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Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

The B cell–depleting monoclonal antibody rituximab is a novel therapy for the rheumatic diseases, with an increasing body of evidence regarding its safety and efficacy in an expanding range of indications. However, there is uncertainty over its potential use in, and impact on, autoantibody-negative diseases. We describe 3 patients, with no known risk factor for psoriasis, who developed psoriasis (and 1 who also developed features of psoriatic arthritis) after receiving rituximab for a variety of indications, namely, seropositive and seronegative rheumatoid arthritis and systemic lupus erythematosus. In all cases, the underlying disease responded well to rituximab. The interpretation of this possible side effect of rituximab remains unclear, but a B cell–depleted environment may induce abnormal T cell responses, possibly provoked either by subclinical infection or by the removal of mechanisms whereby B cells regulate T cells. These cases suggest that the pathogenesis of psoriasis may not require normal numbers of B cells and that proposed treatment of psoriasis and psoriatic arthritis with rituximab may result in unpredictable responses.

The B cell–depleting anti-CD20 monoclonal antibody rituximab, licensed for treatment of relapsed or refractory low-grade or follicular B cell non-Hodgkin's lymphoma (NHL), is a novel therapy for a range of autoimmune disorders associated with autoantibody production, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). (Rituximab has recently been approved in Europe and the US for patients with RA that does not respond to anti–tumor necrosis factor [anti-TNF] agents.) There is increasing evidence regarding the safety and efficacy of rituximab in these conditions (1–3).

B cell depletion is associated with reductions in autoantibody levels, but B cells are also thought to have other functions relevant to the pathogenesis of these conditions. Results in patients with RA who are seronegative for rheumatoid factor (RF) are less conclusive (1, 2). There has therefore been debate over whether rituximab would be beneficial in diseases that are not associated with autoantibodies, such as psoriasis (4). We describe 3 patients who developed psoriasiform skin lesions following rituximab therapy for RA or SLE. These cases may offer important lessons in the pathogenesis of psoriasis and emphasize the potential for this disease to occur despite a state of B lymphocyte depletion, as well as having implications for therapy.

CASE REPORTS

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

Patient 1.

The patient, a 17-year-old girl, presented in 1992 with seronegative erosive inflammatory arthritis. A diagnosis of RA was made on the basis of the distribution of symptoms and erosions, which were present in a typically symmetric, small joint rheumatoid distribution. There was no family history of psoriasis or psoriatic arthritis. The patient was positive for HLA–B27 and negative for RF and anti–cyclic citrullinated peptide (anti-CCP) antibodies. There were no extraarticular features or enthesopathy prior to rituximab therapy. During the next 8 years, she developed progressive, widespread arthritis that was resistant to standard disease-modifying antirheumatic drugs (DMARDs), including methotrexate, sulfasalazine, and cyclosporine. In 2000, she underwent myeloablation with high-dose cyclophosphamide (CYC) and subsequent autologous stem cell transplantation with a good but short-lived response. Further therapy with anti-TNF agents was effective, but only in the short term.

The patient was subsequently treated with a standard course of rituximab (2 infusions of 1 gm 2 weeks apart) with CYC (750 mg with each infusion of rituximab) as well as 100 mg of intravenous methylprednisolone and 2 weeks of oral prednisolone. B lymphocyte depletion was achieved within 4 weeks of the second rituximab infusion. An improvement in her symptoms was seen immediately after administration of rituximab, but this lasted for only 6 weeks and thus was probably a corticosteroid effect. Six months after therapy with rituximab, she developed scalp psoriasis (confirmed by a consultant dermatologist), onycholysis, pan-uveitis, and ruptures of the Achilles tendon. She has since received topical and systemic therapy, but both skin and joint disease remain active.

Patient 2.

The patient, a 52-year-old woman, was diagnosed as having RA. She was seropositive for RF (125 IU/ml [normal <40]) and anti-CCP antibody positive at presentation. She was negative for HLA–B27, and there was no personal or family history of psoriasis. Despite standard DMARD therapy, she had progressive disease, with persistent synovitis and the development of erosions. Following a lack of response to anti-TNFα therapy, she received 2 standard courses of rituximab. She received CYC (750 mg) with each infusion of the first course, but not with the second. She had good responses to both courses in terms of the RA disease activity. She had sustained B lymphocyte depletion for ∼12 months following each course, and her RF level decreased to 18 IU/ml. Her symptoms deteriorated ∼12 months after the first course of therapy, and so she received a second course. Four months after the second course, at a time of complete B lymphocyte depletion, she developed psoriatic plaques over both knees and on the extensor surfaces of her thighs. The diagnosis of psoriasis was confirmed by a dermatologist. The lesions were treated with topical steroids for 3 months and subsequently resolved without recurrence.

Patient 3.

The patient, a 26-year-old woman, was diagnosed as having SLE after presenting with an inflammatory arthritis, photosensitivity, hemolytic anemia, and thrombocytopenia. She subsequently developed neurologic features, with cerebral infarction and hemorrhage. She had raised levels of anti–double-stranded DNA (anti-dsDNA) antibodies and was also positive for antinuclear antibodies and anticardiolipin antibodies. She was negative for RF, and she did not have antibodies to any other extractable nuclear antigens or to CCP. She was negative for HLA–B27, and there was no personal or family history of psoriasis. Despite comprehensive therapy with a wide range of DMARDs, CYC, intravenous and oral steroids, and intravenous immunoglobulin (IVIG), thrombocytopenia persisted (<2 × 109/liter) and she had a life-threatening hemorrhage.

The patient was treated with a standard course of rituximab with CYC (750 mg with each infusion of rituximab). B lymphocyte depletion was achieved within 4 weeks of the administration of rituximab and persisted at 16 months following therapy. Platelet levels rose following rituximab therapy to the extent that she no longer required treatment with IVIG, and other markers of disease activity, such as levels of anti-dsDNA autoantibodies, also improved. However, 4 months after rituximab therapy, she developed widespread psoriasis over her elbows and the extensor surfaces of her arms and thigh (Figures 1 and 2), as well as over her trunk, with the development of onycholysis. The diagnosis of psoriasis was confirmed by a consultant dermatologist, and her skin was sufficiently severely affected for her to require admission to a hospital. Her condition has partially responded to topical steroids, and she currently takes azathioprine 100 mg daily and oral prednisolone 7.5 mg daily.

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Figure 1. Widespread psoriasis over the extensor surfaces of the arm in patient 3.

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Figure 2. Widespread psoriasis over the elbow in patient 3.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

The safety profile of rituximab has been established from the treatment experience in >730,000 patients with hematologic malignancies (5) as well as from clinical trials in RA (1, 2) and SLE (3). The development of psoriasis has not been identified as an adverse consequence of rituximab in those studies, although concomitant treatments with anti–T cell effects may have reduced the likelihood of such complications. We report the onset of psoriasis in 3 patients after B cell depletion with rituximab. In these patients, there was no other medication known to induce psoriasis and no family history or other risk factor. These cases may add to our understanding of the safety of B cell depletion and the roles of B cells in antibody-negative diseases.

In attempting to establish a relationship between the use of rituximab and the development of psoriasis, it could be argued that patient 1 had psoriatic arthritis from the outset and the disease simply progressed with time, with the progression following rituximab being merely coincidental. However, the patient had symptoms and signs much more consistent with RA, although seronegative, for several years. The pattern of synovitis and erosive change was typical of RA. It has been suggested that the defining lesion in psoriatic arthritis is that of enthesopathy (6), and there were no features of enthesopathy in this patient until after rituximab therapy. The coexistence of psoriatic arthritis and RA in patients has also been reported (7). Patient 1 would have met CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria (8) following rituximab therapy, but not before. The possibility remains that patient 1, while having had the phenotype of RA, may either have switched to a psoriatic phenotype or developed an additional disorder following B cell depletion.

If there is uncertainty about the sequence of pathologic events in patient 1, that in patient 2 would seem to be clearer. This patient had seropositive RA and only developed psoriatic plaques after rituximab therapy, at a time when she was B cell depleted, had become seronegative for RF, and had a beneficial response to rituximab. The features of arthritis in this patient were consistent with a diagnosis of RA in terms of the distribution of joint involvement, and following resolution of the skin lesions after a brief course of topical therapy, there was no recurrence and no involvement at sites such as the distal interphalangeal joints to suggest that an underlying psoriatic arthritis could have been present.

Patient 3 also responded well to rituximab, but her psoriasis has been more severe and prolonged. The coexistence of SLE and psoriasis seems quite rare. One series of 520 patients with SLE had an incidence of psoriasis of 0.6% (9). Antibody to the Ro antigen is more frequent in patients with both SLE and psoriasis (10), but our patient was negative for this. Neither patient 2 nor patient 3 would meet CASPAR criteria.

The pathogenesis of psoriasis depends on T cell–mediated autoimmunity as well as changes in the innate immune system. There are clonal populations of CD4+ and CD8+ T cells in the psoriatic plaque, and T cell–directed therapies are effective. Susceptibility to psoriasis has been associated with mutations in the CARD-15 gene, which is involved in the innate immune response to bacteria, and other mediators of innate immunity have been identified in psoriatic keratinocytes and dermal dendritic cells (11). T cells and dendritic cells, with their associated proinflammatory cytokines, collaborate to create a proinflammatory environment in the skin which stimulates the proliferation of resident keratinocytes and endothelial cells, leading to the pattern of tissue growth recognized as psoriasis. Known triggers for the formation of a plaque include physical injury, rapid withdrawal of immunosuppressive drugs, or bacterial or viral infection (12).

It is therefore not immediately obvious how depletion of B cells could induce psoriasis. It could be hypothesized that B cells have an unknown beneficial regulatory effect on T cell function that is removed by B lymphocyte depletion. Another possibility is that blunted humoral immunity due to B lymphocyte depletion causes an imbalanced response to infection. There is a modest increase in infection rates in rituximab-treated patients (1, 2) and a reduction in total serum immunoglobulin (13). Few patients treated for NHL were able to mount a significant new response or show a boosted response to pneumococcal vaccination after B lymphocyte depletion (14). In a susceptible patient, this reduction in humoral immunity may increase the likelihood of a disease that is associated with an abnormal T cell response to infection.

These cases may have implications for the use of rituximab. Clinical evidence suggests that rituximab is an effective therapy for a variety of rheumatic diseases, and it is likely to be used more widely in the near future. It has been suggested that the mode of action of rituximab may be due to effects other than antibody production. There is uncertainty over its use in autoantibody-negative diseases such as psoriasis and seronegative spondylarthropathy. Our experience with these cases suggests that it ought to be used with caution in patients in whom the diagnosis of RA, as opposed to psoriatic arthritis, is uncertain. That psoriasis began while the patient was in a B cell–depleted state indicates that normal numbers of these cells are not necessary for the initiation of psoriasis. The occurrence of psoriasis for the first time following B lymphocyte depletion suggests that B cells may have a role in the regulation of T cell–mediated immune responses. Our understanding of the interactions between B and T cells is still incomplete, and these cases emphasize the importance of continuing vigilance in this novel therapy.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

Dr. Emery had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Dass, Vital, Emery.

Acquisition of data. Dass, Vital, Emery.

Analysis and interpretation of data. Dass, Vital, Emery.

Manuscript preparation. Dass, Vital, Emery.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES