choice of tnf b. for extra-articular manifestations in spa

Irene van der Horst-Bruinsma, Mirjam de Vries, Filip Van den Bosch A previous version was co-authored by Joachim Sieper, Hildrun Haibel, Herman Mielants and Philippe Carron

IN-DEPTH DISCUSSION II

Choice of TNF blocking agents in relation to extra-

articular manifestations in Spondyloarthritis

Management of spondyloarthritides

EULAR on-line course on Rheumatic Diseases

Management of spondyloarthritides – Module 7

Spondyloarthritis (SpA) is a chronic inflammatory disease with either predominant axial symptoms of the spine

and sacroiliac joints (axial SpA, including ankylosing spondylitis) or predominant peripheral manifestations,

such as arthritis, enthesitis, or dactylitis (peripheral SpA). Next to these spinal and articular symptoms, many

patients with SpA also suffer from extra-articular manifestations (EAMs).

Spondyloarthritis-concept related EAMs include anterior uveitis (25-30%), psoriasis (10-25%) or inflammatory

bowel disease (IBD) (5-10%). The treatments, used for the rheumatological manifestations of the disease, such

as NSAIDs, DMARDs and TNF-blocking agents may have a differential effect on these EAMs, and therefore the

presence of these manifestations should be taken into account when taking therapeutic decisions.

Uveitis.

Acute anterior uveitis is an acute attack with inflammation of the uvea and can be the first presenting

symptom of the disease. In a study among 433 patients with different types of uveitis, 44 cases (almost 10%)

of SpA were detected, whereas others showed a percentage up to 50% of previously undiagnosed cases of SpA

among uveitis patients (1-3).

The occurrence of acute anterior uveitis is increased in the HLA-B27 positive population, with a lifetime

cumulative incidence of 0.2 % in the general population compared with 1% in the HLA-B27 positive population

(4).

The attacks of uveitis are usually recurrent and unilateral. The symptoms are sudden ocular pain with redness

and photophobia. Inflammation can lead to debris, which accumulates in the anterior chamber and may cause

papillary and lens dysfunction with blurring of vision. In some cases glaucoma and severe visual impairment

occurs if adequate treatment is delayed, but most of the time, with local treatment, the uveitis subsides

spontaneously within 3 months. In SpA patients with sudden symptoms of a painful, red eye, it is

recommended to refer the patient to the ophthalmologist as soon as possible.

In most cases acute uveitis can be successfully treated by the ophthalmologist with local corticosteroids and

mydriatics. Sometimes high oral dosage of prednisone (up to 60 mg daily) is necessary to control

inflammation. In most cases there is no residual visual impairment.

Some data suggest that continuous use of NSAID’s show efficacy for uveitis flares. There is some evidence that

the use of sulfasalazine reduces the recurrence rate of uveitis (5, 6). Other immunosuppressive drugs used by

the ophthalmologists to treat refractory uveitis, such as azathioprine and methotrexate, do not have much

efficacy on the disease activity of SpA.

Some TNF-blocking agents, can be used for both indications, active disease of SpA as well as refractory uveitis.

Infliximab is an adequate treatment of SpA, decreases the recurrence rate of uveitis and is effective in

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refractory uveitis (7, 8). The efficacy of etanercept, on uveitis is doubted, as etanercept does not seem to

prevent a relapse in combination with methotrexate (9) and it was suggested that etanercept might even

trigger an attack of uveitis (10). However, a comparison of three randomised studies with etanercept in AS

showed a lower number of cases with uveitis in the etanercept-treated patients compared with placebo (11)

indicating that etanercept inhibits the recurrence of uveitis.

An analysis of 4 placebo-controlled studies and 3 open-label studies with TNF agents in AS showed a frequency

of flares of anterior uveitis in the placebo-group of 15.6 per 100 patient-years, compared with 7.9 per 100

patient-years in etanercept group and 3.4 per 100 patient-years in the infliximab treated patients (8). The

attacks of uveitis during these studies were reported by the patients and no follow up studies or

ophthalmologic controls were performed.

Reports on the efficacy of adalimumab on uveitis are mainly based on retrospective analysis of placebo

controlled trials which show beneficial results (12). In a prospective study, AS patients were treated with

adalimumab because of their high disease activity and screened by an ophthalmologist on uveitis as well. This

study demonstrates a significant decrease (73%) of the recurrence rate of uveitis (13) during adalimumab

treatment.

Data on the efficacy of golimumab and certolizumab on the recurrence rate of anterior uveitis are lacking so

far.

It can be concluded that in most cases, attacks of anterior uveitis respond very well to (local) treatment by the

ophthalmologist. In cases with refractory uveitis or a high uveitis recurrence rate, treatment with TNF blocking

agents can be successful, especially if the treatment is indicated for high disease activity of SpA. Adalimumab

and infliximab seem to be more effective in lowering the recurrence rate of uveitis compared to etanercept.

Psoriasis

Psoriasis is a common skin disease with plaque lesions and nail deformities and is primarily treated by the

dermatologist. Psoriatic arthritis occurs in 5-20% of the people with psoriasis and can present as a symmetrical

polyarthritis, resembling rheumatoid arthritis, but with additional involvement of the DIP-joints (14). Axial

disease occurs in about 5% of the psoriasis patients with asymmetrical sacroiliitis in one-third of the cases and

spondylitis without sacroiliitis in the rest. Enthesitis and dactylitis are common, especially in the oligoarticular

form of the disease. In SpA, patients with psoriatic arthritis excluded, psoriasis occurs in approximately 5-10%.

In case of scaling skin lesions or nail changes suspicious for psoriasis in SpA it is recommended to refer the

patients to a dermatologist.

Skin manifestations of psoriasis usually respond very well to local corticosteroids or PUVA therapy.

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In case of psoriatic arthritis, NSAID’s and intra-articular injections with corticosteroid are effective in mono-or

oligoarthritis (15). Methotrexate is proven to be effective in daily clinical practice for treating the skin and

oligo- and polyarthritis, despite the lack of randomized controlled trails to support this (15, 30).). Leflunomide

is also effective in both psoriasis and peripheral arthritis, but not on the axial manifestations of SpA (16).

TNF alfa blockers, such as infliximab, etanercept, adalimumab, certolizumab and golimumab are efficacious on

the skin and nail lesions of psoriasis (15). In some cases treatment of SpA with TNF blocking agents can result

in a new manifestations of psoriasis, such as palmoplantarpustulosis (17).

Inflammatory Bowel Disease

Inflammatory Bowel disease includes Crohn’s disease and ulcerative colitis and is primarily treated by the

gastro-enterologist. Approximately 10% of the IBD patients develop SpA. On the other hand, the chance of SpA

patients to develop IBD is 5-10%. Asymptomatic inflammatory bowel disease is described in a high percentage

of SpA patients (60%) and can be detected by endoscopy of the colon and terminal ileum (18). During follow

up studies it appeared that up to 20% of the SpA patients with chronic gut inflammation eventually develop

Crohn’s disease (19).

Another indication that diseases as SpA and IBD show some overlap is a study on serological markers of IBD. In

this study, a high percentage (55%) of AS patients without abdominal complaints had a positive tests for

pANCA, ANCA or Omp-C ASCA antibodies (20).

In case of persistent or frequently recurring diarrhoea and/or blood or mucus production with the stools it is

advised to refer the SpA patients to the gastro-enterologist in order to perform a colonoscopy.

Treatment of IBD by the gastro-enterologist is based on immunosuppressive drugs and anti-TNF. The use of

NSAID’s can worsen the colitis manifestations, therefore it is advised to minimise the use of these drugs by

SpA patients with IBD, except for celecoxib which does not seem to increase the risk at exacerbation of the IBD

(21). The use of sulfasalazine can be beneficial for both SpA as well as IBD. The efficacy of other

immunosuppressive drugs often used in IBD however, have in most cases not proven efficacy in SpA (22). Of

the TNF blocking agents only infliximab and adalimumab are effective in SpA as well as IBD and golimumab is

not yet registered for IBD but shows efficacy in ulcerative colitis (23-28). Certolizumab is also effective in IBD

but not yet registered in all countries for this indication.

Etanercept works well for spinal symptoms in SpA but not on IBD and new manifestations of IBD might even

occur during etanercept treatment (28, 29).

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Therefore, in SpA patients with IBD the use of NSAID’s should be minimised, except for celecoxib, sulfasalazine

might show some improvement for both indications and the first choice of anti-TNF is infliximab or

adalimumab.

Conclusions

In SpA physical exercises and NSAID’s are the choice of treatment. In case of peripheral arthritis,

sulphasalazine can be added as a useful DMARD.

In case of insufficient response at NSAID’s TNF blockers are very effective in SpA, especially infliximab,

etanercept, adalimumab, certolizumab and golimumab. These drugs all work very well on the axial

manifestations as well as on arthritis, enthesitis and psoriasis.

Concerning the treatment of other extra spinal manifestations, anterior uveitis can be treated adequately by

the ophthalmologist with local treatment. In refractory uveitis or a high recurrence rate, treatment with

adalimumab and infliximab seem to be more effective for this indication compared to etanercept.

In case of IBD in SpA, the use of NSAID’s should be minimized but celecoxib can be used if needed. The choice

of anti-TNF therapy inSpA with IBD is in favour of infliximab and adalimumab instead of etanercept.

Overall, it is important to realize that in SpA extra-articular manifestations do occur frequently and should be

taken into account in the choice of treatment,

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choice of tnf b. for extra-articular manifestations in spa

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