Anti-tumour necrosis factor therapy associated with cutaneous vasculitis

P. A. Livermore and K. J. Murray

Paediatric Rheumatology Unit, Great Ormond St Hospital for Children, Great Ormond Street, London WC1N 3JH, UK

SIR, We read with interest the letter by McCain et al. [1] and we wish to add our experience of a case of probable vasculitis or cutaneous reaction secondary to anti-tumour necrosis factor (anti-TNF) therapy, as has been noted by others. While injection site reactions can occur in up to 20% of patients receiving etanercept [2], more generalized reactions are only recently being recognized [1, 36].

We report a Caucasian girl who was referred to our rheumatology unit at 91/2; yr of age in October 1995 with a 6-month history of intermittent daily high-spiking fever, lethargy, evanescent rash accompanying the fever, and joint pain and stiffness. Clinical examination revealed a typical macular salmon-pink rash, which came and went with the fever, and evidence of active chronic synovitis of multiple joints, and limited range of movement in her left wrist and right knee particularly. Initially she had an erythrocyte sedimentation rate (ESR) of 36 mm/h (normal range: 0–10 mm/h), a C-reactive protein (CRP) of 7.6 mg/l (normal range: 0–2 mg/l), a low haemoglobin level (8.0 g/dl) and elevated platelet count (600x10-9/l). She was diagnosed as having typical systemic-onset juvenile idiopathic arthritis (SOJIA) and she was commenced on low dose oral prednisolone and non-steroidal anti-inflammatory drugs.

She had a progressive worsening in the course of her disease over the next 2 years with widespread polyarthritis and severe neck and back pain along with marked elevation of inflammatory markers (>100 for ESR and >10 for CRP) which required increases in her prednisolone dose up to 2 mg/kg. While this controlled some of the clinical features her polyarthritis progressed, necessitating introduction of low dose oral methotrexate (10 mg/m2) in addition to intensive in-patient physiotherapy and intra-articular steroid injections, with some initial improvement. Dyspnoea on exertion at this time was noted, and she was thought to have possible restrictive-type lung disease due to previous pleural inflammation as part of her SOJIA (40% predicted on lung function tests).

Fifteen months into her course she developed severe back pain and limited mobility after a fall. Radiographs showed a compression fracture of T8 with severe osteoporosis. She was fitted with a spinal brace with improvement in back pain, and her steroid dose was progressively weaned and methotrexate increased to 20 mg/m2 and converted to subcutaneous administration. Persistent respiratory symptoms and radiographic changes consistent with pleural effusion required high dose i.v. steroids in the following months. Concern regarding possible development of interstitial lung disease (though never proven) led to cessation of methotrexate, and cyclosporin was subsequently started.

A sudden further increase in back pain occurred with acute collapse and neurological signs and symptoms in her legs consistent with spinal cord compression. Imaging revealed a likely infective process in the previously collapsed vertebrae with spinal cord impingement.

This required operative drainage and mechanical stabilization of the spine. She recovered slowly but sustained a possible anoxic brain injury during or after surgery. Cyclosporin was discontinued as she continued to suffer from seizures. She made slow progress and after 6 months she was discharged and admitted to a rehabilitation unit for the following 6 months.

From February 1997 until April 1999 she was maintained on low dose oral prednisolone, with pulses of high dose i.v. steroids being used in response to numerous flares due to her polyarthritis. Ophthalmological examination revealed posterior subcapsular cataracts and so in an effort to wean her oral steroids further and to regain disease control, oral methotrexate was again added. Within 4 months she had developed a follicular erythematous rash on the right leg thought possibly secondary to methotrexate, which was again stopped.

In October 1999, she was commenced on anti-TNF therapy (etanercept), at a dose of 0.4 mg/kg subcutaneously twice weekly. Six weeks later she presented with a diffuse pruritus and erythematous rash over her face, legs and back with superimposed marked purpura [similar in appearance to a Henoch–Schönlein purpura (HSP)-type rash]. Apart from the rash the child was systemically unchanged and so she continued on etanercept initially. She had no serological evidence of any autoantibodies including antinuclear antibodies and rheumatoid factor at this or any other stage, and no clinical features to suggest a primary vasculitis otherwise.

Oral antihistamines were added in before and after the etanercept doses, as it was felt they might possibly be related. The rash slowly improved, but did not resolve completely. Skin biopsy was considered but refused by the parents and we felt it would not change her management at this stage. Two months after etanercept commencement she required further high dose i.v. steroids, owing to active disease and worsening joint disease. Subsequently she presented with a more widespread, palpable, purpuric rash below her knees on both lower limbs only (see Figs 1Go and 2Go). Etanercept was stopped and a pulse of steroids was given again. Over the next month the rash recurred intermittently, but eventually resolved completely by 4 months.



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FIG. 1. Lateral view of the leg of the 13-yr-old girl showing the HSP-like palpable purpuric rash upon reintroduction of etanercept.

 


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FIG. 2. Anterior view of both legs of the 13-yr-old girl, with calamine lotion partially obscuring the left leg.

 
Reintroduction of etanercept was made at this stage at the same dosage as previously, along with i.v. steroids. After a month the rash returned in the same manner. Etanercept was stopped again, with resolution of the rash over a number of weeks and reintroduced subsequently at a quarter of the original dose (0.1 mg/kg) with a further i.v. steroid pulse. From this time onwards the child's etanercept dose was gradually increased with the support of oral antihistamines, and the rash never reappeared.

Fourteen months after the etanercept was originally started, the child's dose was back to 0.4 mg/kg (10 mg twice weekly) without requiring antihistamines. Her ESR at this stage remained elevated at 141 mm/h. Three months later in March 2001 her dose was increased to 0.5 mg/kg, to try to establish better disease control and cyclosporin was reintroduced as a second disease-modifying anti-rheumatic drug. She has since made steady improvement with a fall in her ESR to between 50 and 80 with better control of her polyarthritis, and no recurrence of her HSP-like rash. By mid-2001 she had markedly improved in her functional status, increased growth velocity and was able to come off her oral steroids. Her Childhood Health Assessment Questionnaire (CHAQ) score had improved by over 30% from 2 years previously, and the parent and physician global visual analogue scale assessment had also improved by more than 30%. On this basis she was considered improved according to the Core Set Outcome Criteria for juvenile idiopathic arthritis [7].

We believe this case report adds to the literature regarding possible or probable cutaneous vasculitis associated with anti-TNF therapy and is the first reported paediatric case. It also documents how careful graduated reintroduction with high dose steroid and antihistamine cover can lead to apparent ‘tolerization’ and allowed continued use of anti-TNF therapy, as has been noted by others [8]. While she still had evidence of an active polyarthritis, she had clear clinical improvement with anti-TNF therapy overall.

Notes

Correspondence to: P. Livermore. Back

References

  1. McCain ME, Quinet RJ, Davis WE. Etanercept and infliximab associated with cutaneous vasculitis. Rheumatology2002;411:116–7.
  2. Zeltser R, Valle L, Tanck C, Holyst MM, Ritchlin C, Gaspari AA. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor:Fc fusion protein. Arch Dermatol2001;137:893–9.[Abstract/Free Full Text]
  3. Brion PH, Mittal-Henkle A, Kalunian KC. Autoimmune skin rashes associated with etanercept for rheumatoid arthritis. Ann Intern Med1999;131:634.[Free Full Text]
  4. Misery L, Perrot JL, Gentil-Perret A, Pallot-Prades B, Cambazard F, Alexandre C. Dermatological complications of etanercept therapy for rheumatoid arthritis. Br J Dermatol2002;146:334–5.[ISI][Medline]
  5. Galaria NA, Werth VP, Schumacher HR. Leukocytoclastic vasculitis due to etanercept. J Rheumatol2000;27:2041–4.[ISI][Medline]
  6. Soykan I, Ertan C, Ozden A. Severe anaphylactic reaction to infliximab: report of a case. Am J Gastroenterol2000;95:2395–6.
  7. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum1997;40:1202–9.[ISI][Medline]
  8. Puchner TC, Kugathasan S, Kelly KJ, Binion DG. Successful desensitisation and therapeutic use of infliximab in adult and pediatric Crohn's disease patients with prior anaphylactic reaction. Inflamm Bowel Dis2001;7:34–7.[ISI][Medline]
Accepted 27 June 2002