Improvement of Comorbid Psoriasis in Patients With MS Treated With Natalizumab

Discussion

Given still limited published data, no definite conclusion on direct relationship between natalizumab treatment and psoriasis condition can be drawn. Moreover, no clinical recommendations can be made. However, these observations provide additional data for better understanding of treatment responses of patients having comorbid MS and psoriasis.

Comorbidity of psoriasis in a fraction of patients with MS was recognized several decades ago,^7,8 and a more recent report suggested that psoriasis comorbidity may influence progression of MS.⁹ There is also similar immunologic connections of psoriasis and MS, with involvement of Th17 cells in both diseases.^10,11 Although both diseases share common genetic risk factors to influence susceptibility to autoimmune disease, the association of MS with other immune-mediated diseases such as psoriasis has recently been recognized to be due predominantly to surveillance bias or similar influence by environmental factors in both diseases.^12,13

Psoriasis is a dermatological chronic immune-mediated disease. The cellular component of the psoriatic lesion tissue includes epidermal infiltration with lymphocytes, including Th1 and Th17, activated T cells, innate lymphocytes, and dendritic cells, causing keratinocyte proliferation.^14,15 Natalizumab blocks immune cell entry to the CNS including the entry of T cells and B cells.¹⁶ Natalizumab also has been studied for the treatment of the Crohn's disease because it was shown to modulate adhesion between the leukocytes and endothelial cells.¹⁷ Natalizumab may exert its putative benefit in psoriasis by blocking immune cell infiltration into the skin in a similar manner.

In spite of this relatively close association between MS and psoriasis and higher incidence of psoriasis in MS population compared with the general population, it is well known that at least some MS DMT not only show no efficacy in psoriasis but also may exacerbate the condition. Two hypotheses could be proposed to explain how treatment with natalizumab was associated with a potential improvement of the psoriasis: (1) transition of patients to natalizumab may alleviate exacerbation of psoriasis resulting from an iatrogenic previous DMT or (2) there may be beneficial effects from the natalizumab toward psoriasis.

It is well known, for example, that IFNb treatment has been suggested to potentially trigger onset of psoriasis in patients with MS. In our population, 5 of the 11 patients who received IFNb were subsequently diagnosed with psoriasis after initiation of IFNb therapy. It has been postulated that IFNb may induce the IL 17-driven conditions such as psoriasis because IL-17 enhances keratinocyte proliferation while inhibiting keratinocyte its differentiation; in the meantime, keratinocytes induce further Th17 cell recruitment and IL-17 production.¹⁵

Regarding potential improvement of psoriasis after discontinuation of IFNb, 4 of the 11 IFNb patients received another DMT before initiation of natalizumab. Notably, of the remaining 7 IFNb patients who transitioned directly from IFNb to natalizumab, 2 of those patients had lag times between therapies of 2–3 years. These results indicate that mere transition from IFNb may not totally account for the improvement of psoriasis observed with natalizumab treatment and suggest that natalizumab may actually exert some beneficial effect toward psoriasis. The possible interaction of other MS therapies with psoriasis (and vice versa) has not yet been investigated. Of note, an effective psoriasis treatment with a monoclonal antibody efalizumab that blocks trafficking through inhibition of LFA-1/ICAM-1 interaction was withdrawn because of risk for progressive multifocal leukoencephalopathy.¹⁸ In light of this example where an effective drug for psoriasis blocks trafficking, it would seem quite plausible that another drug for MS, such as natalizumab that also blocks trafficking, might also be effective in psoriasis. This also raises the question as to whether other MS drugs that interfere with trafficking might also have efficacy in psoriasis.

Preclinical studies showed that Th1 cells preferentially infiltrate the spinal cord via an α4 integrin-mediated mechanism, whereas the entry of Th17 cells into the brain parenchyma occurs in the absence of α4 integrins but is dependent on the expression of αLβ2.¹⁹ If these preclinical findings are applicable to psoriasis, it emphasizes that α4 integrin blockade does provide benefit in psoriasis when accompanied by MS.

There has been one case reported of a patient who developed disseminated psoriasis over the course of six infusions with natalizumab.³ The direct link of natalizumab was not established in this case, but those authors noted that psoriatic (and not rheumatic) arthritis patients can harbor anti-integrin antibodies and that natalizumab might similarly alter laminin function to promote dermal changes seen in psoriasis. However, there are not any subsequent reports of natalizumab-associated exacerbation of psoriasis, suggesting that if this was the cause, then the incidence would be more wide-spread. In our case, we have seen just the opposite in that natalizumab was associated with clinical improvement of psoriasis. It would be potentially more plausible that natalizumab may potentially block the deleterious effects of patient associated anti integrin antibodies. More studies would be needed to test this possibility.

This observational study was limited because only a small number of patients were observed and were not compared against any control group. Further randomized studies will enable neurologists to obtain definitive answers to the optimal therapy when this comorbidity arises.