The modified Stoke Ankylosing Spondylitis Spine Score  is currently the most sensitive to change of the methods and is therefore the radiographic method of choice for detecting radiographic progression . Reliance on anterior changes at two segments of the spine and exclusion of the posterior elements and thoracic segment are, however, undoubted limitations. Assessment of disease progression has also been hampered by lack of long-term follow-up of randomised controls on both ethical and practical grounds. Treatment groups have therefore been compared with historical control groups such as the Outcome Assessments in Ankylosing Spondylitis International Study cohort, in which patients received nonsteroidal anti-inflammatory drugs, analgesics and regular exercise therapy. Acknowledging these limitations, no significant difference has been detected in disease progression (modified Stoke Ankylosing Spondylitis Spine Score) between patients with active AS treated with etanercept, adalimumab or infliximab therapy compared with controls [34–36].
Currently it appears probable that most patients will require indefinite treatment, although dropout-rate ranges from 8 to 16% per year are described [12, 37, 38]. Stopping treatment appears to allow relapse in almost all patients  but most patients respond again on retreatment. Everyday clinical experience, however, indicates that some patients are able to withdraw treatment for periods of months and occasionally indefinitely. There are few data to clarify the numbers of patients in whom drug-free remission may be expected or the characteristics of patients in whom achievement of this is likely. Results of on-demand treatment led to results that were inferior to those of regular treatment .
Response to anti-TNF treatment in AS is greatest in patients with short-duration disease , high BASDAI and high acute phase markers, in particular C-reactive protein . Biomarkers predictive of responsiveness to treatment or other outcomes have not clearly been identified; serum levels of metalloproteinase-3 may predict radiographic progression in AS . Failure of the first anti-TNF drug does not predict success or failure of switching to a second or third anti-TNF drug [43–45].
Few studies have focused specifically on these lesions within the context of SpA, the majority of studies of peripheral SpA addressing psoriatic arthritis (PsA). It is not clear to what extent data on this condition are applicable to the generalisation of peripheral SpA; nor is it clear whether data on small joint polyarthritis are applicable to large joint oligoarthritis. With these caveats, however, it is reasonable to summarise the position in PsA and the disparate data of other peripheral SpA lesions, with the expectation that many conclusions are broadly applicable to peripheral SpA with or without axial or other associated lesions.
Key outcome measures in common use for assessment of psoriatic arthritis
ACR 20, 50, 70 response
Percentage improvement in tender and swollen joint counts in addition to improvement in three out of five measures: physician's and patient's assessment of disease activity, patient's assessment of pain, acute phase reactant, and functional questionnaire
Improvement by >1 point in both physician's and patient's assessment of disease activity in addition to >30% reduction in tender and swollen joint counts
PASI 50, 75
Percentage improvement in severity and extent of skin involvement
Minimal disease activity
Having five of the following seven criteria: tender joint count <1; swollen joint count <1; PASI <1 or body surface area <3; patient pain VAS <15; patient global disease activity VAS <20; health assessment questionnaire <0.5; and tender entheseal points <1
Joint erosion + joint narrowing scores
Etanercept treatment has led to significant improvement in both arthritis and skin symptoms in patients with PsA . Further studies have shown that 60% of those receiving etanercept achieved an American College of Rheumatology (ACR) 20 response, with one-quarter of eligible patients achieving a 75% reduction in the Psoriasis Area and Severity Index (PASI). ACR 20 criteria, Psoriatic Arthritis Response Criteria, and PASI 50 criteria were met by 64%, 84%, and 62%, respectively, of patients receiving etanercept at the end of the 48-week open-label period . Approximately 80% of patients meet Psoriatic Arthritis Response Criteria by 4 weeks, and substantial falls in the PASI are seen by 24 weeks of treatment. Comparable ACR and Psoriatic Arthritis Response Criteria responses have also been demonstrated with infliximab  and adalimumab . Comparable outcomes over 24 weeks have been reported recently with golimumab, with approximately 50% achieving ACR 20 responses and concomitant improvements in PASI, nail involvement (NAPSI) and a PsA-modified version of the Maastricht Ankylosing Spondylitis Enthesitis Scale (MASES) . Although originally devised and validated for rheumatoid arthritis, the Disease Activity Score is also frequently used in the assessment of PsA - although this is inappropriate for patients with oligoarticular disease.
Data from the British Society for Rheumatology Biologics Register indicate that advancing age, female gender and corticosteroid therapy were associated with poorer clinical response rates .
In clinical trials most data have been obtained from patients receiving TNF blockers and methotrexate in combination. It is clear, however, that TNF blockade alone is effective treatment for PsA  and the place of monotherapy versus combination therapy for PsA has yet to be fully defined.
In observational studies, switching between the three licensed anti-TNF agents due to adverse events or loss of efficacy has conferred improvement in clinical outcomes when switching from the first to the second agent, but larger trials are required to confirm this effect .
Improvement in physical disability, in terms of improvement in the Health Assessment Questionnaire score, has been widely reported in response to anti-TNF therapies, although this is partially dependent upon the pre-treatment state. Randomised control trial data for anti-TNF agents confirm improvement in the physical component of the SF-36 and Health Assessment Questionnaire [55, 56, 59] and the SF-36 mental component with infliximab [55, 56, 59]; these effects are maintained in follow-up trials for up to 2 years [60–62]. Adalimumab, etanercept and infliximab are associated with similar responses in terms of quality of life (SF-36) and functional status (Health Assessment Questionnaire) in normal clinical practice .
Conventional DMARDs have not been shown to induce significant inhibition of radiographic disease progression. In contrast, studies with adalimumab, etanercept and infliximab have all demonstrated inhibition of radio-logical progression as evidenced by plain radiography scoring. Mease and colleagues reported a greater inhibition of radiographic progression in etanercept therapy versus placebo therapy at 1 year, with a mean unit change in total sharp score of -0.03 and +1.00, respectively . Patients completing 2 years of etanercept had a mean adjusted change in total Sharp score of -0.38 from baseline . Equally effective inhibition of structural damage has been reported with infliximab  and adalimumab  up to 2 years. It is not clear whether concomitant methotrexate enhances this effect or helps to maintain efficacy.
In spite of the concept that reactive arthritis is initiated and driven by persistent bacterial infection, evidence that this is so or that the course of the disease is influenced by antimicrobial treatment is limited and controversial. Studies of short-term and long-term antibiotic mono-therapy have indicated both the presence and lack of clinical efficacy . Establishing or refuting a role for antibiotic treatment in reactive arthritis is hindered by the lack of a gold standard diagnostic test to identify a presumed causal microorganism(s) and to demonstrate its eradication by appropriate treatment. Evidence relating to persistent infection in reactive arthritis has focused principally on Chlamydia trachomatis and Chlamydia pneumoniae. These organisms are known to possess the property of persisting in synovial tissue in a metabolically active state. A recent randomised control trial of patients with chronic reactive arthritis and detectable chlamydial DNA in synovial biopsy or blood demonstrated significantly greater clinical response and probability of eradication of chlamydial DNA amongst patients randomised to combination antibiotic treatment compared with placebo . Further studies are required to establish the role of antibiotics in the treatment of reactive arthritis.
Anecdotal reports on the use of anti-TNF therapy in a few patients with severe, chronic reactive arthritis suggest value , although the possibility of persistence of viable microorganisms within the joint and elsewhere raises the prospect of potentially serious sepsis with increased morbidity.
Treatment of peripheral SpA is usually influenced or constrained by the associated key SpA conditions, with the exception of undifferentiated forms of peripheral SpA. Although criteria for diagnosis of peripheral SpA arthritis are clear , validated disease outcome measures for peripheral SpA are limited. It remains unclear whether treatment of SpA at an undifferentiated stage influences the subsequent development of irreversible differentiated disease.
Anti-TNF treatment is associated with substantial sustained reductions in tender and swollen peripheral joint counts [70, 71], although longer-term outcome data on subsequent need for surgery are awaited. It may be reasonable to transfer conclusions drawn from studies in PsA (vide supra) to other forms of peripheral SpA but, in reality, much information is still missing. In particular, data on the efficacy of TNF blockade with respect to rapidly progressive hip destruction, which is a key indicator of bad prognosis in SpA, would be of great value.
In clinical practice, large joint monoarthritis, especially of the knee, remains a challenging problem that may not respond well to either conventional or biologic therapy. Current guidelines do not recommend anti-TNF treatment for monoarthritis as the potential value in this context is unknown. Anecdotal accounts of intraarticular instillation of TNF-blocking agents into the knee of patients with AS and refractory peripheral monoarthritis indicate short-term value only .
Clinically relevant enthesitis lesions are common throughout SpA, with up to 50% of patients with AS experiencing symptomatic enthesitis at some time [73, 74]. For many, conservative measures are adequately effective although the small benefit afforded by sulpha-salazine does not justify the side-effect profile .
Evidence of efficacy of biologic treatment of enthesitis has been obtained principally from observations of concomitant peripheral enthesis lesions during studies of AS or PsA, with no clear data on treatment of severe individual lesions such as Achilles' tendonitis. Short-term randomised controlled trials of 12 and 24 weeks of treatment demonstrated significant improvement in enthesitis [10, 24]; and in the open-label Rhapsody trial of adalimumab treatment of AS, MASES scores were reduced from a mean of 5 at baseline to 1 at the 12th week: 122 of 173 patients had resolution of plantar fasciitis over the same time frame .
While topical corticosteroids and mydriatics remain the primary treatment of anterior uveitis, anti-TNF therapies may be of value in those with recurrent or especially severe episodes. Meta-analysis of the use of infliximab and etanercept in treatment of AS showed that both agents significantly reduced the frequency of episodes of uveitis compared with placebo therapy, conferring an incidence of anterior uveitis of 3.4/100 patient-years, 7.9/100 patient- years and 15.6/100 patient-years, respectively . Similarly, adalimumab treatment has also been associated with a reduced incidence of acute anterior uveitis from 15 to 7.4/100 patient-years .
Retrospective analysis of the use of adalimumab, etanercept and infliximab in the treatment of spondyloarthritides indicated that etanercept treatment led to a smaller reduction of uveitis flares than the other two agents studied and, in addition, flares of uveitis have been reported in patients starting etanercept therapy. Data for newer anti-TNF agents are awaited. It is not clear to what extent TNF blockade is appropriate for treatment of isolated uveitis in patients without other SpA features.
It is clear that the licensed TNF-blocking drugs provide substantial benefit for many, but by no means all, patients and that newer anti-TNF drugs are likely to share class effects. A number of newer licensed biologic agents are also effective in improving recognised disease outcomes for joint disease and/or co-morbidities, although the range of clinical benefits seen thus far with anti-TNF drugs will be hard to match or exceed.
Of the newer TNF-blocking agents, golimumab - a human anti-TNFα monoclonal antibody - has been shown to achieve ACR responses similar to those achieved with other TNF blockers in the treatment of people with PsA and is generally well tolerated . Treatment is also associated with improvement in health-related quality of life (SF-36) and function (Health Assessment Questionnaire). Effectiveness in short-term trials of treatment for AS has already been cited above. Information about the efficacy of certolizumab pegol is awaited.
It is well recognised that new agents entering the field face particular challenges as recruitment to clinical trials is increasingly likely to include subjects with milder, less typical or more resistant disease. In consequence, data should be compared with earlier anti-TNF studies with some caution.
Ustekinumab, an anti IL-12/IL-23 monoclonal antibody, has been shown - in a placebo-controlled randomised study of 70 patients with PsA - to be associated with significant improvement in five out of seven of the ACR component scores at week 12 of therapy. Reductions in the C-reactive protein level and swollen joint count did not achieve significance in the treatment arm . Ustekinumab has demonstrated efficacy in most patients with moderate to severe psoriasis in phase III trials . IL-10 treatment showed some improvement in skin disease (PASI) but no improvement in measures of PsA in a small, double-blind, placebo-controlled study in patients with PsA . Alefacept, a fully human fusion protein that inhibits leucocyte function by binding to CD2 on the surface of T cells, is an effective treatment of moderate to severe chronic plaque psoriasis . In a recent study, combined with methotrexate, similar ACR and PASI responses to those obtained with anti-TNF treatment were demonstrated . The safety profile also appears similar, so this agent appears promising for the treatment of both skin and musculoskeletal disease.
No randomised control trial data for abatacept or tocilizumab in the context of SpA have yet been reported.
The safety profile of the widely used TNFα blocking agents has been extensively documented in the treatment of rheumatoid arthritis; safety data are also extensive in SpA but less complete. Long-term studies with infliximab, etanercept and adalimumab in AS and PsA have revealed mostly mild to moderate adverse events, including upper respiratory tract infections, diarrhoea, headache and injection-site reactions [11–13, 59, 60, 64, 83]. A recent analysis of data from the British Society for Rheumatology Biologics Register has confirmed that TNFα blocking agents in PsA have a similar adverse event profile and incidence of malignancy to DMARD therapy in seronegative arthritis . Further studies of adequate statistical power and duration are required, however, before excluding a carcinogenic property of these drugs in SpA.
Other biologic agents have been less thoroughly evaluated. In the predominantly young SpA population, effects on cardiovascular risk and pregnancy are especially relevant. Accelerated atherosclerosis is likely to be the major contributor to increased standardised mortality rates seen in the spondyloarthritides. Provisional data from open- label studies have reported significant amelioration of the proatherogenic lipid profile and acute phase reactants of 92 patients with highly active AS after 3 months of etanercept , although it is not clear whether such changes will confer cardiovascular disease protection.
Use of any biologic drug in pregnancy is not supported. Data on fertility and teratogenicity have generally been drawn from non-SpA populations, although it is clear that foetal and maternal risks are small with TNF blockade treatment. Decisions about cessation or introduction of anti-TNF treatment in both men and women when pregnancy is desired or possible should be made on an individual basis taking into account known risks and maternal health .
Guidance regarding the use of anti-TNF agents in the treatment of AS [26, 86, 87] and PsA [9, 88–90] have been issued by several national and international agencies. Consensus on the classification of pre-radiographic axial SpA  may lead to revised regulatory decisions on the use of TNF blockade treatment in early AS with radiographic changes.
It is clear that TNF blockade treatment exerts a profound beneficial effect on symptoms in the majority of, but not all, patients with severe SpA. It is also clear that peripheral joint damage is significantly reduced by treatment, although this appears not to be the case for spinal disease. There is thus a need both to establish the case for early treatment that will prevent, rather than minimise, joint damage and to understand the reasons for apparent lack of damage prevention in spondylitis.
Inevitably availability of biologic therapy is and will remain restricted on the bases of potential toxicity and cost. Thus better targeting of treatment through use of clinical criteria and biomarkers is essential to ensure that only those who need them receive biologic drugs. Such need must be based both on the biology of the disease and on the life quality of the individual. Prevention of damage can surely underpin a better lifestyle and perhaps a longer life in good health. But attaining wellness even if some skeletal damage is done may well provide an equally strong and reasonable motive for use of biologic agents provided that the data to support this contention are robust and the criteria for improved quality of life are clearly established. In this context, enabling people with SpA to remain in work and maximise their individual productive potential must be seen as key elements for the efficacy of treatment. The balance point must be found between the social cost-benefits of restoring people to good health and productive working lives and the substantial costs and risks of treatment.
American College of Rheumatology
Assessment of Spondyloarthritis International Society
Bath Ankylosing Spondylitis Disease Activity Index
disease-modifying anti-rheumatoid drug
Maastricht Ankylosing Spondylitis Enthesitis Scale
magnetic resonance imaging
Psoriasis Area and Severity Index
tumour necrosis factor.