Update on treatment of psoriatic arthritis.
Abstract: Some of this past year's key papers or abstracts on psoriatic arthritis (PsA) assessment and treatment are reviewed in this paper. Treatment begins with identification of the PsA patient. Several screening questionnaires have been developed to be used in dermatology and primary care settings to identify which patients with psoriasis have developed PsA as opposed to other common musculoskeletal problems, such as osteoarthritis andfibromyalgia, thus increasing case-finding and targeting referral. PsA can present in a heterogeneous manner, involving arthritis, enthesitis, dactylitis, spondylitis, and skin and nail disease. Measures of these individual domains have been developed for use in clinical trials and improved PsA-specific composite measures of these domains are being evaluated as well. A quantitative therapy target, Minimal Disease Activity criteria, has been developed by the GRAPPA group. Treatment recommendations have been published by EULAR and GRAPPA. Obesity is a risk factor for the development of PsA and may adversely influence treatment outcomes. Although pharmacologic treatment often begins with methotrexate, a recent study does not provide clear evidence of its effectiveness. Anti-TNF therapies remain the gold standard of effectiveness. New therapeutic options are potentially emerging including ustekinumab, abatacept, several 1L-17 inhibitors, apremilast, JAK inhibitors, and possibly 1L-6 inhibitors.
Subject: Psoriatic arthritis (Causes of)
Psoriatic arthritis (Complications and side effects)
Psoriatic arthritis (Diagnosis)
Psoriatic arthritis (Care and treatment)
Practice guidelines (Medicine)
Author: Mease, Philip
Pub Date: 07/01/2012
Publication: Name: Bulletin of the NYU Hospital for Joint Diseases Publisher: J. Michael Ryan Publishing Co. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 J. Michael Ryan Publishing Co. ISSN: 1936-9719
Issue: Date: July, 2012 Source Volume: 70 Source Issue: 3
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 311498764
Full Text: Proper treatment of psoriatic arthritis (PsA) requires that the patient is correctly identified and brought to the attention of rheumatologists and other clinicians skilled in the treatment of PsA. Thus, the initial discussion in this article is an update on screening for and assessment of PsA.

In the great majority of patients with PsA, disease manifests in the skin and nails well before advent of inflammatory musculoskeletal disease. Therefore, dermatology or general practice clinicians, attending to the patient's psoriasis, are in an excellent position to screen for the first signs of PsA and begin management or refer to a rheumatologist. Although simple history and selected musculoskeletal physical exam may uncover PsA, in a busy dermatology practice this may not be done and if done, the clinician may not be able to reliably assess whether the symptoms and exam are consistent with PsA or an alternative diagnosis such as osteoarthritis or fibromyalgia. Several screening questionnaires, which can be filled out by the patient, have been developed for use in dermatology and primary care offices. These include the TOPAS (University of Toronto), PEST (University of Leeds), PASE (Harvard), PASQ (Khraishi), and most recently, the EARP (University of Verona). Several of these have been tested and validated in a variety of clinical settings and generally show good sensitivity and specificity for detecting the possible presence of PsA, which may then prompt more appropriate referral. For more detail, the reader is referred to a recent review of this subject. (1)

Comprehensive treatment of PsA involves assessment of and focus on each of the heterogeneous clinical domains of the disease, including arthritis (synovitis), enthesitis (inflamed attachment sites to bone of tendons, ligaments, and joint capsule fibers), dactylitis (swelling of a whole digit), spondylitis (potentially involving sacroiliac joints and vertebrae), psoriasis, and nail disease. Rheumatologists should be skilled in assessing the musculoskeletal elements and variably skilled in assessing skin and nail disease--or work in teamwork with dermatologists. Measures of these individual clinical domains have been developed and generally shown to be responsive (i.e., demonstrate change with effective therapy) and discriminant (i.e., able to tell difference between treatment and placebo). A comprehensive review of measures used in PsA clinical trials and occasionally in clinical practice has been published within the last year. (2)

Clinical trials have also used composite measures, which attempt to take into account the whole person and weave together individual clinical domains. For example, in rheumatoid arthritis (RA) joint disease, the ACR and DAS systems take into account both swollen and tender joints, patient global (overall assessment), and an objective measure such as a CRP or ESR. The ACR system additionally takes into account a measure of function. Traditionally, measures, which focus on joints (ACR and DAS systems) or skin (Psoriasis Area and Severity Index) (PASI), derived from RA and psoriasis, respectively, have served this purpose. However, in order to try (in one measure) to take into account all of the clinical domains of PsA, including skin, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has been working on the development of new composite measures specific to PsA, which more comprehensively assess the various clinical domains of PsA, for the measurement of disease activity and response to therapy. Three new measures in particular, the CPDAI, the PASDAS, and the AMDF, have been developed, tested in the GRACE data set (a longitudinal group of over 400 subjects seen in GRAPPA investigator centers), and ratified at the recent Outcome Measures in Rheumatology Clinical Trials (OMERACT) meeting to carry forward and test in prospective clinical trials. (3,4)

An emerging paradigm of treatment of RA is that of "treat to target" (i.e., a state of remission or low disease state). This requires quantitative measurement of disease severity (e.g., DAS28 in RA) and numeric thresholds to be ideally achieved. A preliminary target for PsA treatment is the criteria for Minimal Disease Activity (MDA) developed by the GRAPPA group based on expert opinion about a set of hypothetical cases (Table 1). (5) The MDA criteria have been further validated in a registry cohort and a clinical trial data set and are now being employed in prospective PsA clinical trials. It is anticipated that in addition, as one of the newly minted composite measures of disease activity and response to therapy moves to the fore, quantitative thresholds of disease activity will be established for remission, low, moderate, and high disease activity.

PsA Treatment

Treatment Recommendations

Two different sets of PsA treatment recommendations have been developed. One is the EULAR set of treatment recommendations, which algorithmically guide the clinician through more serial treatment steps and choice of medications based on the severity of clinical domains (arthritis, enthesitis, and spondylitis) involved and serial response to therapy. (6) These recommendations focus on musculoskeletal aspects of disease. The GRAPPA group has also developed a set of treatment recommendations, similarly, based on evidence derived from a literature review of treatment of the various clinical domains, including skin. These recommendations use a "grid" approach in which the clinician evaluates the severity of disease in each clinical domain (arthritis, enthesitis, dactylitis, spondylitis, and skin psoriasis) as well as impact of these domains on physical function and quality of life, in order to assess the relative severity of the domain that in turn guides treatment choices (Table 2). (7)

Obesity

Obesity appears to be a risk factor not only for the development of PsA in patients with psoriasis (8) but may also be a negative predictor of achieving and maintaining MDA (9) and may even influence the ability of anti-TNF therapy to exert optimal therapeutic effect. (10) This raises the possibility that obesity may be a modifiable risk and therapeutic factor. One possible explanation for this phenomenon is that fat cells may produce adipokines, which may have a proinflammatory effect. However, another study (11) suggested that BMI did not predict disease remission following anti-TNF therapy, so we need to be cautious about our understanding of the influence of obesity on disease activity until further studies are done.

New data on currently available therapy and therapy that is on the horizon for PsA has emerged in the past year.

Methotrexate

Although methotrexate (MTX) is generally regarded as one of the most basic and widely used oral immunomodulatory drugs for PsA, the evidence base for its effectiveness in treating the various clinical domains of PsA is scant. Indeed, historically there has been only one small controlled trial, which was both underpowered and used a standard dosing regimen in only one of three arms of the study, thus no surprise that it did not demonstrate meaningful efficacy. (12) To try to rectify this state of affairs, Kingsley and colleagues generated the Methotrexate in Psoriatic Arthritis (MIPA) trial. (13) The intent was to enroll an adequately powered trial using at least 15 mg/wk of MTX (with option to dose up to 25 mg) compared to placebo. Over the course of approximately 5 years, 221 subjects were enrolled. At 6 months, statistically significant improvement was observed in patient and physician global assessment and mean PASI score, but only a trend was seen (not statistically significant) in improvement of tender and swollen joint count, measures of pain or function, PASI75, or composite measures such as ACR20, DAS28, or Psoriatic Arthritis Response Criteria (PsARC). The investigators concluded that MTX does not improve synovitis and is therefore not disease-modifying and had "borderline" symptom-modifying properties. Numerous problems abounded with the study, including dropout of at least a third of patients in each arm, the possibility that investigators channeled less severe patients to the study, and perhaps insufficient aggressiveness of dose increase, making it difficult to know if MTX was given a fair chance. In contrast, various open label studies, including one comparing MTX with MTX+infliximab in a relatively early patient cohort, (14) showed, as expected, very high joint and skin responses in the combination arm, but also substantial improvements in both domains in the MTX monotherapy arm, consistent with our experience in clinical practice. Although it has been difficult to conduct a proper controlled trial to demonstrate its efficacy, MTX will for now remain a mainstay drug for initial and combination therapy for PsA. We will simply need to wait for possible future properly powered trials comparing MTX monotherapy to "New Therapeutic" monotherapy to "New Therapeutic + MTX" to truly learn about its efficacy in joints and skin, as well as in domains such as enthesitis, dactylitis, nail disease, and structural damage.

Anti-TNFs

Data from a phase 3 pivotal trial with certolizumab pegol in PsA demonstrated clinical efficacy with this anti-TNF agent similar to other anti-TNFs of monoclonal antibody construct. (15) ACR 20, 50, and 70 responses were 58%, 36%, and 25% vs. placebo 24%, 11%, and 3% and PASI 75 response 68% vs. 15% in the 200 mg every 2 week arm, all highly statistically significant. A dose of400 mg every month yielded similar results. Unique about this study was that a fifth of the patients had been on anti-TNFs previously, yet still this degree of response occurred, which bespeaks the potential utility of this agent when a switch from a previous anti-TNF is needed.

Continued follow-up of the golimumab phase 3 PsA study has shown sustained efficacy in clinical parameters, improvement of function, benefits for quality of life and work productivity, and inhibition of radiographic progression. (16, 17) These results are not unexpected since consistent with other anti-TNFs but unique in having a large cohort of patients being followed for up to 5 years.

IL-12/23 Inhibitor: Ustekinumab

There has been considerable interest in targeting the TH17 cell pathway as our understanding of the prominent role of this inflammatory pathway, especially in psoriasis and the spondyloarthritides, has increased. IL23 is a key cytokine promoting the activation of TH17 cells and the generation of IL17 and other pro-inflammatory cytokines. IL12 is a key cytokine in the TH1 inflammatory pathway. Ustekinumab binds to the common p40 subunit of IL12 and IL23, inhibiting the receptor binding of these two pro-inflammatory cytokines. This drug is highly effective for psoriasis administered subcutaneously every 3 months. Phase 2 PsA data has been published, (18) and phase 3 data presented recently. (19) In the latter study, which involved 615 patients who had not previously been exposed to anti-TNF therapy, the ACR 20, 50, and 70 and PASI75 responses in the 90 mg vs. placebo arms were 49.5%, 27.9%, 14.2%, and 62.4% vs. 22.8%, 8.7%, 2.4%, and 11%, respectively, all significant. Significant improvements in dactylitis and enthesitis were also noted. Radiographic responses are due to be reported separately, as is a TNF-IR trial, which will be of considerable importance since this drug may be positioned, in practice, after use of an anti-TNF agent in some instances.

Co-Stimulatory Blockade: Abatacep

In a phase 2 placebo-controlled study exploring the effect of several doses of IV abatacept in 170 patients with PsA, ACR 20 response was achieved by 48% of those receiving the RA-labeled dose of 10 mg/kg at 6 months. (20) Since patients with previous experience with anti-TNF therapy were allowed to participate, an analysis of patients naive to anti-TNF treatment showed an ACR20 response of 56%. It is unclear why this differential effect occurs, other than patients who have failed a previous anti-TNF may in some way be more "refractory" to treatment in general. Clinical response data was corroborated by significant improvement in MRI scores. Improvement of psoriasis skin lesions was not as robust as joint improvement. In a separate report of 12 month data, ACR and skin responses were maintained in completers, and originally placebo patients had similar degrees of response. (21) Further study of this agent in PsA will involve the newer subcutaneous version, which has shown efficacy in RA.

B Lymphocyte Ablation: Rituximab

Several small open label cohorts of PsA patients received rituximab therapy in the same regimen as used in RA (1,000 mg IV every 2 weeks X 2); an experience that was recently reviewed. (22) Modest improvement of joint count was demonstrated in several patients, although there was little impact on skin lesions. A logical application of rituximab, off-label, would be a patient with PsA and current or recent lymphoma or other contra-indication to therapy with other agents (e.g., anti-TNFs).

IL17 Inhibitors

As described above, there is considerable interest in targeting the TH17 pathway of T lymphocyte differentiation and activation because of its considerable activity in inflammatory diseases, including psoriasis, the spondyloarthritides, and RA. One of the key cytokine products of TH17 cell activation is IL17. There are currently three main inhibitors of IL17 making their way through clinical development, two of which are direct inhibitors of IL17, secukinumab and ixekizumab, and one which is an IL17 receptor inhibitor, brodalumab. A basic generalization about these agents is that they each display striking efficacy in the treatment of psoriasis, with PASI75 responses in the 80% range seen in higher dose arms in studies conducted thus far. However, their efficacy in rheumatoid arthritis has not been as robust. Trials in PsA are currently underway or soon to be underway, and it is anticipated that we will have a better sense of their efficacy in this population reasonably soon. A preliminary study of an intravenous form of secukinumab in 42 PsA patients showed a trend toward improvement over placebo in ACR responses at 6 weeks. The safety profile of these agents, thus far, has been favorable, encouraging further development. (23)

Phosphodiesterase 4 (PDE4) Inhibitor: Apremilast

Apremilast is an oral PDE4 inhibitor that modulates cyclic AMP metabolism and in inflammatory cells results in decreased production of pro-inflammatory mediators, such as TNF, IL17, and IL23, and increased production of anti-inflammatory mediators, such as IL10. This agent has been most extensively studied in psoriasis and PsA. A phase 2 study using a 20 mg bid dose yielded an ACR 20 response in 43.5% as compared to 11.8% in the placebo group. (24) Tolerability issues include headache, nausea, and diarrhea, and there has been a paucity of serious adverse events. An extensive phase 3 program in PsA will be reported soon, including assessment of response to a 30 mg bid dose.

Janus Kinase (JAK) Inhibitors

Several JAK inhibitors are making their way through development in RA, psoriasis, and other inflammatory diseases. PsA trials will embark soon. Robust efficacy in RA has been demonstrated with 5 and 10 mg bid doses both in monotherapy and combination therapy with other oral DMARDs, analogous to efficacy seen with anti-TNFs. Efficacy in psoriasis has also been demonstrated in a phase 2 trial, with 15 mg bid upper dose. Phase 3 will demonstrate results with 5 and 10 mg bid. It is not yet known what dose will be approved by the FDA for RA. There are notable potential safety issues with these agents, including risk for infection, malignancy, hyperlipidemia, neutropenia, and anemia, as a result of which, appropriate monitoring will need to be done. (23)

IL6 Inhibitors

An IL6 receptor inhibitor, tocilizumab, has been approved for the treatment of RA. It is known that IL6 is a pleiotropic inflammatory cytokine that is upregulated in psoriasis skin lesions and PsA synovial tissue. Isolated case reports of tocilizumab in PsA present a mixed picture, with some showing efficacy and others not. Formal controlled PsA studies are anticipated. (23)

Other Agents

As patients become refractory or develop side effects to current treatment options, it will be important to have new and effective drugs to treat PsA. Fortunately, there are many such agents in the RA and psoriasis pipelines, which will also be tried in PsA and other spondyloarthritis conditions. Because the pathophysiologic phenotype of PsA is distinct from RA, as well as psoriasis, it will be necessary to test these agents in PsA patients to gain a reliable understanding of their impact on the heterogeneous clinical domains of the disease, as well as to assess ability to inhibit progressive structural damage.

Disclosure Statement

The author has no financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.

References

(1.) Dominguez P, Gladman D, Helliwell P, et al. Development of screening tools to identify psoriatic arthritis. Curr Rheumatol Rep. 2010 Aug;12(4):295-9.

(2.) Mease PJ. Measures of psoriatic arthritis: Tender and Swollen Joint Assessment, Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), Modified Nail Psoriasis Severity Index (mNAPSI), Mander/Newcastle Enthesitis Index (MEI), Leeds Enthesitis Index (LEI), Spondyloarthritis Research Consortium of Canada (SPARCC), Maastricht Ankylosing Spondylitis Enthesis Score (MASES), Leeds Dactylitis Index (LDI), Patient Global for Psoriatic Arthritis, Dermatology Life Quality Index (DLQI), Psoriatic Arthritis Quality of Life (PsAQOL), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Psoriatic Arthritis Response Criteria (PsARC), Psoriatic Arthritis Joint Activity Index (PsAJAI), Disease Activity in Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11:S64-85.

(3.) Helliwell P, Fitzgerald O, Fransen J, et al. The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project). Ann Rheum Dis. 2012 Jul 13. [Epub ahead of print].

(4.) Helliwell PS, Fitzgerald O, Strand CV, Mease PJ. Composite measures in psoriatic arthritis: a report from the GRAPPA 2009 annual meeting. J Rheumatol. 2011 Mar;38(3):540-5.

(5.) Coates LC, Fransen J, Helliwell PS. Defining minimal disease activity in psoriatic arthritis: a proposed objective target for treatment. Ann Rheum Dis. 2010 Jan;69(1):48-53.

(6.) Gossec L, Smolen J, Gaujoux-Viala C, et al. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann Rheum Dis. 2012 Jan;71(1):4-12. Epub 2011 Sep 27.

(7.) Ritchlin CT, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis. 2009 Sep;68(9):1387-94.

(8.) Love TJ, Zhu Y, Zhang Y, et al. Obesity and the risk of psoriatic arthritis: a population-based study. Ann Rheum Dis. 2012 Aug;71(8):1273-7.

(9.) Di Minno M, Peluso R, Iervolino S, et al. Obesity and the prediction of minimal disease activity. A prospective study in psoriatic arthritis. Arthritis Care Res (Hoboken). 2012 Apr 18. doi: 10.1002/acr.21711. [Epub ahead of print].

(10.) Di Minno M, Iervolino S, Peluso R, et al. Weight loss and induction of minimal disease activity in psoriatic arthritis patients starting TNF-a blockers treatment. Ann Rheum Dis. 2012 Oct 4;14(5):R211. [Epub ahead of print].

(11.) Iannone F, Fanizzi R, Scioscia C, et al. Body mass does not affect the remission of psoriatic arthritis patients on anti-TNF-therapy. Scand J Rheumatol. 2012 Sep 20. [Epub ahead of print].

(12.) Mease PJ. Spondyloarthritis: Is methotrexate effective in psoriatic arthritis? Nat Rev Rheumatol. 2012 May 2;8(5):251-2.

(13.) Kingsley GH, Kowalczyk A, Taylor H, et al. A randomized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology (Oxford). 2012 Aug;51(8):1368-77. Epub 2012 Feb 17.

(14.) Baranauskaite A, Raffayova H, Kungurov NV, et al. Infliximab plus methotrexate is superior to methotrexate alone in the treatment of psoriatic arthritis in methotrexate-naive patients: the RESPOND study. Ann Rheum Dis. 2012 Apr;71(4):541-8.

(15.) Mease P, Fleischmann R, Deodhar A, et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24 week results of a phase 3 double blind randomized placebo-controlled study (RAPID-PsA). Ann Rheum Dis. 2012;71:S150.

(16.) Kavanaugh A, McInnes I, Mease P, et al. Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: Twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum. 2009 Apr;60(4):976-86.

(17.) Kavanaugh A, Mease P, Krueger GG, et al. Golimumab, a new, human, TNF alpha antibody, administered subcutaneously every 4 weeks in psoriatic arthritis patients: 104-week efficacy and safety results of the randomized, placebo-controlled GOREVEAL study. Ann Rheum Dis. 2009 Jul;68:S136-7.

(18.) Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet. 2009 Feb 21;373(9664):633-40.

(19.) McInnes I, Kavanaugh A, Gottlieb A, et al. Ustekinumab in patients with active psoriatic arthritis: Results of the phase 3, multicenter, double-blind, placebo-controlled PSUMMIT I study. Ann Rheum Dis. 2012 Jun;71:S107.

(20.) Mease P, Genovese MC, Gladstein G, et al. Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheum. 2010 Apr;63(4):939-48.

(21.) Mease P, Genovese M, Gladstein G, et al. Abatacept (ABA) in the treatment of Psoriatic Arthritis (PsA): 12-month results of a phase II study. Arthritis Rheum. 2010 Oct;62:S802.

(22.) Mease P. Is there a role for rituximab in the treatment of spondyloarthritis and psoriatic arthritis? J Rheumatol. 2012. [Epub ahead of print].

(23.) Mease PJ. Psoriatic arthritis: update on pathophysiology, assessment and management. Ann Rheum Dis. 2011 Mar;70 Suppl 1:i77-84.

(24.) Schett G, Wollenhaupt J, Papp K, et al. Oral apremilast in the treatment of active psoriatic arthritis: Results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2012 Oct;64(10):3156-67.

Philip Mease, M.D., is at the Swedish Medical Center, and the University of Washington, Seattle, Washington.

Correspondence: Philip Mease, M.D., Seattle Rheumatology Associates, 601 Broadway, Suite 600, Seattle, Washington 98122; pmease@philipmease.com.
Table 1 Minimal Disease Activity (MDA) Criteria in
PsA (GRAPPA) (5)

A PsA patient is classified as "in MDA" when they meet 5 of
the following 7 criteria:

Tender joint count                        [less than or equal to] 1
Swollen joint count                       [less than or equal to] 1
PASI [less than or equal to] 1 or BSA     [less than or equal to] 3
Patient pain VAS                          [less than or equal to] 15
Patient global activity VAS               [less than or equal to] 20
HAQ                                       [less than or equal to] 0.5
Tender entheseal points                   [less than or equal to] 1

Table 2 GRAPPA Treatment Grid for PsA Based on Disease Severity (7)

                  Mild              Moderate          Severe

Peripheral        < 5 joints No     [less than or     [less than or
arthritis         damage on X-      equal to] 5       equal to] 5
                  ray No LOF        joints (S or      joints (S or
                  QOL-minimal       T) damage on      T) severe
                  impact Pt         X-ray IR to       damage on X-
                  evaluation        mild Rx           ray IR to
                  mild              Moderate LOF      mild-moderate
                                    Moderate          Rx Severe LOF
                                    impact on QoL     Severe impact
                                    Pt evaluation     on QoL Pt
                                    moderate          evaluation
                                                      severe

Skin disease      BSA < 5 PASI <    Non-response      BSA > 10 DLQI
                  5 Asymptomatic    to topicals       > 10 PASI > 10
                                    DLQI PASI < 10

Spinal disease    Mild pain No      Loss of           Failure of
                  loss of           function or       response
                  function          BASDAI > 4

Enthesitis        1-2 sites No      > 2 sites or      Loss of
                  loss of           loss of           function or >
                  function          function          2 sites and
                                                      failure of
                                                      response

Dactylitis        Pain: Absent      Erosive           Failure of
                  to mild Normal    disease or        response
                  function          loss of
                                    function
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