Recombinant biologic response modifiers

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As previously discussed, variant TNF-a gene expression has been implicated as a predisposing genetic factor for SCLE. This plus the remarkable efficacy of thalidomide, a known inhibitor of TNF-a expression, has suggested the possibility that the new recombinant TNF-a inhibitors such as etanercept, infliximab, and adalimumab might potentially be of benefit to SCLE patients. However, a drug-induced form of cutaneous LE including SCLE has now been recognized as a potential complication of treatment with this class of biologics. Despite this, one report describes rapid improvement of SCLE in a patient with rheumatoid arthritis who was treated with etanercept (Fautrel et al., 2002).

In addition, other recombinant biologics that interfere with antigen presenting cell:T-cell interaction that have proven to be of benefit in psoriasis (Amevive [Alefecept], efalizumab [Raptiva]) theoretically could be of benefit in other T-cell-dependent autoimmune skin diseases such as cutaneous LE. The author is personally aware of one recent case of therapeutically refractory SCLE seen by others that was said to have responded quickly and remarkably well to efalizumab [Raptiva].

B-cell depleting recombinant biologics acting through CD-20 such as ritixumab (Rituxan) have been recently been reported in preliminary studies to be of possible benefit in humoral autoimmune diseases such as SLE and pemphigus (Saito et al., 2003; Cooper et al., 2003; Herrmann et al., 2003; Perrotta et al., 2002; Heizmann et al., 2001). It would be interesting to know what their impact might be on SCLE.

By way of summary, an algorithm of the author's personal approach to using the various treatment options discussed above is presented in Fig. 5.

8. Prognosis

Data from the original SCLE study cohort suggested that patients presenting with SCLE skin lesions might have an illness intermediate in severity between that of those presenting with isolated chronic cutaneous LE (discoid LE) skin lesions and those presenting with SLE not accompanied by SCLE or chronic cutaneous LE skin lesions (Sontheimer et al., 1979, 1981, 1982; Gilliam and Sontheimer, 1981). However, longer term follow-up studies including an informal one in which the author has participated have indicated that the large majority of SCLE patients enjoy a good prognosis over their disease course (Chlebus et al., 1998; Pellowski et al., 2005). The combined international experience of a quarter century now suggest that no more than 10-15% of SCLE patients are at risk for developing potentially life-threatening manifestations of the SLE (Sontheimer, 1989; Costner et al., 2004; Pellowski et al., 2005).

Unfortunately, prognostic indicators for those destined to have a more severe course have yet to be identified. As previously mentioned, it has been

Antimalarials

I Baseline ophthalmologic exam

Protection from Ultraviolet Light

Local Therapy

Local Therapy

(a)

Clinical response hydroxychloroquine 6.5 mg/kg lean body mass/day in 2 divided doses for 6-8 weeks + i

Continue for 1-2 years then attempt to discontinue

Flare

Supportive measures for any short-term headache, nausea, vomiting side effects

No clinical response

Clinical response

1

r

Decrease to maintenance dose

Continue for 1-2 years then attempt to discontinue

Clinical response

Clinical response

Add quinacrine 100 mg/day as a single daily dose for 4-6 weeks

Clinical response

No clinical response

Substitute chloroquine 3.5 mg/kg lean body mass/day for hydroxychloroquine for 4-6 weeks

Clinical response

No clinical response

Repeat ophthalmologic exam annually

Alternative therapy

Non-Immunosuppressive Anti-Inflammatory Agents for Antimalarial Failures

Non-Immunosuppressive Anti-Inflammatory Agents for Antimalarial Failures

Figure 5. The author's approach to the management of SCLE presented in algorithm format. (A) Overview of management. (B) Approach to the use of systemic aminoquinoline antimalarials. (C) Approach to the use of non-immunosuppressive anti-inflammatory agents for antimalarial failures.

Figure 5. The author's approach to the management of SCLE presented in algorithm format. (A) Overview of management. (B) Approach to the use of systemic aminoquinoline antimalarials. (C) Approach to the use of non-immunosuppressive anti-inflammatory agents for antimalarial failures.

the author's impression that patients having the papulosquamous type of SCLE and a high titer ANA may be at greater risk for developing clinically significant SLE including nephritis (Sontheimer, 1985; Pellowski et al., 2005). Other investigators have subsequently had similar impressions especially in males with pap-ulosquamous SCLE skin lesions (Cohen and Crosby, 1994). In addition, the author has the impression that the appearance of localized acute cutaneous LE (facial butterfly rash) in a SCLE patient also places them in a higher risk category for the development of clinically significant SLE. The presence of laboratory changes that are seen typically in active SLE (e.g., hypocomplementemia, elevated levels of double-stranded DNA antibody, high erythrocyte sedimentation rate) would also be reason for concern that an SCLE patient might be at greater risk for more aggressive manifestations of SLE.

• The majority of SCLE patients will require systemic therapy. Single agent or combination aminoquinoline antimalarial therapy will suffice for 75-80% of SCLE patients. The remaining 20-25% will require other forms of systemic anti-inflammatory therapy (e.g., diamino-dipenylsulfone [Dapsone], retinoids, thalidomide) or conventional systemic immunosuppressive/immunomodulatory therapy. Several types of the new recombinant biologic response modifier drugs may provide future benefit to severely affected SCLE patients.

Acknowledgements

All of the original work by the author pertaining to SCLE discussed in this chapter was supported either directly or indirectly by NIH (NIAMS) grant AR019101 (the contents of this chapter are solely the responsibility of the author and do not necessarily represent the official views of NIAMS). This NIH grant was initially funded in 1979, the same year that the description of the original cohort of SCLE patients was published. This grant will terminate in 2005. The author wishes to thank the US taxpayers and NIAMS Skin Disease Program staff for their long-term support of this work.

Key points

• ''Subacutecutaneous lupus erythematosus'' (SCLE) is the 25-year-old designation for a widespread, photosensitive, nonscarring, nonindurated form of LE-specific skin disease.

• SCLE skin lesions are associated with a distinctive immunogenetic background including the production of Ro/SS-A autoantibodies.

• Individuals who have SCLE skin lesions as a prominent component of their presenting illness represent a distinctive subset (sub-phenotype) of LE that enjoys a good prognosis with respect to life-threatening systemic manifestations of LE.

• SCLE skin lesions and Ro/SS-A autoantibody production can be triggered by UV light and a number of different drugs, the majority of which are capable of producing photosensitivity drug reactions in non-lupus patients.

• The etiopathogenesis of SCLE skin lesions is thought to result from four sequential stages: (1) inheritance of susceptibility genes, (2) loss of tolerance/ induction of autoimmunity, (3) expansion/ maturation of autoimmune responses, and (4) tissue injury/disease induction resulting from various autoimmune effector mechanisms.

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Handbook of Systemic Autoimmune Diseases, Volume 5 The Skin in Systemic Autoimmune Diseases

Piercarlo Sarzi-Puttini, Andrea Doria, Giampiero Girolomoni and Annegret Kuhn, editors

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