Leprosy in the rheumatology clinic: an update on this great mimic

Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae. The first description of the disease dates back to the 6th century BC by Indian surgeon Sushruta. The invasion of Asia by the armies of Alexander the Great saw the spread of the disease across Europe. Leprosy now remains endemic predominantly in the developing world, with pockets of high prevalence identified in Brazil, Indonesia and India (South-east Asia [SEA]). Together, these three countries account for 80% of all newly registered cases.1 Although the number of new cases detected globally has been on the declining trend, it remains a major problem in some of developing countries. Improved connectivity across the continents has led to increasing global travel, and case reports of this disease amongst the migrants have surfaced in developed nations as well. These are likely to be missed by unaware physicians. The use of newer immunosuppressants, anti-tumor necrosis factor in particular, have also been associated with reports of leprosy.2 Early diagnosis and full course of treatment are critical for prevention of lifelong neuropathy and disability in these cases. Although a vast majority of cases manifest with dermatologic and neurologic features, musculoskeletal manifestation are also quite common. The prevalence of rheumatic manifestations in leprosy varies across case series, ranging from 1–2% described in large dermatology series to 60–80% from rheumatology clinics.3-5 This wide variability in the reported prevalence suggests that documentation of rheumatologic signs and symptoms depends on the specialty in which the patient is being treated, and rheumatic manifestations of leprosy as a whole is often under-reported by non-rheumatology services. Therefore, it is a felt need for awareness of the condition among rheumatologists, as joint involvement can be the only manifestation in some cases. The World Health Organization (WHO) achieved the elimination of leprosy as a public health problem (prevalence less than one case per 10 000 persons) globally in the year 2000. The prevalence rate of leprosy has dropped by 99% from 21.1 per 10 000 in 1983 to 0.24 per 10 000 in 2014. The annual leprosy statistics in 2015 from 121 countries indicate that leprosy still exists at least in small numbers of cases in many countries. In 2014, 213 899 new cases were reported in the world; 94% of these were from 13 high endemic countries, with the remaining 6% of new cases from the 108 other countries.6 The leprosy control program now aims to focus on the 13 most highly endemic countries in order to achieve its targets. Most of these endemic countries belong to SEA and Central America. Lepromatous manifestations are most often seen in males across all series. These are more common in people from rural areas although some studies have found equal prevalence in rural and urban areas. Although rheumatologic manifestations can be seen in all types of leprosy, these are more common in the lepromatous variety. The classic manifestations of leprosy vary from macules to plaques and nodules, which are often hypo-pigmented or hypo-anesthetic. Neurologic manifestations can range from mononeuropathy to mononeuritis multiplex and distal symmetric polyneuropathy. Charcot's arthropathy is the classic rheumatologic manifestation of leprosy often described in textbooks; it is usually seen in long-standing cases with neurologic involvement. Ankle and knee are most commonly involved. Findings may range from subluxation, dislocation or pathologic fractures to complete joint destruction. Although it is deemed to be prevalent in one in 10 cases, data from rheumatology units has yielded a surprisingly lower number.7 This change could also be attributable to the early and widespread use of multidrug therapy (MDT). Interestingly, a plethora of rheumatologic phenomena may be uncovered in a host with poor immunity after the initiation of MDT. Acute symmetric polyarthritis in leprosy is often explosive in onset and associated with Lepra reaction. Small joints of the hands and feet are most commonly involved, although knees and elbows can be affected. These usually last for a few weeks and resolve completely with treatment, although recurrences have been described.8 Leprosy can also have chronic polyarthritis resembling rheumatoid arthritis (RA). Atkin et al.9 were the first to describe such presentations in the absence of Lepra reaction. Messina et al. have described similar manifestations in 39 cases. The mean duration of arthritis in their patients was 11 years, and most had erosive disease with classic hand deformities, making differentiation from RA difficult.10 Chopra et al. have also described seven cases of leprosy with coexistent RA.11 Prasad et al. have described articular manifestations akin to spondyloarthropathy (spA). In that study, one-third of those with arthritic manifestation had asymmetric lower limb oligoarthritis.12 Sacroiliitis is not a common manifestation, although Messina et al.10 had an astonishing prevalence of 63% in their 55 cases. Most had bilateral sacroiliitis, although it did not correlate with lower back pain. Lepromatous leprosy is the most common subtype associated with this manifestation. Prasad et al.12 have also reported arthritis and tenosynovitis with or without paraesthesias or thickened nerves in 18% of cases in their series. These cases belong to pure neuritic subtypes of leprosy, as they do not have cutaneous manifestations. Presence of thickened or tender nerves may clinch the diagnosis. Ulnar and common peroneal nerve thickening should always be looked for; at times the radial, supraclavicular, grater auricular and facial nerves can also be thickened.12 At times, patients present with only tenosynovitis in the form of swollen hands and feet syndrome (SHFS). A series from Argentina has described up to 66% prevalence of this manifestation in their patients.13 This may be a feature of pure neuritic leprosy, or less commonly a part of generalized Lepra reaction. Leprosy may mimic vasculitis at times. This happens in cases with high bacillary load where the vascular endothelium is teeming with bacilli. Popularly known as 'lucio leprosy', as 'lucio' means beautiful in Mexican, the skin of the patient is diffusely infiltrated so the natural wrinkles are obliterated, imparting a shiny hue. This variety is extremely rare in Asia, most cases being described from Mexico and Costa Rica. It is one of the most severe forms of leprosy and can be fatal at times.14 Albeit rare, cryoglobulinemia can be another cause for vasculitis in a leprosy patient without lucio phenomenon. Although cryoglobulins have been described in up to 40% of leprosy cases, vasculitis is rare and limited to case reports. The cryoglobulins in these cases are polyclonal immunoglobulin G (IgG) and IgM.15 In the present issue of this Journal, Dionelle and colleagues from Malaysia have described a case of an elderly man presenting with painful neuritis and fingertip ulcers mimicking systemic necrotizing vasculitis. It is of note that laboratory workup was inconclusive; however, careful clinical examination revealed indurated hypoaesthetic plaques and nerve thickening followed by skin biopsy which clinched the diagnosis of paucibacillary leprosy. It is to be noted that Malaysia is a non-endemic zone for leprosy.16 Leprosy is a great masquerader and true to this name, varied manifestations resembling different connective tissue diseases have been described in this infectious disease. Biopsy-proven cases of leprosy can present with heliotrope rash, muscle weakness and elevated muscle enzymes, oral ulcers, malar rash and photosensitivity, or a picture completely resembling scleroderma with Raynaud's phenomena, pitting scars and skin thickening.17, 18 In another case series, Danda and colleagues reported three patients with Lepra reaction presenting as arthritis, lupus-like and polyarteritis nodosa-like disease, respectively.19 Reactional states are systemic inflammatory complications arising from immunologic phenomenon, seen in 30–50% of all leprosy patients.20 Type 1 Lepra reaction most commonly affects patients with borderline disease and is called upgrading reaction when induced by anti-lepromatous therapy. Rarely, it can signify deterioration in patient's immunity when it occurs spontaneously; it is then called downgrading reaction. Type 2 Lepra reactions on the other hand, affect lepromatous leprosy (LL) patients or those with borderline leprosy (BL). It is also called erythema nodosum leprosum (ENL). Type 1 reaction is characterized by new inflammation in pre-existing skin lesions marked by erythema and induration. SHFS and ulcerated skin lesions have also been described. Neuritis is marked by pain and tenderness in one or more nerves. It can result in severe nerve injury if not treated early. A type 2 reaction is marked by the sudden appearance of numerous painful nodules due to panniculitis. Some of these lesions can ulcerate and exude pus. The patients with ENL look ill; they usually have high fever, lymphadenopathy, orchitis, iridocyclitis, muscle tenderness and arthritis. The natural course of the condition is 1–2 weeks, but recurrences are common. ENL has been more commonly described from rheumatology units than type 1 reaction.11, 12 Demonstration of acid-fast bacilli (AFB) in the dermis forms the cornerstone of diagnosis. Patients with good immunity (tuberculoid end of spectrum) usually have well-developed granulomas and may not have AFB in tissues. Patients at the lepromatous end of the spectrum have no apparent resistance to M. leprae as seen by sheets of foaming macrophages teeming with AFB. Paucibacillary (PB) leprosy is defined as five or fewer skin lesions without detectable bacilli on skin smears. Patients with only a single skin lesion are classified separately as single-lesion PB. Multibacillary (MB) leprosy is defined as six or more lesions and may be skin-smear positive.21 A high index of suspicion is required for diagnosis as leprosy closely mimics other rheumatologic conditions. Leprae bacilli are not always found on investigations; hence other differentials need to be excluded. False auto antibody positivity is another confounding variable, often leading to confusion in the clinic. Most series have described rheumatoid factor (RF) and anti-nuclear antibody (ANA) positivity in up to one-third of all leprosy cases and two-thirds of the lepromatous variety. False cytoplasmic positivity for anti-neutrophil cytoplasmic antibody (ANCA) is common on immunofluorescence assay.3 Testing for anti-proteinase 3 and myeloperoxidase by enzyme-linked immunosorbent assay can be useful under these circumstances to rule out underlying ANCA-associated vasculitis, as these are usually negative in leprosy. Anticitrullinated peptide antibodies (ACPA), serology for human immunodeficiency virus and syphilis are usually negative.11 In an another study, except for IgA RF, none of the serological tests showed any association with articular manifestations in leprosy. IgA RF are generally not available in routine day-to-day clinical practice. However, ACPA antibodies are less common in arthritis of leprosy as reported by others. This paper also appears in this issue of IJRD.22 The gold standard for diagnosis in cases of arthritis is demonstration of AFB in joints. It is rare to find M. leprae in the joint fluid.18 Joint aspirates can range from non-inflammatory to turbid effusions with high total leukocyte count. Synovial biopsies can have variable histological findings in the form of non-specific chronic inflammation, epitheloid cells infiltration, granulomas or AFB. Radiographs of hands and feet can show specific changes like acro-osteolysis, periosteal reaction, sub-articular cyst, enlargement of nutrient foramina, subluxation or complete joint destruction.23 Classical changes like acro-osteolysis are seen in cases with long-standing neuropathy. Non-specific changes such as soft tissue swelling and generalized or juxta-articular osteopenia are seen in almost all cases.9, 10 Interestingly, most rheumatology series have failed to demonstrate destructive changes in joints; this again raises the possibility that rheumatologic manifestations occur before irreversible damage sets in. Antibodies to phenolic glycolipid 1 (PGL-1) are more often seen in lepromatous disease (90%) as they have polyclonal reactivity.24 Patients with tuberculoid disease seldom produce antibodies to PGL-1 and therefore the test is not useful for diagnosis of this subset of patients in whom establishing the diagnosis is most difficult. Polymerase chain reaction for detection of M. leprae DNA in tissues is still considered to be a research tool, although it has sensitivity and specificity of 90% and 100%, respectively.25 Although MDT forms the cornerstone of leprosy management, presence of rheumatologic manifestations often mandates the addition of immunosuppression. Drug resistance in leprosy is extremely rare and failure to improve is almost always due to poor compliance. With the reduction in global prevalence of leprosy, WHO26 has reduced the recommended duration of MDT to 12 and 6 months for multibacillary and paucibacillary leprosy respectively, as a cost-cutting measure. However, shorter treatment regimes have been associated with greater incidence of relapse; hence, in hotspots like SEA more intensive regimes may be more appropriate. It is, therefore, recommended to continue therapy for at least 2 years in paucibacillary leprosy and 5 years to lifelong in multibacillary leprosy.27 Neuritis must be treated aggressively to prevent or minimize nerve injury. Nerve function improves in 60–70% of cases with timely management. In a controlled trial of treatment for type 1 reactions with three different treatment regimes, greatest improvement occurred in those receiving concurrent high-dose steroids for long duration (prednisolone 1 mg/kg for 20 weeks or longer).28 Prednisolone should be slowly tapered in type 1 leprae reaction once it is controlled. In general, it takes 3 and 9 months in tuberculoid and LL, respectively to achieve optimum control. Prophylactic steroids are not helpful in preventing type 1 Lepra reaction. Cyclosporine has been tried in non-responders and those with contraindication to steroids.29 In cases with ENL, a shorter course may suffice, although recurrences are common on withdrawl of cyclosporin. Tapering over 2 months may be possible when reaction is controlled, but those who relapse may require a longer duration of therapy. The setting of chronic ENL necessitates the addition of clofazimine at higher doses. Thalidomide has also been proven effective in ENL, although neuropathy and teratogenicity are limiting factors.30 Management of Lucio phenomenon requires antibiotics and steroids with good wound care. Anti-tumor necrosis factor agents also have been beneficial in refractory ENL.31 Leprosy is a great mimicker (may mimic RA, seronegative SpA, lupus or systemic necrotizing vasculitis) as far as the rheumatologic manifestations are concerned. Even in areas of the world where leprosy is endemic, inflammatory arthritis and other rheumatological manifestations due to leprosy remain underdiagnosed. Thus, leprosy should be diligently searched in a case with unexplained articular manifestations, especially if the patient is hailing from endemic areas, as these may be the first and only presenting complaint. All authors had access to the data and played a role in writing this manuscript. None. None. The authors would like to thank Professor Ramnath Misra, Head, Department of Clinical Immunology, for his critical inputs and valuable guidance in preparing this manuscript.