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To the Editor:

It seems that editorials in medical journals are designed principally to identify problems rather than find solutions. With this in mind, I am intrigued by the editorial blitzkrieg you have unleashed against that common, unfortunate malady we call fibromyalgia (FM). It would appear that your purpose is to ban FM once and for all from rheumatology practices, research endeavors, and training programs and to exile these ladies to a medical limbo and into the clutches of con men, charlatans, and the expert advice of the Internet. Just one year ago, one of our leaders was widely quoted¹ that rheumatologists were too busy and too important to waste their time with patients with FM. I am distressed at the disinterest and lack of compassion of my colleagues. Dr. Ehrlich states that tuberculosis is always tuberculosis², but I do remember historic terms such as consumption and the miasmas and curses and other causes which were entertained. Fortunately, Dr. Ehrlich's namesake, a century ago, did not dismiss syphilis, tuberculosis, and other infectious diseases and abandon his pioneering studies, which have led to modern immunology³. I also believe that it is safe to assume that none of the wives of your editorial contributors have symptoms we associate with FM or other imaginary illnesses.

I agree with Dr. Wolfe's opinion about the inappropriate use of American College of Rheumatology (ACR) criteria in the diagnosis of FM⁴, but he is the one who devised the criteria, published the information, and has since been widely quoted. The problem is that the ACR has a long history of describing diagnostic criteria for their various diseases of interest which have been constructed after many committee meetings. Such criteria and medical algorithms are sloppy methods to use in the practice of sound medicine and merely encourage the uninformed to render diagnoses which he is not competent to make. They do not serve any purpose other than in research and should otherwise be abandoned.

It may be helpful to understand how these criteria came about. Almost 50 years ago, I directed the Streptococcal Disease Laboratory at Western Reserve University, a group of investigators who were given the Lasker Award for studies in strep infections and rheumatic fever. One of my consultants was Dr. T. Duckett Jones, who headed the House of the Good Samaritan in Boston and was a member of the Streptococcal Disease Commission. Dr. Jones undoubtedly had seen more patients with rheumatic fever than anyone before or since. He was also acutely aware of the problems in the diagnosis of rheumatic fever, particularly studies in prevention and therapy such as we were then conducting (I hate to think what he would do with the current problems with Lyme disease). So that we were all on the same wavelength, he devised the widely quoted Jones Criteria⁵, but its sole purpose was for epidemiologic and clinical research and not to help a physician in individual patient care. Those of us who knew Duckett Jones will confirm this. The ACR over the past few decades has seen fit to copy Dr. Jones's effort in composing such criteria for many of the illnesses seen by rheumatologists, but these have been distributed to help the non-rheumatologist physician rather than as a research tool. Dr. Wolfe, his colleagues, and their predecessors have produced a litany of such shortcut diagnostic aids to enable the non-rheumatologists to arrive at a correct conclusion. But as Dr. Wolfe states, there is considerable overlap between the findings in FM and rheumatoid arthritis and although not mentioned, probably all forms of polyarthritis and perhaps other illnesses. The same is probably true of all diagnostic criteria for other illnesses which have been devised. In brief, Dr. Wolfe implies that such criteria are near-worthless and I would not disagree.

As a practicing rheumatologist, I must agree with much of what Drs. Ehrlich and Hadler state^2,6. I do not have the foggiest idea what FM and chronic fatigue syndrome are, and the diagnosis is essentially made on a basis of the history and an absence of abnormal physical findings and laboratory tests. In my practice, most have had the diagnosis of FM made prior to my examination, by another physician, a relative or friends, or by exploring the Internet. At best, the diagnosis is correct in perhaps half of them. Without a specific physical or laboratory finding and with no knowledge of its cause or pathophysiology, I do not know how to explain this condition to the patient. I can only paraphrase Justice Potter Stewart, who, in describing pornography, said he doesn't know how to define it but he knows it when he sees it. In contrast to your experts, I find it difficult to believe that this is an iatrogenic disease. We saw such patients when I was a house-officer and subsequently labeled them as having fibrositis, a term which was hardly descriptive. And then the label was changed to FM, which is as specific as telling someone that they have a headache or a pain. Does it matter what we use as a term so long as we all understand what we are saying?

As I stated, editorial writers are great at defining problems, but your writers have failed to provide any solution other than to abandon these people and tell them to get out of our back yard. Whether we like it or not, the patient with FM is sick or believes that she is ill, and is able to function only on a reduced level. She is not liked by any male with whom she has close contact, whether it is her husband or her physician. She cries out for help but rarely receives it. She does not respond to drugs, is at risk of becoming habituated to analgesics, and is shunted between physicians and support groups, and quacks. As a rheumatologist, I would prefer to spend my time on other diseases, yet I would feel ashamed to neglect such patients or to refer them to whoever will get them out of my hair. At present, we are exploring other alternatives, which are thus far successful and which allow us to show the compassion these people deserve.

Finally, I need to admonish Dr. Gordon as the editor⁷. Americans have recently criticized our Canadian friends are being too liberal, politically correct, and too willing to accept social change. Knowing that men invariably dislike ladies with FM, it would have been more fair if you had had at least one female physician to join this group of male chauvinists. I believe that there would have been a more valid conclusion.

ALTON MORRIS, MD, Kingsport, Tennessee 37660, USA.

REFERENCES

1. Wolfe F. Stop using the American College of Rheumatology criteria in the clinic [editorial]. J Rheumatol 2003;30:1671-2.

2. Ehrlich P, Hata S. Die experimentelle Chemotherapie der Spirillosen. Berlin: Springer: 1910.

3. Ehrlich G. Pain is real. Fibromyalgia isn't [editorial]. J Rheumatol 2003;30:666-7.

4. Blann EF, Jones TD. The natural history of rheumatic fever: a 20 year perspective. Ann Intern Med 1952;37:1006-26. No abstract available.

5. Jones TD. The diagnosis of rheumatic fever. JAMA 1944;126:481-4.

6. Hadler NM. Fibromyalgia" and the medicalization of misery. J Rheumatol 2003;30:1668-70.

7. Gordon DA. Fibromyalgia. Real or imagined? [comment] J Rheumatol 2003;30:1665.

Fibromyalgia. Reflections About Empirical Science and Faith

To the Editor:

This essay refers to the editorials by Gordon, Ehrlich, Hadler and Wolfe, published in the August 2003 issue of The Journal.

As medicine, rheumatology is an empirical science. In science, empiricism must be understood according to the ideas of the philosophers, like Hume and Berkeley^1,2, who concluded that knowledge could only be acquired through sensory experience. In other words, the object of knowledge must be perceptible through one's senses.

When a scientist is looking for T CD4 lymphocytes in a human tissue, he or she is looking for empirical evidence. To achieve this, he or she works with a visible and tactile piece of tissue; stains it with visible, tactile, and smelly chemical substances, and gets something that can be visible with a microscope and that can be photographed. This is the empirical part of scientific work and the facts that are produced in it are empirical facts and empirical knowledge. They are visible, tactile, perceptible, and real.

However, when T CD4 lymphocytes are detected in a human tissue, what does this mean? To answer this, we need a different kind of knowledge, an abstract knowledge. This is a "theoretical" knowledge and it is expressed with words. It can be based on empirical facts or faith.

When a patient has clinical manifestations of tuberculosis, like cough and sputum, fever, weight loss, and radiographically visible pulmonary lesions, the person really only knows that he or she has tuberculosis after a sequence of empirical facts. First, a laboratory test of tissue or secretion from that person has to show a structure, conventionally named Mycobacterium tuberculosis, which is visible by staining methods. Second, the result of the laboratory test is written on paper. Finally, a physician reads the result and translates into one word: tuberculosis.

One who gets M. tuberculosis, gets tuberculosis. This is a form of circular reasoning, which is scientifically acceptable because it is the presence of the bacillus (empirical fact) that defines the disease (theoretical knowledge). The same is true for cancer, of which the empirical basis is the malignant cell.

The development of criteria for fibromyalgia (FM)³ classification was an attempt to give empirical support to a common situation in medical practice. A patient who complains of body pain over a long period of time represents this situation. When the complaint persists longer than 3 months and is diffuse, it is conventionally named widespread chronic pain.

With lack of empirical and specific evidence to define that clinical situation, the committee takes 2 additional items of evidence, which are the complaint of widespread chronic pain and the finding of tender points in a physical examination. I say "the complaint of widespread chronic pain" and not "widespread chronic pain" because "the complaint" is the only empirical form describing the phenomenon. When one says "widespread chronic pain," one is accepting the pain as being real, but that is an act of faith and causes judicial consequences.

The idea behind the development of the criteria attempts to define the word fibromyalgia as being the empirical evidence of someone complaining of widespread chronic pain and the finding of 11 or more tender points in a physical examination. The reasoning used is the passage of empirical evidence (complaint of widespread chronic pain and tender points) to a verbal significance (fibromyalgia). A mental process known as induction leads to this. Personally, I call it an inductive jump. The jump is from empirical facts to words. Induction is a process of thought where an act of faith turns empirical evidence into words, words into meanings, meanings into feelings, and feelings into realities. These realities reinforce the initial faith.

When someone jumps from a malignant cell to cancer or from M. tuberculosis to tuberculosis, those acts are accepted as scientific truth because there is no evidence showing there is tuberculosis without M. tuberculosis and cancer without a malignant cell. The association of these words is specific and complete. Even if in these cases there are inductive jumps from one word to another, they represent the same reality, in spite of using "malignant cell" for the isolated cell and "cancer" for the clinical expression of the disease; we are saying in an empirical way, malignant cell is cancer and cancer is a malignant cell. This "scientific tautology" is the basis of the meaning of words in science.

But this is not true for FM. Tender points are not specific for the complaint of widespread chronic pain, and the complaint of widespread chronic pain is not specific for FM, so the combination of tender points and the complaint of widespread chronic pain is not sufficient to construct a scientific tautology with the word fibromyalgia. The result is a concept that is not empirical, that is not verifiable. But it is useful.

It is useful because the construct has initiated scientific efforts to prove its veracity or deny its existence. These works have produced meaningful scientific knowledge of anatomical and biochemical phenomena involved in perception and modulation of pain. It is useful because it explains to patients that pain does not mean lesion or deformity, does not mean arthritis or cancer, does not mean disability or incapacity. And the prognosis of someone complaining of widespread chronic pain is not hopeless. There are patients that even complain of widespread chronic pain for a long time, who stop complaining after some time. If those patients had pain and the pain disappeared, it is a conclusion that current medicine cannot explain; there is no empirical evidence to do so. But if there are patients that complain of widespread chronic pain for some time and at the same time have sleep disturbance, fatigue, and tender points, and then stop complaining and these manifestations disappear, we can say that there is hope for someone complaining of widespread chronic pain.

However, while the construct is useful in some aspects, it has failed in others because it is not empirical. Because FM is not verifiable, it cannot be denied, and this is more important than proving its existence. Nobody will go to court to request compensation for cancer without showing the malignant cell that defines the disease. Without the empirical proof, a claim for cancer cannot be defensible. But someone with bad intentions can claim compensation for FM because this complaint cannot be overturned by present-day knowledge. Astute lawyers certainly have perceived that, and the scientifically useful construct has been abused in legal proceedings, taking advantage of the law's inexactness and subjective determinations of incapacity and compensation⁴.

Physicians who have testified that patients complaining of widespread chronic pain really felt the pain, were moved by faith in words, but not by empirical evidence to support the scientific statement. Yet giving testimony, the physician is called to answer empirically, perhaps as follows:

Does the patient complain about widespread chronic pain?

"Yes."

Does the patient feel the pain?

"I can't affirm that."

Does the patient have fibromyalgia?

"No one can have fibromyalgia. Fibromyalgia is just a word we use to represent the situation of someone complaining about widespread chronic pain, fatigue, and sleep disturbance who has tender points on physical examination. It is not a disease, it's a description."

That's the difference between scientific tautology and pleonasm.

LUIZ CLAUDIO da SILVA, MD, Rheumatologist, Hospital de Clínicas da Universidade Federal do Paraná, Curitiba, Brazil. E-mail: lclaudiosilva@terra.com.br

REFERENCES

1. Hume D. In: Norton DF, Norton MJ, editors. A treatise of human nature: being an attempt to introduce the experimental method of reasoning into moral subjects. (Oxford Philosophical Texts). Oxford: Oxford University Press; 2000.

2. Berkeley G. In: Dancy J, editor. A treatise concerning the principles of human knowledge (Oxford Philosophical Texts). Oxford: Oxford University Press; 1998.

3. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160-72.

4. Wolfe F. The fibromyalgia problem [editorial]. J Rheumatol 1997;4:1247-9.

Systolic Blood Pressure in Patients with Osteoarthritis and Rheumatoid Arthritis

To the Editor:

The recent article by Singh, et al¹ raises an increasingly important issue: with the advent of cyclooxygenase-2 (COX-2) inhibitors, doctors seem to have forgotten that nonsteroidal antiinflammatory drugs (NSAID) have important adverse effects. The effects on blood pressure are often more severe than the few mm Hg that they highlight. I frequently see patients whose blood pressure has been significantly aggravated by NSAID, including COX-2 inhibitors. However, like many, they seem to have forgotten that not all NSAID are created equal with respect to effects on blood pressure.

We showed² that in contrast to other NSAID, sulindac does not raise blood pressure, and that this difference was due to sparing of renomedullary vasodilator prostaglandins. I have suspected for some time that the (to me) surprising neglect of our report may have been related to the apparent small size of the sample (30 patients). However, because it was a 4-way complete-crossover design, the study had a greater power than would a parallel-group study in 120 patients. It was also more relevant to the clinical situation than some other negative studies at the time done in healthy volunteers, in that we studied patients with hypertension, stabilized on beta-blocker and diuretic.

As Santayana pointed out, those who forget history are doomed to repeat the mistakes of the past. Patients with hypertension, congestive heart failure, or other conditions aggravated by retention of salt and water will do better taking sulindac than other NSAID.

J. DAVID SPENCE, MD, Stroke Prevention and Atherosclerosis Research Centre, 1400 Western Road, London, Ontario N6G 2V2, Canada. E-mail: dspence@robarts.ca Phone 519-663-3113; fax 519-663-3018

REFERENCES

1. Singh G, Miller JD, Huse DM, Pettit D, D'Agostino RB, Russell MW. Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol 2003;30:714-9.

2. Wong DG, Spence JD, Lamki L, Freeman D, McDonald JWD. Effect of non-steroidal anti-inflammatory drugs on control of hypertension by beta-blockers and diuretics. Lancet 1986;1:997-1001.

Acute Polyarthritis Related to Once-Weekly Alendronate in a Woman with Osteoporosis

To the Editor:

In regard to reports of alendronate therapy¹, we describe our experience treating a woman for postmenopausal osteoporosis with a once-weekly formulation of bisphosphonate, who, 12 hours after each intake, developed severe myalgia and symmetrical polyarthritis. She recovered spontaneously without sequelae.

A 63-year-old woman had a history of total hysterectomy at the age of 42 years and of recurrent episodes of lumbar pain since the age of 60. She also had pains involving the base of both thumbs and the right big toe, related to osteoarthritis (OA). Lumbar radiographs showed mild signs of OA of the zygapophyseal joints of the last 2 lumbar vertebrae. Densitometry dual energy x-ray absorptiometry evaluation revealed reduced mineral density in both vertebral (T score -3.6) and femoral neck (T score -2.02) sites. Postmenopausal osteoporosis was diagnosed.

For therapy, she was given once-weekly alendronate (70 mg) in addition to oral calcium (1 g daily) and vitamin D3 (800 IU daily). Twelve hours after the first ingestion of alendronate, she started to have severe diffuse myalgia and pains of both hands, feet, and knee joints; the pain was so severe that she was confined to her bed for one day. There was no fever, chills, cutaneous erythema, or esophageal irritation. After the second dose of alendronate 70 mg, one week later, she experienced the same symptoms. Clinical examination after 3 days revealed swelling of both wrists, index fingers (Figure 1), forefeet, and the right knee. Flexion of the fingers was limited bilaterally. The grip strength was very weak. Aspiration of the right knee yielded 4 ml of synovial fluid, which contained 6800 leukocytes/mm³ (30% polymorphonuclears, no eosinophils); no birefringent crystals were seen. C-reactive protein (CRP) was 14 mg/l. Erythrocyte sedimentation rate (ESR; Westergren) was 16 mm/h. Rheumatoid factor was negative. Radiographs of the hands and knee joints revealed mild signs of OA. There was no chondrocalcinosis. Sacroiliac joints were normal on pelvic radiographs. Alendronate was discontinued. During the 6 month followup myalgia and symptoms of arthritis did not reappear. CRP values returned to normal (3 mg/l) after 10 days. ESR after one month was 6 mm/h.

To our knowledge, this is the first report of acute polyarthritis that can be related to therapy with alendronate. In a series of 476 patients receiving glucocorticoids treated with oral daily alendronate, no case of arthritis as an adverse event was reported². In a series of 38 children treated with daily alendronate during 1 year, one dropped out of the study after the first 2 days of therapy because of severe bone pain³. With pamidronate given intravenously to patients with osteoporosis or conditions related to cancer, Thiébaud, et al⁴ have reported bone pains, arthralgia, and flu-like syndrome in 12.5%. These authors postulated that this reaction, which resembled the acute phase response, could be mediated by release of cytokines after bisphosphonate therapy. In an in vitro study, the same authors³ found an increase of tumor necrosis factor-a (TNF-a) and interleukin 6 (IL-6) in blood incubated with 2 aminobisphosphonates, pamidronate and zoledronate. In a collagen-induced arthritis model in mice, the aminobisphosphonates showed an exacerbating effect on development of the arthritis⁵. Alendronate, also an aminobisphosphonate, has been found to favor cytokine release by macrophages (IL-1ß, IL-6, and TNF-a); however, this effect was not observed with a non-nitrogen-containing bisphosphonate, clodronate⁶. These findings suggested to the authors that amino-containing bisphosphonates such as alendronate could have proinflammatory properties⁶. However, in chronic inflammatory arthritides, the effect of longterm treatment with bisphosphonates is still controversial⁷.

Our observation suggests that not only arthralgia but also transient true polyarthritis may be a rare side effect of alendronate given to patients with primary osteoporosis. Whether this compound could also occasionally aggravate articular manifestations in patients with preexisting chronic arthritis such as rheumatoid arthritis should be assessed in prospective studies.

JEAN C. GERSTER, MD, Professor of Rheumatology, Division of Rheumatology, Centre Hospitalier Universitaire Vaudois, Av. Pierre Decker 5, CH 1011 Lausanne; FRANÇOIS NICOLE, MD, General Pratictioner, Lausanne, Switzerland. E-mail: jean-charles.gerster@chuv.hospvd.ch

REFERENCES

1. Schnitzer T, Bone HG, Crepaldi G, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group. Aging 2000;12:1-12.

2. Adachi JD, Saag KG, Delmas PD, et al. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids. Arthritis Rheum 2000;44:202-11.

3. Bianchi ML, Cimaz R, Bardare M, et al. Efficacy and safety of alendronate for the treatment of osteoporosis in diffuse connective tissue diseases in children. Arthritis Rheum 2000;43:1960-6.

4. Thiébaud D, Sauty A, Burckhardt P, et al. An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int 1997;61:386-92.

5. Nakamura M, Ando T, Abe M, Kumagai K, Endo Y. Contrast between effects of aminobisphosphonates and non-aminobisphosphonates on collagen-induced arthritis in mice. Br J Pharmacol 1996;119:205-12.

6. Makkonen N, Salminen A, Rogers JM, et al. Contrasting effects of alendronate and clodronate on RAW 264 macrophages: the role of a bisphosphonate metabolite. Eur J Pharm Sci 1999;8:109-18.

7. Maksymowych P. Bisphosphonates for arthritis — a confusing rationale. J Rheumatol 2003;30:430-4.

Wegener's Granulomatosis with Massive Skin Necrosis

To the Editor:

Wegener's granulomatosis (WG) is an idiopathic multisystem necrotizing vasculitis of small and medium size vessels with a predilection for the upper airways, lungs, and kidneys^1,2. Skin manifestations of WG occur in 17% to 50% of patients², and include pustules, maculae, bullae, palpable purpura, and petechiae, mainly on the lower (52%) and upper (22%) extremities^1-3. Most skin biopsies in WG show nonspecific histopathology; in only 25% of cases can typical features such as leukocytoclastic vasculitis (80%) or extravascular granuloma (10%) be found^1-3. We describe a case of WG with a diffuse cutaneous necrosis.

A 38-year-old man was referred to our university hospital because of extensive cutaneous necrosis (roughly 14% of the total body surface area), associated with fever and dyspnea. He had been well until 3 months earlier, when he noted a slight edema of the left eyelid and exophthalmus, along with arthralgias. A month later he presented with fever, nonproductive cough, hemoptysis, a bloody nasal discharge, and maculonodular hemorrhagic rash followed by rapid necrosis (Figure 1A). Laboratory abnormalities included elevated inflammation markers, anemia (hemoglobin 9 g/dl), leukocytosis (18,000/mm³), proteinuria (< 7 g/day), microhematuria, and elevated serum creatinine (229.7 µmol/l) and liver enzymes.

Immunological tests revealed the presence of antineutrophil cytoplasmic antibodies (c-ANCA) at a titer of 1:40, identified as antiproteinase-3 antibodies by ELISA. Antinuclear, anticardiolipin, and anti-ß₂ glycoprotein I antibodies, along with tests for lupus anticoagulant and cryoglobulins, were negative. Factor V Leiden was absent; protein C and S concentrations were normal. Hepatitis B and C viruses and human immunodeficiency virus tests were negative. Cultures of bronchoalveolar lavage were negative, as were blood cultures. Chest radiograph showed a nodular infiltrate (4 ´ 3 cm) in the right upper lobe, confirmed by computer tomography (CT) scan. CT scan of the facial region revealed a mucous membrane thickening in both maxillary sinuses and a hyperdensity in the left orbit, with no bone or muscle infiltration.

A diagnosis of WG was established. He was successfully treated with intravenous methylprednisolone (1 mg/kg daily) and IV pulses of cyclophosphamide (1000 mg) every fourth week along with 3 broad-spectrum antibiotics. Topical treatment of skin lesions included ethacridine lactate, 10% NaCl, followed by gradual excisions of necrotic tissue. In the following weeks his condition improved, with a complete healing of necrotic changes at 6 months (Figure 1B) and resolution of the consolidation in the right lung.

To our knowledge, this is the first report on a massive skin necrosis in a patient with WG. Necrotizing ulcerations or digital necrosis are rare manifestations of WG^3,4; their surface is much smaller than in our patient^1,3,5. Skin lesions indicate active systemic disease, especially with renal involvement⁶. Differential diagnosis included other autoimmune diseases with common skin manifestations: polyarteritis nodosa, microscopic polyangiitis, cutaneous leukocytoclastic vasculitis, giant cell arteritis, and angiocentric lymphomas, along with diseases referred to as ANCA-associated vasculitis (microscopic polyangiitis, Churg-Strauss vasculitis, necrotizing pauci-immune glomerulonephritis)⁷. Our patient fulfilled clinical and laboratory criteria for the diagnosis of WG, supported by a good response to cyclophosphamide⁸. Further, absence of the necrotic core and violaceous border speak against pyoderma gangrenosum. The patient did not receive coumarins, a potential cause of skin necrosis.

Since he presented with extensive necrosis, a skin biopsy was not performed for ethical reasons (risk of provoking new ulcers at the biopsy site⁴). In this case, rapid initiation of aggressive immunosuppression and wound care led to therapeutic success.

Our case illustrates that skin necrosis, although rare, could be a potentially devastating manifestation of WG that requires a rapid diagnosis and vigorous treatment.

AGNIESZKA CYBULSKA, MD; ANETTA UNDAS, MD, PhD; WOJCIECH J. SYDOR, MD; AGNIESZKA FLAK, MD; JACEK MUSIAL, MD, PhD, Department of Medicine, Jagiellonian University School of Medicine, Skawinska 8, PL-31-066 Kraków; ANTONI SYDOR, MD, PhD, Department of Internal Medicine, Nephrology and Center of Dialysis, Saint Lucas Hospital, Tarnów, Poland.

REFERENCES

1. Daoud MS, Gibson LE, DeRemee RA, Specks U, el-Azhary RA, Su WP. Cutaneous Wegener's granulomatosis: clinical, histopathologic, and immunopathologic features of 30 patients. J Am Acad Dermatol 1994;31:605-12.

2. Barksdale SK, Hallahan CW, Kerr GS, Fauci AS, Stern JB, Travis WD. Cutaneous pathology in Wegener's granulomatosis: A clinicopathologic study of 75 biopsies in 46 patients. Am J Surg Pathol 1995;19:161-72.

3. Patten SF, Tomecki KJ. Wegener's granulomatosis: cutaneous and oral mucosal disease. J Am Acad Dermatol 1993;28:710-8.

4. Walsh JS, Gross DJ. Wegener's granulomatosis involving the skin. Cutis 1999;64:183-6.

5. Abdou NI, Kullman GJ, Hoffman GS, et al. Wegener's granulomatosis: Survey of 701 patients in North America. Changes in outcome in the 1990s. J Rheumatol 2002;29:309-16.

6. Frances C, Du LT, Piette JC, et al. Wegener's granulomatosis. Dermatological manifestations in 75 cases with clinicopathologic correlation. Arch Dermatol 1994;130:861-7.

7. Gibson LE, Su WP. Cutaneous vasculitis. Rheum Dis Clin North Am 1995;21:1097-113.

8. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum 1990;33:1101-7.

Juvenile Polyarteritis: Is It a Different Disease?

To the Editor:

In 1897, Still suggested that the rheumatoid arthritis of children was different than that of adults¹. He contended that the disease in children started in childhood and had an insidious onset. He also pointed out the marked differences in clinical features and sex distribution, and suggested it might include more than one disease¹. Today, juvenile (idiopathic) arthritis is still evolving in terms of nomenclature and classification.

Küssmaul and Maier had described polyarteritis nodosa (PAN) some 30 years before Dr. Still's report². The description was based on pathology, where necrotizing arteritis characterized the disease. In 1994, PAN was separated into 2 subtypes according to the vessel size involvement, on the basis of the classical presentations in adults: classic PAN and microscopic polyangiitis³.

The peak frequency of PAN in adults is in ages 40s and 50s, whereas in children the peak age of onset is before puberty, around 10 years^4-10. Both classic PAN and microscopic polyangiitis in adults are known to be more common in males; however, in children the frequency is roughly equal^5,8,9. In adults the disease has a poor outcome. In children, however, the outcome is better^6,9,10. In adults the reported survival rates are around 80%. On the other hand mortality is very rare in children after the 1990s; indeed there were no deaths reported in the 2 recent series published after 1997^9,10. The disease in children has a rather insidious onset as in juvenile idiopathic arthritis.

Clinical features of the disease in children are also different than in adults. The pulmonary-renal involvement that characterizes microscopic polyangiitis is very rare in children; the typical cases with high myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) have been rarely reported^9,11. In adults there are large series of reports with classic PAN associated with hepatitis B surface antigen (HBsAg)¹². This group is very rare in children, which may partially be due to the increased vaccination in children. Although we had described a number of patients associated with HBsAg in our series before 1990, we have seen only 2 cases since 1990⁷. However, when present it necessitates a different treatment regimen.

Thus the typical presentation in children is of isolated one or 2 organ involvement, with constitutional symptoms, and the diagnosis is often based on pathology. Further, the disease does not necessarily confine itself according to vessel size¹³.

As well, a large group of child patients are characterized by cutaneous PAN, which is rare in adults and is not even included in the Chapel Hill nomenclature criteria^3,5. Thus, similarly to juvenile arthritis, we may talk about subtypes in childhood PAN. These may be: (1) Cutaneous PAN: this will be disease confined to the skin. These patients may describe accompanying myalgia, arthralgia, and sometimes arthritis. (2) Systemic PAN with organ involvement other than the skin, regardless of the vessel size (both small and middle size). Constitutional symptoms and elevated acute phase reactants are almost always present. (3) Microscopic polyarteritis as in adults associated with MPO-ANCA: this would be the typical pulmonary-renal syndrome with a guarded prognosis. Some patients may just present with renal disease (pauci-immune, crescentic necrotizing glomerulonephritis) or, rarely, just pulmonary disease. (4) Hepatitis B associated classic PAN of adults: this is an immune complex disease characterized by aneurysms in the renal arteries.

These 4 groups have different etiology; cutaneous PAN is associated with streptococci, whereas the last group is associated with HBsAg^13,14. They have different disease courses^5,6,13. They also require different treatment regimens, which remain to be proven¹⁵. As pediatricians, we need to validate our own classification criteria and severity scores, and to develop treatment protocols for the disease subtypes. These subtypes may well be different parts of the spectrum of the same disease process, which vary in their manifestations according to the modifier genes/factors. In the future we may be able to define these factors; for the time being the features noted here may justify a subclassification.

Infantile PAN has not been included as a separate subtype, since probably all the cases reported in the literature fit with the classification of Kawasaki's disease¹⁶.

Since the disease has different features and perhaps different subtypes, it might be time that we recognize PAN in children as a different entity, and call it "juvenile PAN."

SEZA OZEN, MD, Professor, Department of Pediatrics, Hacettepe University Faculty of Medicine, 06100 Ankara, Turkey. E-mail: sezaozen@hacettepe.edu.tr

The author would like to thank Dr. David N. Glass for reviewing this manuscript.

REFERENCES

1. Still GF. On a form of chronic joint disease in children. Med Chir Trans 1897;80:47.

2. Kussmaul A, Maier K. Über eine bisher nicht beschriebene Eigenthümliche Arterinerkrankung (Periarteritis nodosa). Dsch Arch Klin Med 1866;1:484.

3. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Arthritis Rheum 1994;37:187-92.

4. Adu D, Bacon PA. Classical PAN, microscopic polyarteritis and Churg Strauss syndrome. In: Maddison PJ, Isenberg DA, Woo P, Glass DN, editors. Oxford textbook of rheumatology. Oxford: Oxford University Press; 1998:1351-65.

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