Psoriasis is a chronic disease not only of the skin, but of the entire body. The etiology of psoriasis is due to genetic factors, but also environmental factors. In recent years, the association between psoriasis and other diseases has gained interest. There is growing evidence that cardiovascular disease, obesity, diabetes, arterial hypertension, metabolic syndrome, nonalcoholic fatty liver disease (NASH), cancer, and depression and inflammatory bowel disease are much more common in psoriasis than in the normal population. These diseases show in an exemplary way that psoriasis does not only affect the skin, as was thought 200 years ago, but that the inflammation is present in the whole body. It is essential that associated diseases are detected in time, as they have a much greater impact on the life expectancy of the patient than psoriasis itself.
Dermatologists as well as general practitioners should consider psoriasis as a signal for clarification of associated diseases. We will discuss some of these comorbidities below.
Cardiovascular disease and risk factors
The dramatic finding made in psoriasis regarding cardiac pathology was that patients aged 30-40 years with severe psoriasis have a sixfold increased risk of myocardial infarction. In addition, these patients have a five-year shorter life expectancy, and heart disease is a major contributor to this difference.
Cardiovascular disease is not only more common in psoriasis, but also in other chronic inflammatory systemic diseases such as arthritis or lupus erythematosus. In understanding this, we focus on inflammatory cells and on proinflammatory cytokines that we see in the skin in the psoriatic plaques as well as in the inflammatory changes that we see in the vessels. The patterns of cytokines (messenger substances) match quite closely. The so-called Th17 pattern with interleukin 17A and 17F is upregulated in both, and we also see T-cell activation as well as production of interferon-alpha, interleukin 2, and tumor necrosis factor alpha.
In both healthy individuals and patients with a history of myocardial infarction, CRP is a very good biomarker to predict the risk of cardiovascular disease. It is known to be associated with atherosclerosis and cardiovascular disease. CRP is driven up by interleukin 1, TNF-alpha and interleukin 6. Patients with psoriasis have much higher readings of CRP in their blood than healthy control patients. In addition, CRP has been shown to correlate very well with psoriasis severity. This implies that severe psoriasis also carries a higher risk of cardiovascular disease, and reminds us clinicians that we should urgently advance cardiovascular workups, especially in severe psoriatics.
Implications for the clinician: it has been shown in surveys that most physicians are unaware of the association between psoriasis and cardiovascular disease. Dermatologists should ask psoriasis patients about cardiovascular disease, but also pick out the particular medications, as these (especially beta-blockers and ACE inhibitors) can, after all, also affect psoriasis. In addition, every physician is encouraged to address healthy lifestyles with patients, such as eating right, exercising, and not smoking.
Effective systemic therapeutics used in psoriasis, such as methotrexate and TNF antagonists, have been shown to reduce the risk of cardiovascular disease independently of psoriasis. Therefore, it seems plausible that patients with severe psoriasis are also treated with a system therapy. Studies have not yet shown that patients with severe psoriasis who no longer have any skin changes at all under system therapy should continue to be treated in order to keep the cardiovascular risks low. In the future, however, biologics such as TNF antagonists may be passed on indefinitely, even with complete cutaneous symptom clearance, to control comorbidities. This is, of course, problematic in terms of medical economics.
Diabetes mellitus
Diabetes mellitus is due to metabolic imbalance with decreased sensitivity to insulin and hyperglycemia. Less well known is that type II diabetes is also an immune disease and is caused by similar cytokine patterns as psoriasis. Thus, TH1 cytokines may also enhance insulin resistance. In addition, diabetes is associated with obesity. Obesity is also a chronic inflammatory disease. This seems counter-intuitive: aren’t they just well-filled fat cells that accumulate in the body? Far from it, adipose tissue is very active and also produces proinflammatory cytokines. While groundbreaking results have shown that fat is central to defending against bacteria that get under the skin, because it produces antimicrobial peptides and thus protects against erysipelas, for example. However, the proinflammatory effects of adipose tissue also contribute to systemic inflammation.
Implications for therapy: The most important lifestyle intervention is and remains reducing body weight. Several studies have shown that this has a positive effect on psoriasis as well.
The system treatment can have too strong an effect. Thus, patients with type II diabetes must be careful with regard to TNF antagonists (there is a risk of hypoglycemia). Indeed, the TNF-alpha messenger of psoriasis can drive up insulin resistance and patients need higher insulin doses than normal. Once the TNF antagonist (described with etanercept and with adalimumab) is started, temporary hypoglycemia may occur.
Screening for associated disease arterial hypertension should also be performed, especially when systemic treatment with ciclosporin is used. Ciclosporin and retinoids can alter lipids, which argues for controlling lipid levels in psoriatics so treated. Interestingly, in addition to lowering LDL and stabilizing atherosclerotic plaques, statins may also reduce the inflammatory response. Simvastatin, for example, was shown to reduce PASI scores by nearly 50% in psoriatic patients. Fibrates, on the other hand, can exacerbate psoriasis.
Liver Pathologies
The most common liver pathology in psoriasis is non-alcoholic fatty liver disease (NASH). This can result in anything from fatty infiltration to cirrhosis. Again, proinflammatory cytokines are thought to drive hepatic lipid accumulation. It affects up to 50% of psoriatic patients.
Therapeutic implications for the clinician: Liver values should be checked in each case of severe psoriatic patients. Liver values are particularly important for systemic therapies such as methotrexate, which can also affect the liver. Nevertheless, there is officially no longer an upper limit for a cumulative dose of methotrexate. Procollagen 3 has also been abandoned as a screening value, and a so-called fibroscan of the liver is performed by the gastroenterologists at the USZ in each case.
Cancer
All chronic inflammatory systemic diseases have slightly increased rates of neoplasia. Lymphomas in particular are more frequent than in the normal population. In psoriatics, additional neoplasms due to long-term therapies such as PUVA/UVB, ciclosporin and methotrexate are discussed. Studies showed that patients with very long psoriasis disease duration had overall increased risks for colorectal carcinoma, pancreatic, renal, and bladder malignancies, and lymphohematopoietic neoplasms.
Consequences for the clinician: knowledge of the increased risk of cancer could have the consequence of ordering a tumor search if symptoms are present. In severe psoriatics who are under effective therapy, the so-called unmasking effect may occur. This is the apparent reappearance of actinic keratoses and spinocellular carcinomas that were not previously clinically apparent within disseminated psoriatic plaques.
Depression
Psoriasis drastically lowers the quality of life. Disfigurement can cause shame, social withdrawal and lack of self-confidence. In particular, psoriasis is also very debilitating during intimate contacts. Even individual forms of psoriasis such as nail psoriasis can have major social consequences, as lay people may assume that the nails are infected with fungus and disgust is involved. Up to 83% of psoriasis patients avoid going to the swimming pool. Stress and psoriasis form a vicious circle that can be perpetuated.
Effective therapy for psoriasis can greatly improve psychological symptoms, but it does not have to. On the contrary, surprisingly, suicide has been observed in some psoriasis patients on systemic therapies that result in 100% control of skin lesions in half of the cases. This has even already led to the halt in development of one of the newer, highly effective anti-IL17 receptor antibodies (brodalumab). The reasons for this are still unknown. However, it is known that inflammatory cytokines such as interleukin 1, TNF-alpha, interferon-gamma and others have an effect on the brain and, depending on the case, can also influence depression. It is known, for example, that cytokines such as interferon-alpha in hepatitis C can also trigger depression.
Implications for clinicians: Physicians should specifically question patients regarding depression and anxiety as well as use the DLQI (Dermatology Life Quality Index) to keep track of their patients’ quality of life impairment. In the event of severe symptoms, trained specialists should be consulted in this regard.
Inflammatory bowel disease
Crohn’s disease and ulcerative colitis are also inflammatory systemic diseases and overlap with psoriasis more often than not. In both, interleukin 23 is involved and drives the diseases. Genetically, there are also important overlaps.
Implications for the clinician: asking about gastrointestinal symptoms is useful in patients with severe psoriasis and may unmask subclinical inflammatory bowel disease, depending. Since TNF-alpha antagonists are commonly used in inflammatory bowel disease, it is important to note that these drugs can also paradoxically trigger acral psoriasis. At the USZ, we are currently conducting a study on the genetics and trigger factors of this disease in collaboration with England and are happy to share our expertise with you.
Psoriatic Arthritis
Not a true comorbidity, but a sister disease, so to speak, is psoriatic arthritis. It is present in up to 20% of psoriatics and often occurs after skin psoriasis. Clinicians should always ask psoriasis patients about joint symptoms. We already have a questionnaire (PEST) in our waiting room to elicit these symptoms. You are very welcome to obtain it from us.
The therapies of both diseases overlap in systems therapies. Topical therapies for psoriasis have no effect on the joints. Nail psoriasis is disproportionately often associated with psoriatic arthritis. It is now known that the nail is actually a continuation of the tendon and bone apparatus, and it is believed that this association is probably related.
Therapeutic consequences: Psoriatic arthritis leads to irreversible damage, whereas psoriasis itself can always heal without scarring. Therefore, early detection of psoriatic arthritis is central, especially since modern therapies can efficiently halt the destruction. At the USZ, we now conduct an interdisciplinary consultation with rheumatology in order to efficiently treat patients with dual involvement.
Challenging clinical picture
In summary, psoriasis is the prime example of medical dermatology, which challenges us greatly with its complexity. However, modern therapeutic options have led to previously unimagined successes in treatment.
DERMATOLOGIE PRAXIS 2015; 25(3): 6-8
